University Of Pennsylvania

NSF Awards · FY 2025 · 2025-06

This I-Corps project is based on the development of a system that converts salty water into concentrated acid and base using only electricity. Acid is widely used in metal refining processes from primary extraction to product finishing across metals including nickel, lithium, rare earths, and steel. However, current acid production and recycling methods are often associated with the generation of hazardous gases that must be managed. The transportation of acids and precursor chemicals adds further logistical complexity and costs to metals processing plants, especially where primary extraction occurs at remote mining sites. Spent acid is often wholly or partially neutralized on site to form salts of calcium, magnesium, sodium, or iron, which can pose environmental risks and space constraints to mine or refinery sites and surrounding ecosystems. Acid procurement and waste management can account for 30% to 80% of operating expenditures in metals leaching processes. This technology may offer a safer, cleaner, and more energy-efficient alternative for metal extraction with no direct emissions or hazardous byproducts. In addition, this technology may enable sustainable domestic supply chains for critical materials. This I-Corps project utilizes experiential learning coupled with first-hand investigation of the industry ecosystem to assess the translation potential of a bipolar membrane electrodialysis platform for acid and base production. The adoption of bipolar membrane electrodialysis in metallurgy has been limited due to the low concentrations of acid electrodialysis can produce with current technology. Metals leaching typically requires more concentrated acids and bases than in common applications of electrodialysis such as in the beverage or desalination industries. This technology allows for the doubling of acid concentrations versus traditional electrodialysis by optimizing membrane compositions, reactor component sizing, and operational parameters. Unlike conventional acid generation technologies, this approach avoids combustion, phase changes, or hazardous byproducts. The research builds on recent advances in membrane materials and stack design to improve efficiency and durability, allowing for high-throughput operation with minimal downtime. This technology may enable production of concentrated acid and thus, has important applications in metallurgy, where concentrated acids are widely used to extract metals from ores. 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 · 2025-06

With the support of the Chemical Catalysis program in the Division of Chemistry, Dr. Anthony Shoji Hall at Johns Hopkins University is studying methods to improve the performance of catalysts to enable storing renewable energy in the form of chemical bonds. Energy storage devices are important for curbing catastrophic climate change. However, renewable electricity from wind and solar is intermittent, which means that this energy must be stored for use at night or when the wind is not blowing. The electrocatalytic reduction of CO2 to chemical fuels is a potential strategy for storing renewable electricity. Catalysts usually exhibit variations in performance when the structure of the material is changed. The proposed study will use experimental methods to understand how the structure of the material influences its performance as a catalyst. Dr. Hall's laboratory also actively engages in outreach at inner city Baltimore high schools. This activity will allow a female minority high school student to study in his laboratory to learn about renewable energy science. With the support of the Chemical Catalysis program in the Division of Chemistry, Dr. Anthony Shoji Hall at Johns Hopkins University is studying the structure-property relationships of nano-structured materials for electrochemical CO2 reduction. Nanomaterials exhibit a broad distribution of sites – such as edges, corners, and terraces – which can exhibit different reactivity. This proposal focuses on preparing catalysts with well-defined populations of active sites by coating defect sites or terrace sites with inert metal oxides; potentially allowing the experimentalist to unambiguously connect catalyst structure to property. Electrochemical kinetic measurements and surface enhanced in-situ infrared absorption spectroscopy (SEIRAS) will be used to interrogate the reaction mechanism of catalysts with well-defined active site structures. Knowledge obtained from these studies will be used to develop materials that promote more efficient catalytic pathways. 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 · 2025-06

This research project looks to enable new capabilities for a type of robot called a "serial chain" manipulator, made from multiple segments connected end-to-end by hinged joints. The goal is to create robots up to one hundred segments long, which would more than double the current state of the art. More segments and joints increase the number and complexity of different shapes that the robot can form. This is important, for example, in manufacturing tasks like inspecting the highly contorted and tightly confined space inside of an airplane wing, or in surgical tasks like accessing a location inside the human body without damaging delicate surrounding tissue. In theory, controlling each joint with its own motor allows the most complete control over such a robot but, as the number of joints grows, the weight, space, and power demand of so many motors quickly becomes impractical. This project explores how the robot can operate with only two motors mounted at the base of the robot, using a gear train that transmits power through every joint, and a set of small controllable pins that can lock the segments to the gear train in various configurations. The project seeks to discover control sequences that allow the robot to achieve full functionality despite this reduced control authority. The project includes a study of how key measures of robot performance change as the number of joints and segments increases. This study will guide serial chain robot design for applications including manufacturing, medicine, and search and rescue, thus benefiting the US economy and society. This project will look to create a new underactuated manipulator design using a novel multiplexing mechanism to enable a modularity that reduces mechanical complexity and eases the limitations of actuator strength. This multiplexing also enables kinematic tuning that can be used for complex environment inspection. Products will include a theoretical framework incorporating an array of possible limitations, to understand the upper limit on the number of articulations. The ultimate goal is systems with hundreds or even thousands of articulations, with conforming abilities for whole-body manipulation and grasping. Such systems will be more like "smart ropes" than they will resemble today's robot manipulators. 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 2025 · 2025-06

PROJECT SUMMARY RUNX1 Familial Platelet Disorder with associated myeloid malignancies (RUNX1-FPD) is caused by inherited monoallelic mutations in the RUNX1 transcription factor. RUNX1-FPD patients have a high risk of developing hematologic malignancies. Chronic inflammation is thought to play a central role in driving the risk for cancer in RUNX1-FPD. As such, controlling inflammation may be an effective therapeutic strategy for preventing cancer. However, the mechanisms by which mutations in RUNX1 promote an inflammatory state are incompletely understood. We previously showed using genetic mouse models that loss of RUNX1 epigenetically derepresses inflammatory signaling pathways in granulocyte-monocyte progenitors (GMPs). These epigenetic alterations are inherited by neutrophils, which become primed to oversecrete cytokines. The epigenetic state induced by loss of RUNX1 in GMPs strikingly resembles the proinflammatory epigenetic state of hematopoietic stem and progenitor cells (HSPCs) in trained innate immunity (TII). In TII, exposure to pathogen or damage associated molecular patterns induces HSPCs to undergo epigenetic remodeling that enables the innate immune system to respond to these stimuli more robustly in the future. In contrast to the adaptive nature of TII, complete loss of RUNX1 appears to induce a fixed and maladaptive proinflammatory state. The first goal of this proposal is to establish whether RUNX1-FPD patients exhibit a state of fixed maladaptive innate immunity. The second goal of this proposal is to determine whether and how the adaptive process of TII is altered in RUNX1-FPD. I hypothesize that fixed maladaptive innate immunity caused by decreased RUNX1 levels in hematopoietic progenitors will augment TII. I will test my hypothesis in a mouse model that faithfully recapitulates RUNX1-FPD using a high fat diet model to induce TII. These studies will provide mechanistic insight into the dynamic role that RUNX1 plays in regulating the inflammatory potential of the innate immune system and may identify opportunities to therapeutically control inflammation.

NIH Research Projects · FY 2026 · 2025-06

Project Summary/Abstract The purpose of this individual National Research Service Award (NRSA) is to provide research training that will enable the applicant to become an independent researcher focusing on interventions for improving outcomes and experiences of hospitalized persons living with dementia (PLwD) and their family caregivers. This NRSA will ensure that the applicant achieves competence in establishing an understanding of the care of PLwD and their family caregivers, develops foundational skills to commence a program of research with this vulnerable population, and gains professional development skills to advance in a rigorous academic setting. This training will occur in a resource rich environment with support from a world-renowned advising team ideally suited to the applicant's topic and training plan. Informed by her work as an acute care nurse and a clinical nurse specialist, the applicant has first-hand knowledge of the importance of improving the outcomes and experiences of hospitalization for PLwD and their family caregivers. PLwD experience adverse outcomes resulting from hospitalization at greater rates than older adults without dementia. The term “dementia friendly” in the context of hospitalization, is a developing concept that describes initiatives aimed at addressing these adverse events and improving the experience of hospitalization for PLwD and their family caregivers. The inclusion of family caregivers during hospitalization is a tenet of the dementia friendly concept and is considered a best practice in dementia care. Key stakeholder perspectives about dementia friendly practices, as well as strategies for implementing the inclusion of family caregivers, are lacking, especially in the United States. This study proposes to fill this gap in knowledge through the following aims: Using qualitative, semi-structured interviews, the perspectives of approximately 16 hospital dementia care triads, including hospital nurses who care for PLwD, hospitalized PLwD, and their family caregivers, will be gathered and analyzed to 1) describe the concept of dementia friendly in the context of hospitalization, 2) describe how family caregivers of PLwD are currently and could be included during hospitalization, and 3) identify facilitators and barriers to the implementation of dementia friendly practices, including the effective inclusion of family caregivers of PLwD during hospitalization. The study will use a descriptive, qualitative approach, guided by the Consolidated Framework for Implementation Research, to describe the triangulated perspectives of these affected individuals within and across the various role types. This study has the potential to provide new knowledge that will 1) advance the concept of dementia friendly in the context of hospitalization and 2) identify facilitators and barriers to the implementation of dementia friendly practices and the effective inclusion of family caregivers for PLwD during hospitalization.

NSF Awards · FY 2025 · 2025-06

Non-Technical Summary: Ordered intermetallic compounds (OICs) are metallic alloys with a periodic atomic arrangement of two (or more) metal elements. These OICs play an important role in technologies such as catalysis, batteries, and shape-memory alloys. Their application space is limited, however, because these materials can only be prepared at high temperatures, often eroding control over important material parameters. Making the low-temperature synthesis of OICs possible requires a precise understanding of how atoms move within solid materials. This Faculty Early Career Award (CAREER) will support research in the laboratory of Dr. Anthony Shoji Hall at the Johns Hopkins University to examine pathways that allow for the control of atom movement at low temperatures and thereby enable the preparation of ordered intermetallic nanomaterials at room temperature and atmospheric pressure. By enabling the synthesis of these materials at low temperatures, this work will substantially broaden the application space of OICs because it now allows for more fine control over important materials parameters. Dr. Hall’s laboratory will actively share their scientific passion and discoveries with the broader community by engaging in outreach at inner-city Baltimore high schools and universities. The first activity will leverage an established program, STEM achievement in Baltimore elementary schools (SABES), to encourage elementary students to pursue a degree in STEM. This project will also create a new program to encourage URM high school students to pursue degrees in STEM and to improve the retainment of URM (under)graduate students in STEM careers. Technical Summary: Despite decades of intense research, OIC nanoparticles have failed to replace conventional nanomaterials due to (1) lack of low-temperature synthetic methods that can overcome slow solid-state diffusion rates which inhibits atomic ordering, (2) inability to tune composition and phase to optimize the desired application, and (3) lack of fundamental understanding needed for progress on these issues. The purpose of this CAREER proposal is to examine the phase transformations of low melting point alloys to higher melting point OICs richer in the nobler and more active metal at ambient temperature and pressure by removal of the less noble component (e.g., transforming PdBi2 to Pd3Bi, or CuZn4 to Cu5Zn8) via a process known as dealloying. Fundamental insights from this project will enable the rational development of OIC nanostructures for applications of technological relevance and improve our understanding of material stability under electrocatalytic conditions. To understand the origin of the electrochemical dealloying-mediated phase conversion process, the PI will investigate the following objectives: (1) Elucidate the role of melting temperature on bulk diffusion and lattice reorganization. (2) Develop synthesis methods for controlled compositions of de-alloyed OICs. (3) Elucidate dealloying via in-situ spectroscopic methods. Materials made by this electrochemically mediated phase conversion process will be evaluated as anodes for Li-metal batteries to demonstrate the utility of the synthetic method. The broader impacts of this proposal will encourage underrepresented minority (URM) K-12 students and (under)graduate students to pursue careers in STEM through engagement in outreach programs. URM students lack access to relatable role models in STEM fields because of underrepresentation. To address this issue, Dr. Hall will make himself available for informal “coffee hour discussions” to serve as a mentor and role model for URM students (high school-aged, undergraduate, and graduate students) in the Baltimore area. The Hall group will also work with K-12 aged URM students on inquiry-based scientific projects by participating in the STEM Achievement in Baltimore Elementary Schools (SABES) program. 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 · 2025-06

Project Summary Nearly 8% of the global population suffers from osteoarthritis, and the burden of disease is much higher among older adults. Current treatment strategies are limited to symptom management or require invasive surgical procedures that carry significant risk for the elderly. Thus, there is an urgent need for minimally invasive, disease-modifying therapeutics for the treatment of OA. The synovium is a bi-layer membrane that lines diarthrodial joints and produces synovial fluid. Fibrosis of the synovium is a hallmark of OA and is believed to promote disease progression, making it a target for novel therapeutics. Myofibroblastic differentiation of fibroblast-like synoviocytes (FLS) is triggered by inflammatory signaling and extracellular matrix stiffening, and is critical to the development of synovial fibrosis. This phenotypic shift requires the sensation of mechanical stimuli and upregulation of contractile machinery. Therefore, intervening in FLS mechanobiology offers a promising means to prevent synovial fibrosis and the development of OA. Non-muscle myosin II (NM-II) is a key component of acto-mysoin contractility and mechanotransduction; however, the impact of NM-II inhibition on FLS behavior, synovial fibrosis, and OA progression has not been evaluated. To address these gaps in knowledge, we will investigate the effect of genetic and pharmacologic NM-II suppression on FLS activation in vitro and on synovial fibrosis and OA pathogenesis in vivo. Use of our novel transgenic mouse in which the genes for both NM-IIA and NM-IIB (Myh9 and Myh10, respectively) are floxed will generate precise mechanistic data on the contribution of FLS mechanoactivation in OA progression, while pharmacologic intervention will demonstrate the translational potential of targeting synovial mechanobiology. Our central hypothesis is that inhibition of NM-II activity will limit myofibroblastic differentiation, reducing fibrosis and slowing OA progression. In Aim 1, FLS will be harvested and either directly plated onto substrates of physiologic stiffness or stiff-primed. Half of the cells in each treatment group will be treated with TGFβ to induce heightened mechanoactivation. In Aim 1a, cells will be harvested from Myh9/Myh10 double-floxed mice and NM-II activity will be suppressed by genetic knockout. In Aim 1b, wild-type (WT) FLS will be treated with a small molecule inhibitor of NM-II. Myofibroblastic differentiation and fibrogenic capacity will be assessed via measurement of morphology, contractility, gene expression, and matrix production. In Aim 2, we will induce OA in mice through destabilization of the medial meniscus (DMM). NM-II will be genetically ablated in Aim 2a and pharmacologically inhibited in Aim 2b. Early and delayed intervention will model “preventative” and “treatment” strategies, respectively. Prevention and/or reversal of synovial fibrosis and OA pathology will be assessed via functional outcomes, histological scoring, staining for fibrotic markers, mechanical testing, and transcriptional analysis. Completion of these Aims will establish the role of NM-II in FLS activation, further our understanding of synovial fibrosis as a driver of OA and guide development of innovative therapeutics.

NIH Research Projects · FY 2026 · 2025-06

Maternal obesity alters mitochondria function in offspring which is associated with abnormal mitochondria function in key metabolic tissues. Treating the pregnant dam with antioxidants prevents the development of obesity in the offspring. These studies strongly suggest that maternal obesity alters mitochondria function in the offspring which is directly linked to the development of obesity and the metabolic syndrome later in life. The molecular mechanisms by which this process occurs is the focus of this proposal. Extracellular vesicles (EVs) contain mitochondria components such as mtDNA and protein, which can be incorporated into the recipient cell mitochondria network resulting in changes in mitochondria function. Adipose tissue produces large numbers of EVs which induce inflammation, modulate glucose and lipid metabolism and recently have been shown to alter placenta function. We hypothesize that obesity during pregnancy increases the secretion of EVs from adipose tissue that contain abnormal mitochondrial cargo, and that these EVs traffic to the embryo, leading to abnormal mitochondria function which in turn reprograms the offspring to develop obesity later in life. In SA1 we will test the hypothesis that transfer of damaged EV mitochondria cargo to the embryo preferentially alters the metabolic homeostasis in the male embryo and offspring of the obese dam. Using our established murine model of obesity in pregnancy, we will isolate and characterize circulating adipocyte EVs from plasma and adipose tissue of obese and lean pregnant dams. In vitro experiments will assess the capability of circulating or in vitro obtained adipocyte EVs from early pregnant obese dams of transferring mitochondria cargo to preimplantation embryos thereby altering embryo metabolic function. Using an in vivo approach, we will determine if circulating adipocyte EVs from obese pregnant dams transfer abnormal mitochondria cargo that is incorporated into mitochondria of embryos from lean pregnant dams. We will generate transgenic mice expressing a mitochondria tag only in extracellular vesicles (Cd9-GFP cre/mKate2). Finally, EVs will be isolated from obese transgenic pregnant mice and injected into lean pregnant mice daily from e1-e4.5. E4.5 embryos will be harvested and localization of donor EV mitochondria to the mitochondria network of the recipient embryo will be assessed by immunofluorescent microscopy. Mitochondria function of e4.5 recipient embryos will also be measured. Body composition, glucose tolerance, and localization of maternally derived mitochondria will be assessed in offspring in adulthood. To determine the specific effect of EVs on embryo metabolic function, embryo transfer experiments will also be performed. In SA2 we will test the hypothesis that in the presence of maternal obesity, maternal adipocyte EVs carrying damaged mitochondria cargo alter the epigenome of the embryo in a sex-specific manner. Single-cell RNAseq and ATACseq will be performed in the same cell and genome-wide DNA methylation will be assessed in parallel and results compared between male and females. Genomic interactions will be mapped by chromatin capture. Novel analytic pipelines will be used to map cell-cell interactions using the integrated omics data.

NSF Awards · FY 2025 · 2025-06

Many plants and animals rely on beneficial microbes for essential nutrients. As a result, these microbes are important for their host’s growth and survival. However, these microbes do not provide a free lunch: the host pays for microbial nutrients by providing resources like sugar back to the microbes. This project will test whether this cost also affects the host’s ability to defend itself. The researchers will address this question in legume plants. Legumes rely on a beneficial microbe for an essential nutrient (nitrogen), which they pay for with sugar. The researchers will test how this beneficial microbe affects the evolution of leaf defensive hairs, an important plant defense. These hairs prevent insects from eating the plant. If beneficial microbes affect leaf defensive hairs, then it means that they can influence whether their host will be able to evolve resistance to natural enemies like insects. This project will also train undergraduates in the fundamentals of field biology. The training will include teaching the next generation of field biologists to develop hypotheses, design experiments to test them, and analyze data. The overarching goal is to lower the barrier of entry to field biology for young scientists. This project will test the hypotheses that microbial symbionts affect defense trait evolution in their hosts, and that this effect is mediated by the resources that they provide and consume. The proposed work will close the existing gap between the hypothesized and realized contributions of microbial symbionts to host trait evolution by (1) determining how heritable variation in host traits arises from genetic variation in symbiont populations; (2) linking symbiont effects on host defense traits to the host resources they provide and consume; and (3) directly testing whether microbial symbionts contribute to host trait evolution in the wild. The resource-exchange mutualism between the legume Medicago lupulina and nitrogen-fixing Ensifer bacteria will be used to test these hypotheses. This proposal represents a novel integration of microbial symbioses into the evolutionary ecology of defense via the overlapping resource physiologies of symbiosis and defense. It bridges the historical gap between the study of mutualistic and antagonistic interactions. 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 · 2025-06

PROJECT SUMMARY This research program focuses on understanding the rhoptry secretion system in unicellular eukaryotes within the Alveolata superphylum, including apicomplexan parasites and non-pathogenic ciliates. Apicomplexans, such as Toxoplasma and Plasmodium, utilize rhoptry secretion for host invasion, a process with poorly understood mechanisms. Recent progress, utilizing cryo-electron tomography, uncovered a novel Rhoptry Secretory Apparatus crucial for apicomplexan rhoptry secretion and host invasion. Similar machineries were found in ciliates, lacking the apical vesicle, suggesting evolutionary adaptations. The research program is structured around three main questions: A) What is the conserved basic architecture of these secretion machineries? Using cryo-electron tomography, the team will systematically image species across the Alveolata superphylum, comparing apicomplexans and ciliates to understand architectural variations. B) How are these machineries built? Focusing on one model apicomplexan, Toxoplasma gondii, and one model ciliate, Tetrahymena thermophila, the team will dissect and compare the detailed assembly of these secretion machineries using a combination of genetics, structural biology, and proteomics approaches. C) What is the mechanism for organelle content secretion? The team will study structural changes of these machineries during active secretion events in both apicomplexans and ciliates, utilizing innovative cryo-correlative microscopy and time-resolved sample freezing methods to capture these spatially and temporally transient activities. Capitalizing on the unique opportunity provided by the recent discovery of the Rhoptry Secretory Apparatus, this comprehensive strategy integrates cutting-edge technologies and multidisciplinary approaches to unravel the molecular structures, mechanisms, and evolutionary aspects of the rhoptry secretion system. The findings will provide unprecedented and fundamental insights into molecular secretions in this prominent branch of eukaryotic organisms for crucial biological functions.

NIH Research Projects · FY 2025 · 2025-06

PROJECT SUMMARY The dorsal root ganglion (DRG) contains diverse types of primary sensory afferents to mediate versatile somatosensation, including pain. Nociceptive DRG neurons (nociceptors) can be divided into different types, including C, Aδ, and Aβ nociceptors, based on their conduction velocities from slow to fast. Though multiple Cre lines targeting mouse C and Aδ nociceptors have been generated, no genetic line is currently available for specifically accessing and manipulating Aβ nociceptors, an important population of nociceptive afferents particularly in humans. Intersectional genetic mapping is a powerful approach for interrogating molecularly defined populations of neurons that can't be specifically manipulated using a single Cre line. Results from our lab suggest the existence of an evolutionarily conserved Aβ nociceptors expressing NTRK3 and neuromedin B (NMB) in both mice and humans. Interestingly, these neurons barely express PIEZO2, suggesting that they may use a different molecular mechanism for sensing mechanical pain. The Luo lab has possessed a Nmb-Cre mouse line, so we propose to generate and characterize a NTRK3-FlpO knockin mouse line in this R21 application. With this new mouse line, we can utilize an intersectional genetic strategy to specifically interrogate mouse Aβ nociceptors for the first time. In Aim 1, we will generate new Ntrk3-FlpO founder mouse lines using the Penn CRISPR/Cas9 Mouse Targeting Core Facility and characterize their recombination pattern by crossing to Flp dependent reporter mouse lines. In aim 2, we will breed the Ntrk3-FlpO line with correct combination patterns to Nmb-Cre and examine the intersectional recombination using Cre and Flp double dependent reporter lines. We will quantify the number/percentage of the double positive DRG neurons, characterize co-expression of known molecular markers of different types of mouse DRG neurons, examine their central and peripheral projections, and determine their physiological properties. Taken together, we anticipate generating a new mouse line, which would allow the field to genetically label and manipulate mouse Aβ nociceptors. This would pave a new avenue to discover molecular mechanisms underlying mechanical nociception and determine functions of Aβ nociceptors in chronic pain. This new Ntrk3-FlpO mouse line will also be an invaluable tool for other investigators to study Aβ low-threshold mechanoreceptors, proprioceptors, or any other cell types expressing Ntrk3.

NIH Research Projects · FY 2026 · 2025-06

PROJECT SUMMARY/ABSTRACT SCN3A-related neurodevelopmental disorder (SCN3A-NDD) is a newly identified syndrome characterized by a spectrum of clinical phenotypes including treatment resistant epilepsy, intellectual disability and developmental delay, and malformation of cortical development. SCN3A-NDD is caused by pathogenic variation in the gene SCN3A which encodes Nav1.3, the predominant voltage gated sodium (Na+) channel a subunit expressed in the embryonic brain. Yet, a role for Na+ channels in regulating brain development has yet to be established and the physiological function of Nav1.3 throughout development and in the early postnatal brain remains largely unknown. This proposal will employ a novel preclinical mouse model to gain deeper insight into the pathophysiology of SCN3A-NDD while advancing the development of effective therapeutic interventions for treatment of this devastating disorder. In this study I will use a novel mouse model of SCN3A-NDD to evaluate how pathogenic variation in Nav1.3 alters the excitability of neurons and leads to the clinical features observed in SCN3A-NDD. First, I will evaluate the manifestation of the core features of SCN3A-NDD in the mouse model by examining developmental milestones, seizure susceptibility/epilepsy, and neuroanatomy (Aim 1). I will then determine the effects of pathogenic variation of Nav1.3 on the electrophysiological properties of neurons and their underlying sodium currents and utilize pharmacology to attempt to ameliorate the cellular phenotype (Aim 2). Lastly, I will temporally manipulate pathogenic Nav1.3 expression to determine the critical window of Nav1.3 pathogenicity and employ pharmacology and antisense oligonucleotides (ASO) to assess the effects of reduced Scn3a levels on phenotypes of SCN3A-NDD in vivo (Aim 3). This proposed study will advance understanding of the mechanistic underpinnings of SCN3A-NDD while also offering insight to a potential novel role of sodium channels in normal brain development. This work will provide me with training in electrophysiological and pharmacological techniques in a mouse model of neurodevelopmental disease which will advance my training towards a career in translational neuroscience research.

NIH Research Projects · FY 2026 · 2025-06

PROJECT SUMMARY An important hallmark of many neuroendocrine cancers, particularly neuroblastoma (NB) and pheochromocytoma/paraganglioma (PPGL), is expression of the norepinephrine transporter (NET). NET facilitates the uptake of catecholamines into vesicles. The guanethidine analog meta-iodobenzylguanidine (MIBG) is a substrate for NET and, when synthesized with radioactive iodine (I) isotopes 123I and 131I, has been approved by the FDA for imaging of NB and PPGL and, with 131I, for the therapy of PPGL. In relapsed/refractory NB, 131I-MIBG has the highest reported single agent response rate. While MIBG is safe and effective, toxicity is a limiting factor in adults. Additionally, complete remissions are rare in adult patients with PPGL. NB is typically treated at much higher administered activity per patient mass than adults can tolerate (the approved administered activity in adults is 296 MBq/kg whereas in children with neuroblastoma the standard administered activity is 666 MBq/kg). Children often receive 131I-MIBG in combination with other treatments and stem cell support. Complete remissions with combination therapy in NB are common, but unfortunately relapsed disease is common. A putative mechanism for relapse is the presence of micrometastatic disease, particularly in the marrow, that is very difficult to target with the b- particles emitted by 131I-MIBG; b- travel up to millimeters in tissue and have low linear energy transfer. (LET) and so deposit very little energy in microscopic sites of disease. The high mass amount of MIBG given in low specific activity formulations of 131I-MIBG result in common infusion reactions in adults. Finally, the high abundance of high energy g rays from 131I result in radiation safety and logistical challenges. The a-particle-emitting halogen 211At can be used to synthesize 211At-MABG, which has biodistribution and cancer uptake kinetics nearly identical to 131I-MIBG. Through extensive in vitro and in vivo pre-clinical studies, we have shown that 211At-MABG is safe and effective. Only standard precautions are needed with 211At, and no other significant radiation safety precautions. Additionally, the exceptionally high specific activity of 211At-MABG will prevent pharmacologic effects with the potential for improved target to background ratio. Finally, the high LET, relative biological effectiveness (RBE), and short path length of a-particles allows cytotoxicity to be maintained down to microscopic disease. Our overarching hypothesis is that 211At-MABG will improve upon 131I-MIBG in the treatment of neuroendocrine cancers with less off-target toxicity and greater potential to eradicate microscopic sites of disease. This should result in higher rates of durable disease control. Additionally, treatment will be more readily given due to a much lower external radiation exposure. Finally, 211At can be cyclotron produced and is therefore less subject to supply chain constraints facing nuclear reactor-produced isotopes like 131I. Building upon our pre-clinical experience we propose to test 211At-MABG in pediatric and adult patients.

NSF Awards · FY 2025 · 2025-06

Artificial Intelligence (AI) systems can take advantage of complex patterns hidden within vast pools of data to make inferences about the world. However, modern systems are too large and complex to manually analyze, and come with little to no guarantees on how they work. A key challenge that remains is how to explain the reasoning behind an AI system, and answer the question: why did a model make a prediction? Such explanations are necessary for doctors and scientists to trust AI systems in high-stakes applications. However, existing explanations can result in highly misleading conclusions, resulting in injury and harm when deployed in downstream applications. This project aims to bridge the gap from formal verification to explainability, to create a new paradigm of explanations with provable assurances that can be relied upon in practice. The project's novelties are formal specifications for explanability, a verification framework for certifying explanations, and a class of AI systems with certified explanations. The project's impacts are heightened trust in AI systems when deployed, trusted scientific discovery, and translation of trustworthy AI to scientific domains. The outcomes of this project are being integrated into both undergraduate and graduate courses in artificial intelligence to bolster and motivate the technical course material. The project aims to develop certificates for AI explanations, to build trust in AI systems via formally verified guarantees. The investigator is investigating two core research thrusts. The first thrust builds a verification framework for feature attributions, including developing specifications for explanations, computing lower-bounds for verification, and estimating probabilistic certificates. The second thrust designs architectures that are well-suited for verification of explanations. These architectures differ in the varying degrees of assumed access to the base AI model being explained, including differentiable certificates for full access, explainable wrappers for gradient access, and gray-box techniques for application programming interface (API) access. The project aims to assess verified explanations in scientific domains including cosmology, surgery, and psychology to assess real-world practicality. The team is sharing project results through open-source software packages, and creating new tools for broader access. 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 · 2025-05

The award will support student participation and travel to the Pacific Symposium on Biocomputing (PSB) for the 2026 meeting, to be held January 3–7, 2026. PSB is one of the oldest continuous conferences in computational biology and bioinformatics. Its unique format—small size, no parallel sessions, and a dynamic, community-driven structure— fosters interdisciplinary discussion and collaboration. Participants (200-300 each year) come from around the world, and the meeting setting promotes open dialogue and sustained collaborations. This award will provide support only for students at US-based institutions, aiming to strengthen the competitiveness of the US in the science and technology areas. This award will provide travel support to U.S.-based students presenting research at PSB. Like a Gordon Research Conference, it encourages deep engagement across all levels of the field. The meeting is built from the ground up each year through a call for session and workshop proposals. Approximately 15 proposals are submitted annually, of which 5–6 sessions and 4–6 workshops are selected. This model supports innovation and the timely introduction of new research topics. All accepted presenters receive information about the travel award application process, and support is prioritized for students giving oral presentations, though poster presenters are also eligible. The small size of PSB creates an ideal environment for students to engage with senior researchers, forge professional connections, and create opportunities for mentorship and future collaborations. Many student participants also take part in session or workshop planning, gaining hands-on leadership experience early in their careers. Because sessions are proposed and developed by participants, PSB often becomes the first venue to highlight emerging research areas. This commitment to community-driven innovation promotes scientific advancement and fosters the next generation of leaders in computational biology 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/ABSTRACT Opioid overdose mortality has increased substantially since the start of the COVID-19 pandemic. Opioid overdose deaths are preventable and can be reversed with the timely receipt of naloxone. To date, naloxone distribution and implementation programs have targeted traditional first responders (e.g., EMS) as well as people with opioid use disorder and their social networks. While these initiatives have resulted in measurable reductions in opioid overdose mortality, major gaps in naloxone availability and use persist. The overarching goal of this work is to save lives by advancing evidence regarding place-based naloxone implementation and overdose reversal readiness in high-risk settings, using public libraries as a test case. More than one in ten public libraries experienced an on-site overdose in 2022. In addition, public libraries—which host 1.2 billion in-person visits annually and are within 2 miles of most Americans’ homes—are an important safety net for vulnerable populations, including those with substance use disorders. For these reasons, libraries represent a novel setting to promote naloxone uptake. There have been nascent efforts to equip libraries with naloxone, however, uptake remains low. Thus, we aim to understand institutional barriers to and facilitators of naloxone uptake (Aim 1). Then, we will establish a Public Libraries Cohort (PLC) to monitor and identify drivers of naloxone uptake and incidence and outcomes of overdose among public libraries (Aim 2). Aim 3 will compare the efficacy of two web-based interventions (facilitator-guided and self-guided training), each vs. the other and vs. usual care, on increasing both overdose reversal readiness and naloxone uptake in libraries. This work will advance the evidence for place-based naloxone implementation and overdose prevention.

NIH Research Projects · FY 2025 · 2025-05

PROJECT SUMMARY Perifusion is the gold standard for physiological assessment of islets of Langerhans, the functional units of the pancreas consisting of various endocrine cell types such as -cells which secrete insulin, -cells which secrete glucagon, and -cells which secrete somatostatin. The Islet Cell Biology Core (ICBC) at the University of Pennsylvania, established in 1997, is a resource that provides functional phenotyping of islets for NIH-funded investigators both locally and throughout the nation. Perifusion is a cornerstone service of the ICBC that offers users dynamic measurements of insulin, glucagon, and somatostatin secretion from isolated islets in response to various secretagogues. Recently, Biorep released the PERI5, a state-of-the-art perifusion system combining the latest technological advancements in protocol capability, throughput, reproducibility, and usability. The main feature of the PERI5 is a disposable 12x12 microfluidic manifold which allows for parallel perifusion of up to 12 independent perifusion chambers, representing a significant improvement in the technology that promises greater reliability and reproducibility of perifusion experiments. The ICBC is well-positioned to leverage the PERI5 system to provide the highest quality perifusion data to the diabetes research community at the University of Pennsylvania and across the United States, in line with the University of Pennsylvania Perelman School of Medicine's mission to “advance knowledge and improve health through research.”

NIH Research Projects · FY 2026 · 2025-05

Abstract: Kidney transplantation is the treatment of choice for patients with end-stage kidney disease. Potent T cell directed immunosuppression has led to excellent short-term allograft survival. However, chronic immune rejection remains a significant challenge as rejection constitutes the most common reason for kidney failure and return to dialysis. Induction of immune tolerance serves the dual benefits of preventing rejection of the kidney and salvage of recipients from toxicities associated with chronic immunosuppression. Our preliminary studies in a murine model indicated a requisite role of B cell antigen presentation in activation of alloreactive CD4 T lymphocytes. Therefore, our contention is that the induction of robust transplantation tolerance will require unresponsiveness at the level of both the B- and T-cell compartments. As such, we performed preclinical trials of kidney transplantation in Cynomolgus macaques utilizing a combined induction immunotherapy regimen, which included a CD20-specific B cell depleting monoclonal antibody (Rituximab) and T cell depletion with Thymoglobulin. This regimen led to marked prolongation of allograft survival in some recipients. However, a majority of allografts succumb to immune rejection with development of donor specific antibodies. Importantly, we demonstrated that prolonged survival was correlated with the re-emergence of the B cells with an immature/naive phenotype. In animals with early allograft loss, the re-emerging B cell compartment was predominantly composed of activate/mature B cells, suggestive of residual Rituximab-resistant tissue-resident B cell clones. Therefore, we contend that stringent B cell depletion is a prerequisite for robust B and T cell repertoire modification toward a tolerant state. The present application utilizes a CD20-targeted CART cell therapy to achieve stringent B cell depletion permitting regeneration of the B cell compartment in the presence of the kidney allograft to recapitulate the ontogeny of B cell tolerance. Importantly, since B cells are potent APCs for T cell priming, the impact of B cell repertoire modification has the potential to provide tolerogenic signals to a responding allo-reactive T cell pool. We test this concept in the setting of kidney allo-transplantation in Cynomolgus monkeys. Mechanistic studies will interrogate both B and T cell alloimmunity at the cellular and molecular levels. Finally, we will develop an mRNA-LNP based method of in vivo CAR T cell generation to facilitate clinical translation. Overall, this proposal develops new therapeutics and introduces novel technologies to the NHP model with the ultimate goal of clinical translation.

NIH Research Projects · FY 2025 · 2025-05

Project Summary/Abstract A dire need for novel chronic pain treatments has arisen due to the opioid crisis and the closure of opioid- prescribing pain clinics, affecting over 50 million US adults. The psychedelic serotonin 2a/c receptor (5HT2a/cR) agonist psilocybin has shown preliminary efficacy in treating various chronic pain disorders, such as cluster headaches, fibromyalgia, cancer pain, and back pain. However, its mechanisms are still unknown. One hypothesis is that psilocybin induces corrective neuroplasticity downstream of 5HT2Rs. While the role of cortical 5HT2aRs in neuroplasticity is known, 5HT2aR activation by psychedelics induces hallucinations, complicating clinical applications. In contrast, cortical 5HT2cR is non-hallucinogenic and anti-addictive, making it a potentially valuable pharmacological target. Although these receptors are Gq-coupled and excitatory in some regions, cortical 5HT2cRs are inhibitory due to their coupling with potassium channels. Recently, I established a role for psilocybin-induced inhibition of retrosplenial cortex (RSC) neurons responsive to an electrical foot shock in mice in enhanced fear extinction. The RSC is one of the few cortical regions expressing 5HT2cRs on Camk2a- expressing pyramidal neurons, which undergo significant transcriptional, morphological, and dynamic changes in chronic pain. Chemogenetic inhibition of these neurons in mice can reduce mechanical hyperalgesia, while excitation enhances it after spared nerve injury (SNI)-induced chronic pain, as can a single dose of 1mg/kg of psilocybin. Therefore, I hypothesize that psilocybin ameliorates chronic pain by altering the encoding of pain in the RSC (Aim 1) via 5HT2cR stimulation (Aim 2a) and inhibition of excitatory 5HT2cR+ neurons (Aim 2b). In Aim 1, I will perform one-photon calcium imaging to investigate the effects of psilocybin on encoding spontaneous pain behaviors acutely, 24 hours post-acutely, and 1 week post-acutely in SNI mice. In Aim 2a, I will perform intracranial pharmacology studies to determine the necessity and sufficiency of intra-RSC 5HT2cR stimulation for psilocybin-ameliorated chronic pain. Finally, in Aim 2b, I will chemogenetically manipulate 5HT2cR+ RSC neurons to determine if inhibition of these neurons is sufficient to replicate some or all effects of psilocybin. Successful completion of these aims will provide (1) the first description of the effect of psilocybin and chronic pain on naturalistic single-cell dynamics and (2) elucidate the role of cortical 5HT2cRs and 5HT2cR+ cells in chronic pain relief, laying the foundation for future efforts to improve the viability of psilocybin pain therapy. The applicant, Sophie Rogers, will receive advanced training in neurobehavioral deep-learning pain assays, intracranial pharmacology and chemogenetics, transgenic approaches, single-cell calcium imaging, experimental design and statistics, and computational analysis of high-dimensional neural datasets from her Co- Mentors Drs. Gregory Corder and Maria Geffen. This NRSA F31 training will support the applicant’s current and future research goals and enable her to impact basic neuroscience research as an independent researcher.

NIH Research Projects · FY 2025 · 2025-05

Summary The bone morphogenetic proteins (BMP) and their downstream signaling pathways are critical regulators of key developmental and physiological processes and when altered, cause severe pathologies including developmental defects, organ failures and cancer. The International BMP Conference - now in its 14th occurrence - is a unique, unmatched and fundamental forum in which to assess the most recent research advances from national and international leaders and identify and discuss the most pressing questions moving forward. As its predecessors, it will offer the unique opportunity to bring together not only established physician-scientists and scientists but also young investigators, students and new-comers to the field who will spend several full days together to hear, assess and discuss the most advanced research, to consider the BMP field in all its facets and to envision its future. The conference will thus integrate basic and essential aspects of BMP signaling and function with the work of developmental biologists, cancer biologists, musculoskeletal, cardiovascular, and physician-scientists, structural biologists and computational biologists, all aimed at understanding the molecular, cellular and biochemical underpinnings of BMP family signal transduction and mechanisms of action in diverse physiological and pathological contexts. Attendees use a broad spectrum of approaches from human patient to model organisms and in vitro experimental methods, along with large-scale proteomic, transcriptomic and other genome-wide methods to unravel, define and understand the roles, regulation, fine-tuning and pathology of BMP signaling in these challenging and different contexts. The Specific Aims are: Aim 1: To assess and disseminate the latest, unpublished results in the BMP pathway signaling field, providing an exchange of knowledge and advice through talks and informal interactions at poster sessions. Aim 2: To foster collaborations, intellectual exchange, and interdisciplinary approaches by bringing together diverse investigators including clinicians, biochemists and cellular and structural biologists, and all those in between in order to promote integrative approaches to elucidate BMP family signaling and its components. Aim 3: Building the next cohort of BMP scientists by providing supportive and interactive forums for graduate students, postdoctoral fellows, research associates, and junior faculty to meet and interact with senior scientists, providing networking opportunities and training and career development venues. In addition to invited experts, speakers will be chosen from submitted abstracts to highlight late breaking high-impact research, emphasizing work by early-stage investigators. The requested support for the 14th International BMP Conference would be a significant contribution toward fulfilling the conference's goals to stimulate creativity and collaborations in basic, translational and clinical research into a key cell and developmental signaling pathway, as well as to provide early career stage investigators with strong support to promote and develop their talent.

NIH Research Projects · FY 2026 · 2025-05

PROJECT SUMMARY Epstein-Barr Virus (EBV)-seronegative kidney transplant recipients of EBV-seropositive donor organs (EBV D+/R-) carry an extremely high risk of developing cancers such as post-transplant lymphoproliferative disorder (PTLD) due to donor-derived EBV infection. Currently, there is no cure or approved vaccine for EBV. The objectives of this proposal are to identify the effect of immunosuppression on the development of PTLD and EBV infection and to evaluate the impact of optimizing the kidney allocation system to reduce complications from EBV infection. The central hypothesis is that immunosuppression modifies the risk of PTLD and EBV infection among kidney transplant recipients, and prioritizing EBV-seronegative kidneys for EBV-seronegative recipients can reduce the incidence of PTLD with acceptable tradeoffs to waiting time and access to transplantation. The central hypothesis will be tested by pursuing three specific aims: 1) Determine if modifiable risk factors such as immunosuppression modifies the effect of EBV D+/R- serostatus on the incidence of PTLD, 2) determine the relationship between immunosuppression on EBV infection and viral kinetics among EBV D+/R- kidney transplant recipients, and 3) evaluate the effect of prioritizing transplantation of kidneys from EBV-seronegative donors into seronegative recipients on access to transplantation. The proposed research will establish a consortium of eight large-volume kidney transplant centers to establish a validated and granular dataset of EBV D+/R- kidney transplant recipients. For Aim 1, transplant centers in the consortium will submit validated data on EBV-serostatus, immunosuppression, and PTLD outcomes. For Aim 2, transplant centers in the consortium will adhere to EBV DNA surveillance guidelines from the American Society of Transplantation and collect longitudinal data on EBV DNA levels in blood. For Aim 3, the proposal will use simulation-allocation modeling to identify the effect of changing the kidney allocation system to prioritize the transplantation of EBV-seronegative kidneys into EBV-seronegative recipients. The proposed research will advance the field through innovation in data validation and clinical phenotyping of EBV infection and PTLD, utilize latent class analyses to identify discrete EBV infection trajectories, test the effect of changing the kidney allocation system to reduce the risk of cancer on equity, and employ a multipronged dissemination strategy. In summary, this proposal aims to identify therapeutic strategies, such as optimizing immunosuppression, identifying EBV infection trajectories, and changing the allocation system to reduce the risk of cancer for EBV D+/R- kidney transplant recipients.

NIH Research Projects · FY 2026 · 2025-05

PROJECT SUMMARY Alcohol use disorder (AUD) is a global disease burden and while biological mechanisms underlying AUD have largely been examined in neurons, the role of glial cells is historically understudied. One glial cell type potentially important in AUD is astrocytes, which undergo transcriptional and functional changes upon alcohol exposure. Knowledge of how this is regulated is limited. Since astrocytes are the most abundant glial cell type in the central nervous system (CNS) and dynamically modulate neuronal activity and synaptic plasticity, it is conceivable that the impact of ethanol (EtOH) and its metabolite acetate on astrocytes may lead to both pronounced intracellular effects and subsequent downstream effects on the CNS through epigenetic mechanisms. In support of this notion, acetyl-CoA synthetase 2 (ACSS2) converts acetate to acetyl-CoA used in chromatin regulation of gene expression. Acetyl-CoA is used by histone acetyltransferases (HATs) to drive histone acetylation, which is associated with active transcription and is thought to underlie alcohol-related behaviours. However, whether acetate contributes to histone acetylation specifically in astrocytes, and whether this process is mediated by ACSS2, is unknown. Our lab has previously shown that EtOH is metabolized and deposited as acetate in the brain. During my preliminary studies, I found ACSS2 is highly expressed in and localized to the nucleus of astrocytes, suggesting an epigenetic, gene regulatory role. Treating primary astrocytes with acetate for 24 hours induced differential regulation of over 800 genes by RNA-seq. Moreover, an ACSS2 inhibitor reduced certain acetate-induced transcriptional effects. Interestingly, treating astrocytes with acetate for only 1 hour increased immediate early gene (IEG) expression, although this was not identified at 24 hours. This suggests astrocytes induce distinct waves of gene expression, which has never been directly tested in astrocytes but can importantly contribute to neuronal activity. Spatial transcriptomics analysis in vivo agrees with this, as stimulating fear memories in mice led to astrocytes upregulating certain IEGs at an early time point. Strikingly, this upregulation did not occur in full-body ACSS2 knockout mice. Based on the these evidence and models, I hypothesize that alcohol and its metabolites stimulate waves of transcription in astrocytes, where ACSS2 incorporates acetate into histone acetylation to activate genes that promote alcohol-associated behaviours. To address this hypothesis, I propose to focus on two specific aims: (1) to determine the wave-trajectory of astrocyte gene expression and the impact of alcohol and its metabolites, and (2) to determine whether astrocytes in the brain respond to alcohol metabolism by incorporating alcohol-derived acetate into histone acetylation at key DNA regulatory regions. Completion of these aims will not only reveal potential new therapeutic targets for AUD but will also unveil the capability and mechanism of astrocytes undergoing wave-trajectory of gene expression, yet to be studied. Notably, my study is different from my supervisor’s current NIAAA R01 submission under review.

NIH Research Projects · FY 2026 · 2025-05

Project Summary/Abstract: Sepsis, the dysregulated host response to infection, is a leading cause of death in the United States and accounts for one-fifth of all deaths globally. A comprehensive mechanistic understanding of the host response during sepsis is imperative because the aberrant host response rather than the pathogen itself drives organ failure and mortality. One fundamental and critical knowledge gap is an understanding of how circulating red blood cells (RBCs) contribute to the abnormal immune response. This project aims to deepen our understanding of the host response in sepsis by focusing on the role of RBCs in regulating the inflammatory response to nucleic acids. This study investigates the hypothesis that RBCs, through the expression of Toll-Like Receptor 7 (TLR7), actively participate in immune responses during sepsis by regulating host derived RNA. Our preliminary data indicate that both human and murine RBCs express TLR7 and can bind single-stranded RNA through TLR7, that host derived RNA is increased on RBCs during sepsis, and that RBCs act as a trap for cell- free RNA, dampening the immune response. Based on these findings, we propose the following aims using human RBC samples from critically ill patients with sepsis, synthetic RNAs, and erythroid-specific genetically deficient mice. In specific aim 1, we will establish the subcellular localization of TLR7 in human RBCs and determine the RNA-sequestration capabilities of RBC-TLR7 during sepsis. RBC- TLR7 expression during sepsis will be compared with healthy subjects. Lastly, we will perform miRNA profiling and whole-genome sequencing of RNA associated with RBCs during sepsis. In aim 2, we will determine the role of RBC-TLR7 in delivering RNA to immune cells. In aim 3, we will employ novel erythroid tlr7 deficient mice to define the erythroid-specific functions of TLR7 in vivo using models of polymicrobial sepsis and reductionist models of TLR-induced inflammation. Knowledge derived from these studies will elucidate novel mechanisms of immune dysregulation in sepsis and serve as the foundation for studying RBC immune function, potentially bridging a significant gap in our current understanding of the host immune response.

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.