University Of Pennsylvania

NSF Awards · FY 2025 · 2025-05

Prof. Abraham Nitzan of the University of Pennsylvania is supported by an award from the Chemical Theory, Models and Computational Methods program in the Division of Chemistry to investigate manifestations of molecular chirality in molecular transport phenomena. Molecular chirality, a property associated with the symmetry of molecular structures, is a long-studied subject with implications ranging from the origin of life to spectroscopy and chemical reactivity. Energy (in its electromagnetic, mechanical, and heat incarnations) and charge transport is another long-studied subject, currently back in focus as molecules become important components of nano-devices. The interplay between chirality and transport properties has been repeatedly demonstrated but many aspects of its manifestations are not well understood. Nitzan and coworkers aim to develop a fundamental understanding of such phenomena by developing the underlying theory that connects molecular symmetry to molecular dynamics, as well as numerical methods for the quantitative evaluation of such effects. Successful completion of their work will provide a valuable tool for predicting, applying and controlling chiral induced transport processes in molecular systems and other nanostructures. Nitzan and coworkers will start from the connection between structural chirality and the symmetry properties of nuclear and electronic motions and will look at consequences for energy and charge transport, diffusion, friction, localization, and interfacial behaviors of charge and energy carriers: (a) The connection between the chirality of the molecular equilibrium structure and its electronic and nuclear dynamics will be established and characterized. (b) Mathematical measures of chiral dynamics (e.g. the scalar product of linear and angular momenta that measure their “locking”) will be developed and applied. (c) Chirality-induced asymmetries (e.g. rectification) in charge and energy transport will be characterized and quantified. (d) Classical and quantum aspects of Brownian motion, diffusion, friction, mobility, (thermal and electrical) conduction, and localization (e.g. polaron formation) in chiral environments will be studied and characterized (e) interfacial phenomena at the interface between chiral and non-chiral environments will be studied. Finally, the suitability of different methods of characterizing and quantifying molecular chirality for the analysis of the interplay between chirality and dynamics will be studied. At the same time, numerical codes to impose a ‘controlled amount’ of chiral character in a molecular structure will be developed to provide a numerical laboratory for these studies. Importantly, the processes that will be studied are ubiquitous in chiral chemical systems, hence it is expected that the results of this research will be relevant to the behavior of all chiral chemical systems, reaching far beyond the scope of the present studies. This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.

NIH Research Projects · FY 2026 · 2025-05

PROJECT SUMMARY Keratinocyte carcinomas (KCs), which include squamous cell and basal cell carcinomas of the skin, are the most common type of cancer in the U.S. with over 5 million new cases annually. The immune system plays a pivotal role in KC development and progression via immunological surveillance. Immunocompromised solid organ transplant recipients face an exponentially increased risk of KC, with significantly higher risks of KC-related morbidity and, in some cases, mortality. The more aggressive tumor biology in the setting of immunosuppression of solid organ transplant recipients also serves as a model for other diseases where immunosuppression is the mainstay of therapy (e.g., rheumatologic diseases, immune-mediated gastrointestinal disease). Yet, due to limited data on the factors influencing this relationship, there remains no risk-individualized approach to KC screening, surveillance and management in transplant recipients. This critical unmet need represents a missed opportunity to reduce incident and recurrent KC and achieve superior skin cancer-related outcomes in this high- risk population. Although exposure to ultraviolet (UV) rays from sunlight and skin type have been extensively studied as the major cause of KC in the non-transplant setting, they are not included in existing skin cancer risk scores for solid organ transplant recipients. Key limitations of existing skin cancer risk prediction models for solid organ transplant recipients also include a lack of immunosuppression treatment variables. Together, these have led to a lack of evidence-based guidelines for KC surveillance and management, contributing to suboptimal KC- related outcomes in organ transplant recipients with preventable morbidity and possibly even mortality. Addressing these knowledge gaps would lead to more accurate KC risk stratification in the immunosuppressed population and for an individualized approach to treatment decision-making that considers the necessary balance of immunosuppression to prevent rejection with skin cancer treatment options. We will leverage a pre- existing data source of linked national transplant registry data and data from the Veterans Health Administration (VA), along with a prospective multi-center cohort study of a diverse population of kidney and liver transplant recipients to develop two clinically-useful sets of deliverables with the potential to change practice: (i) validated prediction models to standardize KC screening and surveillance in a high-risk population and (ii) a Markov simulation model to enhance immunosuppression-related decision-making for patients who experience post- transplant KC. To achieve these objectives, we will: a) derive and internally validate a model that includes immunosuppression treatment variables to predict incident and subsequent KC in a retrospective cohort of kidney and liver transplant recipients in the VA; b) externally validate and refine these models in a prospective diverse multi-center cohort of kidney and liver transplant recipients, capturing detailed data on UV exposure, skin type, and photosensitivity; and c) construct a Markov simulation model to guide immunosuppression-related management strategies for incident and subsequent KC.

NIH Research Projects · FY 2025 · 2025-05

Proposal Summary/Abstract Candidate: Dr. Leo Wang holds a BA, MS, MD, and PhD from the University of Pennsylvania, where he is currently completing dermatology residency and a postdoctoral fellowship. Since 2018, Dr. Wang has been working with Dr. George Cotsarelis, MD, with a primary focus on biomaterial-based approaches for addressing hair and skin disorders. Support from a K08 award will strategically position Dr. Wang to become an R01-funded investigator and a leader in the fields of biomaterials and dermatology. Environment: The mentor, Dr. Cotsarelis, is the Milton Bixler Hartzell Professor and Chair of Dermatology. He is internationally recognized for expertise in hair disorders, animal models of skin diseases, and therapeutic development. Dr. Cotsarelis boasts a remarkable track record as a mentor, including for previous K08 awardees. Dr. Cotsarelis will be joined by a mentoring committee comprising experts in relevant domains. Dr. Christopher Madl, PhD, Assistant Professor of Materials Science and Engineering, is a leading authority in hydrogel biomaterials, who will provide expertise in synthesis, characterization, and applications. Dr. David Margolis, MD, PhD, Gerald Lazarus Professor of Dermatology, is a world-renowned specialist in clinical trials, biostatistics, and biomaterials for clinical translation, who will advise animal studies. Dr. John Wherry, PhD, the Richard and Barbara Schiffrin Professor and Chair, Department of Systems Pharmacology & Translational Therapeutics, will provide mentorship in immunologic analysis of the alopecia areata model. The K08 proposal encompasses training in engineering, mass spectrometry imaging techniques, in vivo models, accompanied by coursework. The University of Pennsylvania offers an outstanding Dermatology faculty, fostering opportunities for collaboration, and boasts NIAMS P30-supported core facilities and other cores to support the proposed studies. Research: Alopecia areata (AA) is an autoimmune disease caused by a cytotoxic T cell-mediated inflammatory response in the hair bulb leading to nonscarring hair loss. Janus kinase (JAK) inhibitors have been approved clinically for use, but their utility is limited by the risk of systemic toxicity, necessitating innovative delivery methods. Injectable hydrogels offer a promising solution by enabling local and sustained drug delivery, concentrating the medication in the skin while minimizing systemic absorption. This research proposal aims to harness the nitrile group present in baricitinib, an FDA-approved oral JAK inhibitor, to form a dynamic covalent thioimidate bond with a thiolated hydrogel to treat alopecia areata. The proposal will test the hypothesis that thioimidates can sustain drug delivery for 12 weeks after injection, ensuring high local bioavailability in human skin xenografts, low systemic absorption, and effectiveness in preventing and treating alopecia areata. This technology has significant translational potential and can be readily utilized by dermatologists and other healthcare providers for various skin and systemic disorders that converge on JAK signaling.

NIH Research Projects · FY 2026 · 2025-05

PROJECT SUMMARY/ABSTRACT Pain represents our ability to detect noxious stimuli in the environment and engage in behaviors to reduce harm. This potentially life-saving function of pain can be disturbed by injury or illness leading to chronic pain that exceeds its biological utility. Chronic pain inflicts long-term suffering and is a common clinical problem that chal- lenges our health services and impairs the lives of millions in the United States. Although prescribed opioids remain an important option for the management of pain symptoms, their use presents substantial risk for abuse and overdose. Mu opioid receptors (MOR) in the brain are a crucial substrate for the analgesic action of exoge- nous opioid drugs, however, our understanding of the endogenous opioid system on which these drugs act remains incomplete and difficult to access. The discovery that the endogenous opioid system is recruited by placebo analgesia – expectation that a treatment or context is pain-relieving even when it is not – stands to vastly improve knowledge of pain-relevant opioid signaling mechanisms when applied to preclinical model systems. My previous postdoctoral work demonstrates that placebo analgesia can be achieved in an operant conditioning paradigm in rodents, which results in the suppression of nociceptive activity within MOR neurons in the ven- trolateral periaqueductal gray (vlPAG), indicating recruitment of opioid peptide release and antinociceptive sig- naling. This career development proposal aims to reveal, at the cellular and neural circuit levels, how the endog- enous opioid system is activated by pain and placebo analgesic behavioral states in two key midbrain structures, the vlPAG and ventral tegmental area (VTA) that have been implicated in pain processes and opioid drug func- tion. Training in advanced imaging technologies and rigorous opioid pharmacology, combined with mentoring/ad- visory team meetings and professional/career development activities will prepare me to completely attain and succeed in an independent faculty position. In Aim 1 (K99 phase), I will use two in vivo approaches, one-photon in vivo miniature endoscope (miniscope) calcium imaging for cellular resolution recordings of neural activity and optogenetic neurocircuit manipulation, to delineate the signaling dynamics and function of the enkephalinergic neural populations in the vlPAG in pain and placebo analgesia. Importantly, the vlPAG does not modulate pain in isolation, but sends pain-relevant signals to affective-motivational regions like the VTA. Therefore, in Aim 2 (R00 phase), I will investigate the functional relationship between the vlPAG MOR-expressing neural population and the VTA through optogenetics and miniscope recordings of VTA neural activity, to understand the role and dynamics of these connected circuits across pain states. The results of these studies will produce fundamental knowledge about the brain’s endogenous opioid system that can be applied to the development of future chronic pain therapies that are safe and efficacious. Completion of this mentored career development plan will advance my scientific skills and professional growth and lay the foundation for my independent research career.

NIH Research Projects · FY 2026 · 2025-05

ABSTRACT Patients with stroke affecting left hemisphere brain regions commonly develop aphasia - major language deficits highly limiting their quality of life. Key to developing novel, targeted treatments for these deficits is better understanding how the brain manages the many cognitive processing demands of language, including semantic demands, which relates to understanding word meanings. These include the ability to retrieve a word with the right meaning from memory or the ability to select the right word from those of similar meaning. While neuroimaging and stroke lesion studies have revealed which isolated brain regions underlie language ability, little is known about how complex interactions between these brain network regions contribute to semantic cognition for language production. The proposed research uses network control theory (NCT), an emerging branch of systems engineering computation applied to neuroimaging - to model cortical brain regions and their white matter tract connections as a network of nodes and edges, respectively. NCT quantifies the properties of anatomical brain network structure that can constrain and control cognitive dynamics that drive complex human behaviors like language production. In Aim 1, I will study how brain network controllability influences healthy language production, and how an individual’s network control characteristics predict language behavior changes after manipulation by focal neuromodulation. Specifically, we used repetitive transcranial magnetic stimulation (rTMS) to experimentally modulate brain connectivity in healthy adults, to discover which language network topologies control word selection and retrieval during open-ended language generation tasks. In Aim 2, I apply these NCT methods in people with chronic post-stroke aphasia, to determine brain network predictors of optimal semantic responses to rTMS, using data from a completed clinical trial of rTMS for language recovery. The proposed work will be carried out in the world class training environment at the University of Pennsylvania’s Laboratory for Cognition and Neural Stimulation. These resources combined with an expert sponsorship team, including experts in studies of aphasia, network control theory and neuromodulation, will fully support completion of this proposal and facilitate my professional development as a future physician-scientist leading rigorous and reproducible clinically relevant research. Ultimately, the results of my proposed work will be key to improving the efficacy of noninvasive neuromodulation by personalizing therapies for aphasia rehabilitation - and will provide an advanced understanding of the neural basis of language more broadly.

NIH Research Projects · FY 2026 · 2025-05

ABSTRACT Prostate cancer (PrCa) is the second leading cause of cancer related deaths in men. Current treatment methods are no longer effective once cancer cells become resistant, allowing cells to progress to metastasis. Two markers for worse patient outcomes in PrCa are the Integrated Stress Response (ISR) and the RNA modification N6- methyladenosine (m6A). The ISR is an adaptive pathway that can be triggered by many stressors within cancer cells and the tumor microenvironment. This pathway can be activated by cancer treatments and its activation can lead to drug resistance and metastasis. The ISR serves as a protective mechanism that limits extraneous protein synthesis and promotes the translation of select stress response and pro-survival transcripts. The mechanism by which this adaptive translation occurs is relatively unknown, but one method by which mRNAs may be selected for increased translation is through m6A. m6A methylation has been observed to alter the splicing, degradation, localization, and translation of mRNAs. In PrCa cell lines, inhibiting m6A deposition leads to growth deficiencies. Recent papers have tied the m6A methylation of specific transcripts to their translation status during the ISR. The goal of this proposal is to determine if m6A modifications on select transcripts are required for their translation during the ISR, and whether blocking m6A will sensitize PrCa cells to targeted therapies. Here, two aims are proposed to determine the role of m6A modifications in marking transcripts for translation during the ISR and to identify how the m6A machinery can drive PrCa. In Aim 1, m6A sequencing will be carried out from polysome fractions with and without inhibition of the ISR to correlate the m6A methylation state of a transcript during the ISR to its translation status. The top targets identified by the m6A sequencing will be validated using a knockout of m6A writer METTL3 and qPCR of mRNAs derived from polysome profiles. Potential impacts on mRNA degradation rates will also be determined by inhibiting transcription and analyzing transcripts with and without the presence of m6A. Additionally, isolation of proteins bound to specific regions of top target mRNAs followed by mass spectrometry with and without m6A will be employed to determine which proteins bind m6A transcripts during the ISR. In Aim 2, four m6A regulatory proteins—VIRMA, eIF3h, YTHDF3, and hnRNPA2B1—found to be significantly upregulated in PrCa datasets and disease progression, will be evaluated. Correlations between their expression profile and oncogenic potential in metastatic PrCa cells, alongside treatment with current PrCa therapies, will be analyzed in cells with stable knockdown and overexpression of these genes. Lastly, the mechanism by which the proteins function will be established by identifying the mRNAs they bind to and the possible downstream consequences of their binding on mRNA translation during the ISR. Pursuing these aims will enable a detailed representation of the role m6A plays in driving select mRNA translation during the ISR. Gaining an increased understanding of the drivers of selective translation may provide novel insights into targeting strategies for treating advanced PrCa.

NIH Research Projects · FY 2026 · 2025-04

PROJECT SUMMARY There are over half a million head and neck cancer (HNC) survivors in the United States. More than two-thirds experience chronic soft tissue swelling (lymphedema) in the head and neck region. Lymphedema not only has adverse cosmetic and psychosocial consequences but can cause a substantial impact on critical functions (e.g., swallowing) and result in decreased range of motion in the jaw, neck, and shoulders. The standard of care for acute or early-stage lymphedema is complete decongestive therapy (CDT). After completion of CDT, 30%-40% of survivors still have clinically evident residual lymphedema that can progress to chronic lymphedema. Currently, there are no proven effective therapies for the treatment of chronic lymphedema. Innovative solutions are needed for the management of this potentially devastating late effect. Photobiomodulation therapy (PBMT) was approved by the FDA in 2006 as a treatment for breast cancer- related arm lymphedema. Evidence supports that PBMT is a potentially effective treatment for arm lymphedema. No data is available on the effects of PBMT on head and neck lymphedema. We conducted two pilot clinical trials. Results demonstrated the feasibility, acceptability, and preliminary efficacy of PBMT for the treatment of chronic lymphedema in HNC survivors. No adverse events were identified during the trials. Given the promising findings from our pilot trials, we propose to conduct a 5-year, multi-site, triple-blind, placebo- controlled, three-arm parallel, phase II randomized clinical trial (RCT) to further investigate and confirm the positive effects of PBMT on chronic lymphedema in HNC survivors. The goals of the proposed research are to evaluate the effects of PBMT on the severity of external and internal lymphedema; to assess the impact of PBMT on symptom burden, functional impairments, and quality of life; and to collect and biobank peripheral blood samples for future analysis if we observe an improvement in chronic lymphedema and associated symptom burden or functionality with PBMT. In our previous pilot trials, participants received 12 PBMT sessions with follow-up through 8-week post-PBMT. Data demonstrated a plateau in the external lymphedema severity reduction and symptom improvement after cessation of PBMT, suggesting that increased duration of therapy may enhance outcomes. To answer this question, we will evaluate if extending treatment will generate improved outcomes. Thus, patients will be randomized (1:1:1) to ARM A – PBMT12 (12 PBMT sessions plus 6 sham therapy sessions), ARM B – PBMT18 (18 PBMT sessions), or ARM C – placebo (18 sham therapy sessions). We will enroll 150 HNC survivors (50 per arm) from two participating sites. Our primary endpoint is improvement in severity of external lymphedema. Study assessments will be conducted pre-intervention, after 12 sessions, after 18 sessions (end-of-intervention), and 3-, 6-, 9-, and 12-month post-intervention. Successful completion of this trial will provide critical data for designing a subsequent phase III RCT to provide level 1 evidence supporting the effectiveness of PBMT in HNC survivors with chronic lymphedema.

NIH Research Projects · FY 2025 · 2025-04

Project Summary/Abstract Chronic pain is a major health burden and constitutes the greatest cause of years lived with disability. Current treatment options for pain are largely non-specific and often have clinically significant adverse effects, poor efficacy in many patients, and addictive potential. A greater understanding of the molecular mechanisms underlying chronic pain is critical to enable identification of novel or repurposed analgesics that are safe and effective. Chronic pain has a substantial genetic component and efforts to inform drug development using genetics are more than twice as likely to yield medication approvals. However, the genetic mechanisms associated with chronic pain are not well understood and studies are limited by a near-exclusive focus on individuals of European ancestry. The principal investigator, Dr. Sylvanus Toikumo, recently conducted the largest multi-ancestry genome-wide association study (GWAS) of pain intensity (N = 598,339) to date, which identified 125 independent genetic loci. This proposal capitalizes on findings from that GWAS and enables Dr. Toikumo to acquire methods and skills to elucidate the genetic risk for chronic pain, and potentially help to identify new analgesic medications. Training opportunities linked to each of the specific aims will enhance Dr. Toikumo's development as an independent investigator. Aim 1 will characterize the genetic architecture underlying chronic pain liability and addiction, which he will achieve by using a) genomic structural equation modeling to derive a common genetic liability factor for pain from the multi-ancestry GWAS of pain intensity and other pain related GWASs b) multivariate GWAS meta-analysis of the chronic pain factor and c) analyses of the unique and shared genetic architectures of pain and addiction risk. Aim 2 will estimate the causal effect of brain and plasma proteins and curate drug targets for causal proteins in silico using drug databases. Aim 3 will use gene mapping to integrate existing GWAS data with functional genomic annotations in ATAC-seq and high-resolution genome- wide promoter-focused Capture C/Hi-C data from human iPSC-derived cortical neurons to identify effector genes. Aim 4 developing mechanistic to identify novel treatments. Specifically, the K99/R00 Pathway to Independence award will provide Dr. Toikumo with training in pain phenotyping, statistical genetics, computational genomics, and gene mapping techniques. These training objectives will be supported by Drs. Kranzler, Kember, Grant, Gandal, Diatchenko, Farrar, Cheatle, and Corder and the technical and intellectual resources of the University of Pennsylvania, the Children's Hospital of Philadelphia, and a yet-to-be determined research institution. Together, the proposed scientific aims and training objectives will form the foundation for an independent research program aimed at identifying risk mechanisms and novel medications for chronic pain. will rioritize risk genes and pathways underlying genomic regulation using i so-QTL data from human fetal brain tissues. Together, these aims will elucidate t he genetic architecture and underpinnings of chronic pain and inform translational models p

NIH Research Projects · FY 2026 · 2025-04

PROJECT SUMMARY Substance use in the United States is evolving. Some of these changes are due to the ongoing opioid crisis while other changes are results of federal and state policy changes. In particular, marijuana access continues to be further legalized throughout the United States, changing behaviors related to alcohol and opioid use. While we have developed an adequate research base on the implications of medical and recreational marijuana laws, researchers have generally ignored the recent growth in cannabidiol (CBD) access, including the legalization of medical CBD in 18 states since 2014 that do not otherwise permit medical or recreational marijuana. CBD access continues to expand in the US with rates of use higher than marijuana, but we have little evidence of the public health impacts of this expansion. This project will study these recent laws and discuss how they fit into the broader marijuana policy landscape in the United States. In addition, we will study how medical CBD adoption impacts CBD use, opioid use, alcohol use, and opioid- and alcohol-related poisonings. Marijuana policies has been shown to impact alcohol use; additionally, they have been found to deter opioid misuse and reduce opioid-related deaths. We hypothesize that CBD policies may have similar effects. In particular, this project is interested in the possible role for alternative pain management availability to impact opioid use and curb overdose death rates. These relationships are important to quantify as CBD use continues to increase. We will also collect information on CBD dispensary locations, study the demographics of CBD dispensary access, and examine more granular geographic effects of CBD access. We will make information on CBD policies and CBD dispensary locations public to promote research in this area. More recent research on the impacts of medical and recreational marijuana laws often contradicts earlier findings. One possible reason for these inconsistent results over time is because the literature ignores recent medical CBD policies. If CBD policies have similar effects as marijuana policies, then including CBD-adopting states as “comparisons” in a difference-in- differences framework will bias the estimates in the opposite direction. This project will conclude by re-analyzing recent findings in the medical and recreational marijuana literature while accounting for CBD adoption. This analysis has the potential to reconcile these literatures by accounting for a policy which has been generally ignored.

NIH Research Projects · FY 2026 · 2025-04

Summary: Globoid cell leukodystrophy (GLD, Krabbe) is a fatal pediatric neurodegenerative disease caused by mutation of the lysosomal enzyme galactosylceramidase (GALC). The greatest hurdle to curing GLD is treatment of central nervous system (CNS) pathology. Allogeneic hematopoietic stem cell transplantation (allo-HSCT) is standard of care, thought to mitigate disease progression by replacing dysfunctional macrophages with competent donor surrogates that provide functional GALC to the brain via a mechanism called cross-correction. However, the brain engraftment of HSC-derived macrophages is inefficient, reducing therapeutic benefit. In addition, allo- HSCT must be administered pre-symptomatically in early infancy, most patients will not have a related HLA- matched donor, and transplants with alternative donors or HLA-mismatched grafts have significant toxicities such as graft-versus-host disease, infections, and death. Autologous HSCs can be genetically modified and transplanted either as part of an HSCT or via direct intracranial delivery. For both approaches, though, low microglia replacement remains the limiting factor to maximum therapeutic benefit. Our central hypothesis is that enhanced engraftment of autologous, genetically modified, GALC-sufficient macrophages throughout the CNS after HSC injection, will safely and effectively address GLD pathology and disease progression. To test this, we combine the expertise of two labs: the Bennett Lab, experts in microglial biology and engraftment; and the Kiem Lab, experts in HSC gene therapy and transplantation in the preclinical nonhuman primate (NHP) large animal model. This MPI approach will foster a unique environment in which we can both investigate the therapeutic potential of this approach in an appropriate mouse model of GLD, as well as demonstrate the translational potential of microglia replacement for the first time in the preclinical NHP model. In Aim 1 we will validate an approach to efficiently engineer murine HSCs with a CSF1R inhibitor resistant (IR) variant for donor cell drug selection, simultaneously with conditional GALC overexpression. We will further demonstrate the efficient engraftment of these cells into the Krabbe disease twitcher mouse model, and study its effects on brain cells, tissue, symptoms, and survival. In Aim 2 the Kiem Lab will work concurrently to establish the preclinical viability of this approach by demonstrating the species cross-reactivity of our editing approach to the nonhuman primate. We will then show the safe and efficient replacement of microglia by introducing IR- HSCs to the CNS of NHPs that have been conditioned with CSF1R inhibition. Completion of these aims will act synergistically to both validate this therapeutic approach in a disease model while also demonstrating translatability and safety in the preclinical NHP model, allowing rapid progression of this modality into the clinic.

NIH Research Projects · FY 2026 · 2025-04

Project Summary/Abstract Candidate: Ashish Thakrar, MD, MS, is an addiction medicine specialist, internal medicine physician, and clinician-scientist committed to improving care for individuals with substance use disorders (SUDs). His career goal is to become an independent investigator developing and adapting safe, effective, and patient-centered pharmacotherapy for SUDs in the era of synthetic drugs. Career Development Plan: To achieve this career goal, Dr. Thakrar will pursue coursework, seminars, externships, and individualized instruction in four specific areas: (1) the behavioral pharmacology of addiction; (2) responsible design and conduct of clinical trials for SUDs; (3) recruitment, assessment, and retention of hospitalized patients for prospective research; and (4) qualitative and survey methods to assess patient experiences in SUD treatment. These training goals are closely aligned with the research aims in this proposal. Research Context: Each year, there are 500,000 medical or surgical hospitalizations for patients with opioid use disorder (OUD), yet outcomes for these hospitalizations are poor: untreated withdrawal is common, patient satisfaction is low, 11-17% of patients leave before medically advised, and less than 10% are discharged on medications for OUD. While methadone at adequate doses treats opioid withdrawal, prevents before medically advised discharges, and reduces mortality, there is little evidence on how to dose methadone to start treatment for OUD with fentanyl use (“fentanyl OUD”). The traditional outpatient dosing approach to methadone initiation does not consistently treat fentanyl withdrawal and takes weeks of titration to reach therapeutic doses. Given methadone's long half-life, a “loading dose” approach could be a safe and effective alternative in the hospital. Specific Aims: The goal of this proposal is to rigorously develop and pilot test a methadone loading dose approach to starting treatment for fentanyl OUD in the hospital. Aim 1: To conduct a dose-finding study to identify the maximum tolerated methadone loading dose appropriate for future study among persons with fentanyl OUD. Aim 2: To conduct a randomized pilot trial of methadone loading dose initiation among hospitalized patients with fentanyl OUD. Aim 2A is to assess trial feasibility, clinical outcomes, and safety; Aim 2B is to assess patient acceptability and other patient-centered outcomes with interviews and a survey. Mentorship Team: Dr. Thakrar has assembled a team of mentors, advisors, and consultants with extensive experience supervising research and with complementary expertise in behavioral pharmacology, clinical trials of OUD pharmacotherapy, hospital-based prospective research, and patient-reported outcomes research. Environment: The University of Pennsylvania and Penn Medicine offer an ideal environment to pursue this training and research. Dr. Thakrar will succeed because of the support of an experienced and dedicated mentorship team, outstanding research infrastructure, and extensive resources for professional development.

NIH Research Projects · FY 2025 · 2025-04

Obesity is one of the most pressing public health challenges of the 21st century. Weight gain occurs in the setting of nutrient excess, which stimulates adipose tissue expansion via both healthy hyperplastic and pathologic hypertrophic processes. The metabolic consequences of obesity, including diabetes and fatty liver disease, are believed to stem from a relative deficiency in hyperplastic expansion of adipocyte progenitor cells specifically within the subcutaneous adipose depot. Subcutaneous adipose is generally considered metabolically beneficial in humans, however our understanding of the developmental origin, and cellular composition of this depot remain relatively limited. Recent studies have revealed the presence of distinct anatomic layers including dermal adipocytes. Dermal adipose is more metabolically dynamic than deeper layers of subcutaneous or visceral adipose, demonstrating massive expansion in obesity and involution with caloric restriction. Given its widespread distribution in humans, dermal adipose is thought to comprise a significant portion of the subcutaneous depot and thus play a significant role in whole body metabolism. Dermal adipose represents a critically important metabolic organ, yet its distinct developmental origins remain unknown. To address this knowledge gap, we have performed preliminary single cell studies during murine embryonic dermal development, which revealed the presence of a novel population of mesenchymal cells marked by Bcl11b expression. We discovered that dermal adipogenesis is dependent upon BCL11b transcriptional signaling and that this effect is highly specific to the dermal adipose. Our central hypothesis is that embryonic dWAT formation is dependent upon niche-forming Bcl11b+ cells, which utilize the transcription factor BCL11b to modulate the local Wnt signaling environment and enable adipogenic differentiation in the dermal compartment. The Aims of this grant are to: (1) Determine the mechanism by which BCL11b promotes adipogenesis within the dermal niche (2) Characterize murine and human dermal adipose progenitor cell dynamics in obesity. To attain these objectives, we will utilize novel mouse models, advanced transcriptomic techniques, metabolic phenotyping and analysis of human subcutaneous adipose tissue samples to investigate the mechanisms driving dermal adipose development. This work will address long-standing questions in the field regarding the developmental regulation of dermal adipose tissue, define the molecular mechanisms underlying its establishment, and generate insight into the relationship between mouse and human dermal adipose, thus highlighting the importance of this understudied adipose depot to human metabolic disease. MODIFIED SPECIFIC AIMS: Obesity is one of the most profound public health challenges of the 21st century. The metabolic consequences of obesity are hypothesized to stem from a relative deficiency in hyperplastic adipose expansion specifically within the subcutaneous depot, leading to compensatory visceral fat hypertrophy, lipid spillover into the liver and muscle, and subsequent insulin resistance. Adipose metabolic activity is strongly influenced by its anatomic location, which is established during embryogenesis. Thus, the distinct developmental environment in which adipose originates is a principle determinate of its expansion capacity, however our understanding of subcutaneous adipose organogenesis is incomplete. This proposal aims to define the molecular pathways directing the development of dermal adipose tissue (dWAT), and relate these discoveries to human subcutaneous adipose pathophysiology. Subcutaneous adipose serves as a central hub for metabolic homeostasis through its capacity for hyperplastic expansion, however this generalization does not capture the complex anatomy of this organ, which can be further divided into discrete anatomic layers including dermal/superficial vs deep subcutaneous. Dermal adipose is more metabolically dynamic compared with deeper layers, capable of massive expansion in obesity and involution with caloric restriction. Furthermore, due to its distinct anatomic location, dWAT engages in many unique physiological processes, including: thermoregulation, wound repair, innate immune defense, support of hair follicle growth, and skin fibrosis/aging. Thus, dWAT represents a critically important yet poorly understood metabolic organ, the developmental regulation of which is unknown. Preliminary single cell studies from my lab identified a novel population of embryonic dermal mesenchymal cells marked by Bcl11b expression. We discovered that dermal adipogenesis is contingent upon Bcl11b regulation of Wnt signaling within the dermal microenvironmental niche, and that this influence is highly specific to the dWAT. Based upon these preliminary data, our central hypothesis is that embryonic dWAT formation is regulated by niche-forming Bcl11b+ cells, which utilize the transcription factor BCL11b to modulate the local Wnt signaling environment and enable adipogenic differentiation within the dermal compartment. Our research team has an established track record of translating single cell discoveries into rigorous and high impact publications. As a physician scientist and Director of the UPenn Human Metabolic Tissue Bank, I am well-positioned to expand these findings into relevant human pathophysiology. In the following specific aims, we will utilize novel mouse models, human adipose tissues, advanced transcriptomics, and metabolic phenotyping to investigate the mechanisms driving dWAT development. Aim 1: Determine the mechanism by which BCL11b promotes adipogenesis within the dermal niche. Dermal adipocytes arise within the Wnt-rich microenvironment of the reticular dermis, however the cell types and mechanisms that facilitate differentiation within this relatively anti-adipogenic niche are unknown. We discovered a novel population of Bcl11b-expressing mesenchymal cells that are essential for embryonic dWAT development. The downstream mechanism by which BCL11b promotes dermal adipogenesis will be determined through in vitro interrogation of BCL11b-regulated genes including: Sost, Adamts18, Nes and Sod3. Aim 2: Characterize human dermal adipose progenitor cell dynamics in obesity and weight loss. The distinct developmental ancestry of adipose depots imprints clinically relevant physiological properties, however the regulation of human dWAT development has not been rigorously studied. To determine the functional changes occurring in dermal adipose with obesity and/or weight loss we will utilize our pipeline to human adipose from lean, obese and weight loss patients to quantify relative adipogenic potential. We will investigate the mechanistic contribution of BCL11b target genes SOST, ADAMTS18, NES and SOD3 in regulating adipogenesis within human superficial and deep subcutaneous layers

NIH Research Projects · FY 2026 · 2025-04

Project Summary Acute Myeloid Leukemia (AML) represents a highly aggressive hematologic malignancy characterized by a multitude of genetic alterations and an exceptionally poor prognosis. Genomic analyses of AML patients have unveiled recurrent mutations in the cohesin complex, with a prevalence ranging from 5.9% to 13.0%. The clinical success of proteasome inhibitors such as bortezomib, along with E3 ubiquitin ligase modulators, in the treatment of hematologic disorders underscores the significance of the Ubiquitin pathway as a promising target for cancer therapeutics. Consequently, understanding the functional roles of novel E3 ligases and their implications in normal and pathological hematopoiesis holds the potential for innovative therapeutic interventions. Our investigations have revealed a pivotal post-translational mechanism regulating genome architecture in AML through ubiquitin-dependent degradation of cohesin complex components. Specifically, we have identified DCAF15 as the E3 ligase responsible for orchestrating the degradation of cohesin- associated accessory proteins PDS5A and CDCA5. These degradation events play a critical role in modulating cohesin acetylation on chromatin, 3D genome organization, and DNA replication. Consequently, our preliminary data elucidates the cell-autonomous role of DCAF15 as a master regulator of cell proliferation by controlling cohesin dynamics. The primary objectives of this proposal are to establish a conceptual framework for understanding the significance of cohesin complex degradation in the context of AML in vivo and to evaluate potential therapeutic interventions. Specifically, we aim to (a) decipher the biological function of DCAF15 in myeloid development and leukemia in vivo, (b) investigate the role of cohesin acetylation in AML pathogenesis, and (c) develop small molecule degraders targeting DCAF15. The outcomes of this grant proposal promise to uncover intrinsic AML mechanisms and explore novel therapeutic avenues by harnessing the Ubiquitin pathway.

NIH Research Projects · FY 2026 · 2025-04

ABSTRACT Distant metastasis is the primary cause of cancer-related death and is generally preceded by metastasis to the lymph node (LN). Since lymph nodes serve as staging grounds for anti-tumor immunity, their high susceptibility to metastatic colonization has been considered a paradox. To date, it has been thought that for tumor cells to survive in the draining lymph node, it must first be preconditioned by extrinsic, tumor-derived, factors towards a state of immune-suppression. Whether intrinsic qualities of the lymph node may also impede its immune response to metastasizing tumor cells is not known. My thesis work to date has identified an intrinsic basis for early lymph node metastasis, independent of preconditioning, linked to the lymph node’s large regulatory T cell (Treg) population. Using murine cancer cell lines that express an antigen, we find that tumor-specific CD8 T cells exhibit markedly lower cytotoxicity in lymph nodes than in circulating blood. T cell depletion greatly enhanced hematogenous metastasis to the lungs but not lymphatic metastasis to regional lymph nodes. Direct injection of parental tumor cells into the lymph node and blood formed tumors at a similar rate in the lymph node and lungs, respectively, but forced expression of antigen conferred a marked growth advantage following intra-lymph node injection. This advantage was dependent upon regulatory T cells, which locally suppressed the cytotoxicity of tumor-specific CD8 T cells in the lymph node to permit tumor growth. Based on my preliminary findings, depleting Tregs is an attractive therapeutic strategy for treating LN metastasis. However, systemic and continuous depletion of Tregs leads to autoimmunity and eventual death. In Aim 1 I will Investigate transient, single LN Treg depletion as a therapeutic strategy to treat LN metastasis. As LNs promote anti-tumor immune responses by facilitating priming events, an accumulation of tumor cells in the LN could represent an opportunity for increased antigen uptake and priming. Consistently, my preliminary data suggests that metastatic LNs have many more antigen-carrying DCs than non-metastatic draining LNs. However, the antigen-carrying DCs in tumor-bearing LNs are significantly suppressed, expressing very low levels of co-stimulatory molecules. As Tregs also accumulate during LN metastasis, I hypothesize that Tregs prevent effective anti-tumor priming by suppressing co-stimulatory molecule expression on tumor-antigen carrying cDC1s. In Aim 2 I will determine whether Tregs suppress anti-tumor CD8 T cell priming in the lymph node by suppressing co-stimulatory molecule expression on tumor antigen-carrying DCs or by preventing antigen stimulation. I hypothesize that transient depletion of regulatory T cells in a single metastatic LN will restore anti-tumor CD8, priming and cytotoxicity and effectively eradicate LN metastasis.

NIH Research Projects · FY 2026 · 2025-04

Project Summary The oocyte-to-embryo transition encompasses several key developmental events that coincide with changes to the microtubule (MT) cytoskeleton. Two such events are oocyte maturation, when the prophase-arrested oocyte completes the first meiosis and arrests in metaphase II, and egg activation, when the egg initiates processes that are crucial for early embryogenesis. We have identified a zebrafish maternal-effect mutant that reveals maternal-specific control of MT organization in the oocyte and egg. Offspring of mutant females fail to complete the first cell division and contain numerous ectopic aster-like MTs throughout the cytoplasm. Chromosomes of unactivated eggs are scattered, suggesting MT dysregulation interferes with meiotic chromosome movements. The mutated gene kif2c encodes a kinesin-13 family MT depolymerase also known as mitotic centromere- associated kinesin (MCAK). Previous in vitro and in vivo model systems have shown chromosome alignment defects and ectopic MT assembly upon loss of kinesin-13. Our model is unique in that the asters seen in mutant embryos arise during oocyte maturation, coinciding with the recently discovered phenomenon of cortical maturation asters (CMAs) in zebrafish. This suggests that Kif2c regulates CMA formation during maturation. Our mutant indicates there is a second period of Kif2c function at egg activation. In wild-type eggs, cortical MTs depolymerize at egg activation, but in mutant eggs, MTs rapidly polymerize at egg activation. This suggests that Kif2c drives MT depolymerization at egg activation. As eggs are translationally silent, the same pool of Kif2c protein functions at oocyte maturation and egg activation. Thus, I hypothesize that Kif2c is precisely regulated to control CMAs during oocyte maturation before depolymerizing MTs at egg activation. In Aim 1, I will determine the nature of Kif2c MT regulation during oocyte maturation by live imaging and identifying at which MT end Kif2c functions. In Aim 2, I will investigate the regulation of Kif2c activity throughout oocyte maturation and egg activation by linking periods of Kif2c function with Kif2c phosphorylation status. In total, these experiments will identify the dynamic function and regulation of a maternal factor that modulates the MT cytoskeleton to promote chromosome integrity and developmental competence. As proper MT organization is required to protect against aneuploidy and MTOC number is often increased in cancer cells, understanding the nature of maternal MT regulation has implications in several biological processes. The institutional environment of this proposed fellowship will support the applicant in the pursuit of successful research and professional development. The applicant’s sponsor has an excellent track record in mentorship, and the applicant’s thesis committee will ensure the studies proposed here are rigorous. The proposed studies will provide insight into maternal MT regulation and are highly significant to female fertility, embryo competence, and reproductive health.

NIH Research Projects · FY 2026 · 2025-04

PROJECT SUMMARY Cohesinopathies are multisystemic developmental disorders characterized by limb abnormalities, intellectual disability, and heart defects. They are caused by mutations in the structural or regulatory components of the cohesin complex. Cohesin is essential for interphase genome organization by forming chromatin conformations that position distal genomic regions into spatial proximity. Cohesin-mediated structures are implicated in gene regulation, DNA repair, and somatic recombination. Indeed, cells from individuals with Cornelia de Lange Syndrome (CdLS), the most well-characterized cohesinopathy, exhibit transcriptional dysregulation, suggesting that impaired interphase cohesin function may be responsible for patient phenotypes. The majority of CdLS patients carry a loss-of-function mutation in the cohesin activator NIPBL. Therefore, balancing cohesin activity on chromatin by inhibiting a negative cohesin regulator may provide therapeutic benefits for CdLS patients. However, the development of targeted therapies for CdLS has been hindered by the lack of characterized cohesin regulators during interphase. To address this, our lab performed a high-throughput imaging screen of the human druggable genome, which identified Glycogen synthase kinase-3 alpha (GSK3A) as a negative regulator of cohesin. My preliminary work has identified three phosphorylated residues on the cohesin regulator PDS5A that depend on GSK3 activity, albeit how GSK3A regulates cohesin is still unclear. The goal of this proposal is to elucidate the mechanism by which GSK3A negatively regulates cohesin and the extent to which GSK3A inhibition can rescue expression of cohesin-sensitive genes. In Aim 1, I will determine the role of the GSK3-dependent phosphorylated residues in PDS5A on cohesin regulation. To this end, I will create transgenic cell lines harboring wild-type, phosphomimetic, or phosphodefective PDS5A mutants at the GSK3-dependent sites. Using these cell lines, I will assay how preventing or constitutively mimicking PDS5A phosphorylation affects PDS5A loading onto chromatin and interactions with cohesin subunits. Furthermore, I will determine how the phosphomutants affect cohesin localization and chromatin folding. In Aim 2, I will identify the role of GSK3A in transcriptional regulation of cohesin-sensitive genes. I will first perform PRO-seq to measure changes in nascent expression of cohesin- sensitive genes upon GSK3A inhibition. Then, I will determine the degree to which GSK3A inhibition is able to rescue expression of genes when NIPBL is knocked down. As a functional readout of transcriptional rescue by GSK3A inhibition, I will assess whether GSK3A inhibition is able to restore cell cycle progression, which is impaired in NIPBL-deficient cells. Completion of these aims will provide mechanistic insights into regulation of cohesin by GSK3A and establish the foundations for studying GSK3A or other negative cohesin regulators as therapeutic targets for CdLS.

NSF Awards · FY 2025 · 2025-04

Stroke and spinal cord injuries can result in paralysis, which affects both movement and sense of touch. Treatments that are designed to restore movement, but do not help restore a sense of touch, have limited benefits to patients. A treatment to restore the sense of touch will rely on a sensor that can measure the force skin exerts on an object when the object is touched. Currently available wearable sensors are bulky, and they interfere with the way skin interacts with touched objects. To address this technology gap, this project will develop a minimally invasive, wireless device that can be placed under the skin and can determine forces caused by touching an object. The device will do this by using light to measure changes in blood volume. The implantable sensor will send signals that bypass damaged nerves and communicate with the brain. Such a device could significantly improve the quality of life for people who have suffered stroke or spinal cord injury. In addition, the project will help train a future workforce by involving a team comprising high school, undergraduate, and graduate students to participate in sensor design and fabrication. The sense of touch is critical to dexterous use of the hands and thus an essential component to efforts to restore hand function after paralysis. The latest advance in functional restoration of a patient’s own paralyzed hand is reanimation through brain-controlled functional electrical stimulation (BC-FES). However, to date, this approach has not included somatosensory feedback. BC-FES places additional demands on tactile sensor design not incurred with brain-controlled robotic limbs. In this project, minimally invasive implantable tactile sensors suitable for long-term use in a patient’s own home will be developed. The proposed implantable sensors utilize an optical sensing mechanism, photoplethysmography (PPG), to indirectly infer tactile forces acting on the skin from blood volume changes in the compressed skin capillaries. The strategy has previously been validated, but only with bulky wearable devices. This project will develop and test a fully wireless, battery free, and hermetically sealed PPG sensor for subcutaneous deployment as an artificial mechanoreceptor. Fundamental engineering knowledge will be gained in the refinement of the three main functional components of the system: (1) an ultralow-power custom integrated circuit for PPG, (2) support for wireless radiofrequency (RF) power and data links, and (3) an optically and RF transparent, hermetic, fused silica package for long-term viability under the skin. Wireless functionality and hermeticity of prototype sensor systems will be rigorously tested in preclinical models in vivo. Beyond the intended neuroprosthetic use case, implantable PPG sensors could have tremendous impact in other applications, given that the PPG signal contains information on respiratory, vascular, cardiac, and autonomic nervous system functions. Technology development here could directly translate to a minimally invasive device for continuous physiological monitoring relevant to many chronic conditions. This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.

NIH Research Projects · FY 2026 · 2025-04

SUMMARY Significant progress has been made in defining the events involved in early cardiac development. Much less is known about the developmental maturation process that begins in late fetal stages and proceeds into the postnatal period, resulting in the terminally differentiated adult heart. Deciphering the regulatory mechanisms involved in cardiac maturation has important translational relevance for understanding the genetic origins of heart disease, development of new therapeutics for heart failure, and optimizing cardiomyocyte (CM) regeneration strategies. The new directions outlined in this R35 proposal stem from a series of discoveries in my laboratory, supported by continuous NHLBI funding since 1998, that defined a transcriptional regulatory circuitry that is critical for cardiac maturation. We have found that the orphan nuclear receptor estrogen-related receptor (ERR) and its coactivator PPARγ coactivator 1 (PGC-1) are critical for the coordinate regulation of mitochondrial and contractile processes during cardiac maturation, and in the adult heart. Genomic interrogation studies have defined the gene annotated ERR cistrome in human cardiomyocytes (CMs) demonstrating that this transcription factor occupies over 50% of super-enhancers, often in close proximity and cooperation with the cardiogenic transcription factor GATA4. These findings provide an opportunity to address several conceptual gaps and bold questions that form the basis for the proposed R35 project: 1) Do naturally-occurring variants in human CM genomic ERR binding sites contribute to genetic and acquired forms of heart disease?; 2) What is the impact of maintaining or reactivating the adult CM maturation program in the failing heart?; and 3) Conversely, can components of the adult CM maturation program be transiently “unlocked” to enable CM proliferation? To address these questions, we will identify and characterize common and rare variants in human CM ERR binding sites associated with congenital heart disease and cardiomyopathy, assess the potential of maintaining or re-activating the transcriptional control of CM maturation as a novel therapeutic strategy for heart failure, and assess targeting the ERR/PGC-1 circuitry to unlock metabolic maturation as a strategy to transiently enable CM regeneration. This project represents a new avenue that has emerged from years of productive research supported by continuous NHLBI R01 funding. The proposed studies show promise for high impact translational breakthroughs including defining the importance of non-coding DNA variants as drivers or modifiers of heart disease - a strategy that can be extended to non-cardiac diseases, optimization of hiPSC-CM maturation by targeting the PGC-1/ERR circuit, re-activation of CM maturation as a potential novel therapeutic approach for heart failure, and the bold goal of transiently enabling CM regeneration.

NSF Awards · FY 2025 · 2025-04

Ammonia is a viable alternate fuel when compared to hydrogen because of its high energy density and relatively easy storability. However, combustion of ammonia can lead to very high pollutant emissions. For example, nitrous oxide can form in low-temperature regions of engines because combustion is slow in these regions. Low-temperature regions often are located near engine walls where heat is lost to surroundings. The slow combustion there is called wall quenching. This project addresses the role of wall quenching in generating emissions in ammonia combustion. The project will use numerical simulations of the flow and chemical reactions to describe the generation of nitrous oxide in wall quenching regions. The results of the project will be predictive computational models that can then be used to provide design rules. Optimized ammonia combustion systems with minimum pollutant emissions could have an enormous impact on several combustion applications such as heavy-duty marine engines. As part of this research program, graduate and undergraduate students will be trained in combustion, turbulence, computational fluid dynamics, software engineering, and high-performance computing. The goal of this award is to computationally investigate emissions in ammonia wall quenching processes and provide a predictive computational model for engineering simulations. First, detailed numerical simulations will be conducted for laminar and turbulent wall quenching in multiple configurations to understand the influence of geometry and wall conditions on the wall quenching phenomena with a specific emphasis on nitrous oxide formation. Second, a new Wall-Modeled Large Eddy Simulation for Reacting Flows framework will be developed for the reacting flow processes near the wall. In brief, evolution equations for the complete set of species mass fractions and energy are solved only near the wall, and a more computationally efficient combustion model is used away from the wall. Finally, the wall modeling framework will be applied to a wide parametric sweep of ammonia combustion wall quenching to better understand undesirable conditions that should be avoided in ammonia combustion systems. These results will be used to train a data-based wall model for implementation into other codes that will be shared publicly. The modeling framework will allow for the efficient computational modeling of emissions from ammonia combustion, which can be leveraged to accelerate the development of new ammonia combustion technologies. This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.

NIH Research Projects · FY 2026 · 2025-04

PROJECT SUMMARY Pancreatic ductal adenocarcinoma (PDA) is a deadly cancer for which effective treatments are urgently needed. Metabolism is extensively reprogrammed in pancreatic cancer to support tumor growth and progression. The epigenome is sensitive to metabolic alterations since many chromatin modifications depend on and are regulated by the abundance of key intracellular metabolites that are substrates of epigenetic enzymes. Disruption of physiological control of the metabolism-epigenome link in cancer cells has been shown to contribute to tumor growth and progression. Our labs recently identified a novel link between metabolism and the epigenome, though which branched chain amino acid (BCAA) availability and catabolism regulates histone lysine propionylation, a mark associated with transcriptional activation. Although BCAA metabolism is known to be remodeled in PDA, how this impacts chromatin modification and gene expression is unknown. Furthermore, the metabolic route through which BCAA catabolism supplies propionyl-CoA to the nucleus for chromatin modification remains unclear. This project will test the hypothesis that propionyl-CoA, the acyl-donor for histone propionylation, is generated in the nucleus of the cell via a nuclear-localized set of BCAA catabolic enzymes to regulate site-specific histone propionylation and gene expression contributing to tumor growth. We will test this hypothesis in two aims, 1) determine the mechanism of nuclear propionyl-CoA production and 2) Examine the role of BCAA-sensitive histone propionylation in gene regulation and tumor growth. Elucidation of these processes will provide insight into the mechanistic links between BCAA metabolism and PDA tumorigenesis, potentially pointing towards new avenues for therapeutic intervention.

NIH Research Projects · FY 2026 · 2025-04

PROJECT SUMMARY Breast cancer is the most common type of cancer for women. In addition, it leads to the second highest number of cancer deaths in women. Breast cancer screening programs using mammography and related methods reduce deaths from this disease due to early detection and are cost-effective. However, the effectiveness of mammography in women with dense breasts (which amount to about 10% of women) is poor. Furthermore, this population are independently at a higher risk of breast cancer. As a consequence, women with dense breasts are recommended to receive supplemental screening via other imaging methods. Dual-energy mammography (also known as contrast-enhanced mammography) is a supplemental screening technique that has high sensitivity and high specificity for breast cancer detection in women with dense breasts. Other imaging methods can be used for breast cancer supplemental screening, such as contrast- enhanced MRI, however, it faces challenges with reimbursement, issues of access and a high false positive rate. Dual-energy mammography is currently done with iodine-based contrast agents that are not well designed for this purpose, such as a very narrow imaging window, relatively low tumor to background ratio and allergic reactions. Novel contrast agents that addressed these issues would be highly appealing. We have recently developed silver telluride nanoparticle contrast agents for breast cancer screening via dual- energy mammography. These nanoparticles generate strong contrast for dual-energy mammography, provide a sustained imaging window, are highly stable and biocompatible and have best-in-class renal clearance. In order to advance these agents towards clinical translation, we will undertake several steps. We will adapt their synthesis so that it can be done with microfluidic chips, which allows rapid prototyping, results in homogeneous products and scale-up of the synthesis. We will characterize the nanoparticles formed from microfluidic chip scale-up and test them in a model of breast cancer. We will transfer the technology to a CRO for GMP manufacturing. With the resulting material, we will perform extensive excretion and safety studies in two species. In addition, we will perform virtual clinical trials to inform the design of clinical trials. Moreover, we will leverage the University of Pennsylvania's rich translational environment to assist in conducting a pre-IND meeting and assembling an IND application. The result of these steps will be a lead formulation ready to enter clinical trials, to enable improved detection of breast cancer and therefore lower mortality from this disease.

NIH Research Projects · FY 2026 · 2025-04

Project Summary/Abstract: Conserved in invertebrates and vertebrates, the Balbiani body (Bb) is an aggregate of maternal RNAs, proteins, and/or organelles that in most animals is the first polarized structure in early-stage oocytes. The Bb recruits and localizes maternal factors required during early embryogenesis at the oocyte cortex, defining the vegetal pole and the animal-vegetal axis. During early embryogenesis maternal factors at the vegetal pole are transported to the blastomeres, where they will serve two key functions: maternal factors known as germplasm will specify the germline, and dorsal determinants will induce the signaling center that mediates dorsoventral axis formation. The intrinsically disordered Buc protein is the only known factor required for Bb assembly, which is hypothesized to be mediated by the self-aggregation of a prion-like domain (PrLD) within the amino terminus of the protein. There is evidence, however, that the PrLD is insufficient to ablate Bb localization and suggests that other regions of the protein contribute to Bb and germplasm assembly. Since protein organizers of other intracellular granules are predicted to be intrinsically disordered, I hypothesize that Buc protein disordered regions also mediate Bb and germplasm assembly in early-stage zebrafish oocytes. To investigate the role of Buc protein disordered regions, I will delete distinct disordered regions of the buc endogenous locus and probe for defects in Bb assembly, oocyte polarity, and germline specification in Aim 1. The Mullins Laboratory has generated a hypomorphic buc allele, which produces a truncated Buc protein that is sufficient to polarize the oocyte but fails to aggregate the germplasm in the embryo and specify the germline. buc hypomorphic mutant mothers produce viable embryos with a grandchildless phenotype. Our data suggest that a key germplasm aggregation factor is deficient that prevents wild-type Buc from rescuing the germline specification defect. Using a candidate list of factors that are sufficient to induce ectopic PGCs in the zebrafish blastoderm, Aim 2 will identify which critical factors are missing from the germplasm of buc hypomorphic mutants by overexpressing these factors in combination. Aim 2 will also investigate if the mutant Buc hypomorphic protein is insufficient to recruit these missing factors. These experiments will systematically test the function of various regions of the Buc protein in Bb assembly and germline specification, thereby performing the first endogenous structure-function analysis of the buc locus. Since protein aggregation is a feature of many neurodegenerative diseases, these studies are expected to provide insight into the aggregation properties of these deleterious protein aggregates.

NIH Research Projects · FY 2026 · 2025-03

PROJECT SUMMARY/ABSTRACT Given the association between the presence of tau aggregates, cognitive decline, and neurodegeneration, tauopathies remain without a cure. The ability of tau aggregates to seed their counterparts, or pathogenicity, is well-documented and is considered to be the cause of tau pathology spread into specific brain regions, resulting in brain dysfunction. Interestingly, different tau aggregates (tau strains) exhibit a certain pathogenicity and can seed human-like tau pathology in preclinical models, highlighting the critical role of tau pathogenicity in the progression of tauopathies. The mammalian suppressor of tauopathy 2 protein (MSUT2) has been demonstrated to modulate tau pathology in various animal models expressing human mutant tau. Stemmed from the study of tau spreading in MSUT2 KO mice, our preliminary data showed that MSUT2 regulates adenosine signaling and ASAP1 regulated endocytosis of pathogenic tau seeds in vitro and in vivo. The mechanism by which ASAP1 regulates tau endocytosis and its therapeutic potential in regulating tau spread remains unclear. We hypothesize that ASAP1 modulates the seeding and spreading of tau pathology via the regulation of tau endocytosis. To test this hypothesis, we propose a study with the following aims. Aim 1: Investigating a potential ASAP1 signaling pathway on tau transmission in human neurons. Using human Induced pluripotent stem cell (IPSC) derived neurons as tau spreading models, we will reveal the mechanism of ASAP1 signaling on endocytosis of tau and the effectors along these pathways contributing to the seeding of tau pathology. Aim 2: Evaluating the involvement of the ASAP1 pathway on tau spread in vivo. We will utilize tau spread models of tauopathy to investigate the suppression of ASAP1 signaling and its effects on tau spread to assess the therapeutic potential of this pathway on tauopathy. Aim 3: Elucidate the involvement of ASAP1 signaling in human tauopathy. We will identify the disease relevance of ASAP1 signaling and study their impacts on tau transmission in AD and tauopathy patients.

NSF Awards · FY 2025 · 2025-03

Electrochemistry – driven by sustainable or renewable electrical energy generated by wind or solar energy – offers a path toward a sustainable, circular carbon economy, thereby reducing our reliance on fossil fuels and mitigating the impacts of climate change. To that end, the project focuses on transforming carbon dioxide (CO2), a major greenhouse gas, into value-added chemicals and fuels. The novelty of the project lies in understanding the role of water in the electrochemical reactions that convert CO2 efficiently and selectively to multi-carbon hydrocarbon chemicals for use as building-blocks for a broad range of products including fuels, plastics, coatings, and construction products. By varying the concentration of salt in a solution, the chemical activity of water (H2O) can be altered, potentially enabling greater control over the reaction of CO2 with H2O to produce the desired multi-carbon products. Beyond the technical aspects, the project offers educational and training opportunities in STEM areas, especially focused on socioeconomically disadvantaged students. The project investigates the role of H2O in modulating the electrocatalytic CO2 reduction reaction (CO2RR) to favor efficient and selective formation of C2+ products. Preliminary data from the investigator’s laboratory has shown that lowering the water activity favors the generation of multi-carbon products. By adjusting the salt concentrations within a range of 0.1 to > 10 molal in the water the investigators have successfully altered the activity of water in the solution, which, in turn, enhances the production of C2 products over their C1 counterparts. Three specific project thrusts will be pursued to understand the origin of improved electrochemical reduction of CO2 to C2 or C2+ products with decreased water activity, namely: 1) optimize solution composition by simultaneously varying the cation, anion, and water activity for improved CO2-to-multicarbon fuels on Cu electrodes, 2) interrogate the role of the electrolyte structure in modulating catalysis with surface-enhanced in-situ infrared absorption spectroscopy (SEIRAS); and 3) explore electrolyte engineering to boost CO2 reduction to multi-carbon alcohols on Cu-alloy catalysts. Broader educational and outreach aspects of the project will introduce socioeconomically disadvantaged students to concepts of renewable energy research. Specifically, the investigator, along with a post-doctoral associate and undergraduate student, will participate in the Engineering Innovation Program (EIP) at Johns Hopkins University. Students will conduct straightforward hands-on experiments to acquaint them with fundamental renewable energy concepts, with the goal of piquing their interest in STEM areas as related to educational and career paths supporting greenhouse gas reduction and mitigation of environmental impacts. This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.

NSF Awards · FY 2025 · 2025-03

Nonconvex statistical estimation and learning algorithms are dramatically improving our capacity to efficiently learn from massive datasets, reshaping society through new technological capabilities in healthcare, imaging, transportation, and information processing. Although such learning algorithms have had widespread empirical success, we have yet to find a coherent mathematical foundation that can explain not only why they work and what tasks they provably solve, but also how practitioners can improve their performance either by adjusting the algorithm or even the task itself. The investigator aims to lay this foundation by advancing the design, analysis, and deployment of rigorously justified nonconvex optimization algorithms. This research will create guaranteed procedures for training practical machine learning systems deployed in government and industry, producing more reliable and robust predictive models with fewer data and computational resources. The investigator will incorporate results from this project in education efforts, including course development, local K-12 outreach, and research mentoring of Ph.D. and undergraduate students. In this project, the investigator designs and analyzes nonconvex optimization algorithms. The project focuses on simple iterative methods that compute with data in its ambient form, a class of algorithms that are uniquely scalable to modern high-dimensional statistical estimation and learning tasks. The overarching goal of the project is to understand when these methods converge to local or global optima and to provide efficiency estimates of their performance, measured both in terms of data and computational resources consumed. To achieve this goal, the investigation will draw on the techniques of variational analysis, nonsmooth optimization, machine learning, statistics, and high-dimensional probability. The investigator will leverage these techniques to design and equip simple, scalable iterative methods for nonconvex data fitting problems with strong performance guarantees: generic initialization strategies, rapid local convergence near optima, and seamless adaptation to nonsmooth constraints, models, priors. Such performance guarantees guide the practical implementation of reliable and efficient numerical methods for high-dimensional estimation and learning. This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.