Yale University

NIH Research Projects · FY 2026 · 2025-02

Project Summary: An estimated 37 million people in the US and over 800 million people worldwide are affected by chronic kidney disease (CKD), which is defined as persistent abnormalities in the structure and/or function of the kidneys. Integral to the filtering function of the kidney are podocytes, which are highly specialized, post-mitotic epithelial cells that line the glomerular filtration barrier. Although damage to podocytes has been implicated in the pathophysiology of CKD, significant gaps in our understanding of podocyte repair and maintenance hinder the development of novel therapies that specifically mediate podocyte injury. To address this problem, I will use a genetically engineered mouse model with a podocyte-specific knockout of cyclin G-associated kinase (GAK) to study cellular mechanisms involved in podocyte maintenance. Our group has previously demonstrated that podocyte-specific loss of Gak results in podocyte damage and kidney failure. Interestingly, we found that re- expression of the truncated 62-kDa C-terminal end of GAK (C62) in mice completely rescues this severe phenotype. I hypothesize that the 62-kDa C-terminus of GAK regulates podocyte autophagy and is indispensable for proper turnover of cellular debris and maintenance of homeostasis. In Aim 1, I will test my hypothesis by measuring autophagic flux in primary podocytes derived from wildtype, Gak knockout, and GAK C62 rescue mice via western blot and immunofluorescence. Furthermore, I will assess the ability of GAK C62 to bind and activate key autophagy regulators via western blot. In Aim 2, I will perform translating ribosome affinity purification sequencing (TRAP-seq) on wildtype, Gak knockout, and C62 podocytes in vivo. This data-driven approach will provide an unbiased view of pathways that are regulated by the C-terminal end of GAK in podocytes. I will validate the results of the TRAP-seq experiment using western blot and qRT-PCR, as well as in vitro knockdown assays in primary podocytes, targeting pathways that exhibit the highest upregulation and downregulation between the three groups. Given that GAK is implicated in other cellular processes, this approach would enable us to both solidify its role in autophagy and determine additional pathways specifically mediated by GAK C62. This proposal to investigate the role of GAK in regulating autophagy in podocytes will advance our collective understanding of mechanisms that contribute to podocyte repair and maintenance and potentially uncover promising therapeutic targets for treating podocytopathies. Furthermore, this project is an integral component of a comprehensive training plan that will provide me with plenty of new learning opportunities and necessary mentorship towards my long-term goal of becoming a physician-scientist in nephrology.

NIH Research Projects · FY 2026 · 2025-02

ABSTRACT Nicotine e-cigarette use in the US has increased to 13 million adult users per year. These devices are now the most popular tobacco product among young people. E-cigarettes deliver nicotine rapidly and are highly Harmful emerging evidence, including work by our team, suggests that e-cigarettes can induce DNA damage and suppress DNA repair, important mechanisms linked to cancer. addictive. In some devices, they can exceed the maximum nicotine delivery of combusted cigarettes. respiratory and cardiovascular effects have also been documented and Although many people want to quit using e-cigarettes, we currently lack evidence-based e-cigarette cessation methods. Varenicline, the most effective monotherapy for smoking cessation, shows promise for e-cigarette cessation including our recent 8-week preliminary trial in adults who reported exclusive daily e-cigarette use (N=40) and either former cigarette smoking or no cigarette smoking history. Specifically, we found that varenicline yielded numerically higher end of treatment relative risk probabilities for e-cigarette cessation (RR=1.51) than placebo and this difference was maintained at Week 12 follow-up (RR=1.36). Thus, varenicline warrants further testing for e-cigarette cessation. In the current study, we propose to conduct a randomized clinical trial in treatment-seeking adults (age 18+) who report exclusive daily e-cigarette use with and without a former cigarette smoking history (N=326) to test the hypothesis that varenicline is efficacious for quitting e-cigarettes. Specifically, we will randomly assign participants to 12-weeks of varenicline (titrated to 2mg daily) or matching placebo and simulate a primary care model in which all participants will receive study medication along with brief cessation advice and self-management resources. We will achieve the following aims. For Aim 1, we will compare the effect of varenicline vs. placebo on e- cigarette quit rates using daily smartphone EMA diaries and biochemical verification of e-cigarette use status. For Aim 2, we will test predictors and moderators of outcomes, such as participant demographics, cigarette smoking history, and e-cigarette device type to determine subgroups and characteristics that may impact treatment response to varenicline. Finally, for Aim 3, we will explore changes in cancer-related biomarkers following e-cigarette cessation treatment. Overall, the results will provide scientific evidence on effective treatment strategies for e-cigarette cessation and the health benefits of cessation.

NIH Research Projects · FY 2026 · 2025-02

SUMMARY Sequencing studies have identified a large set of variants in the human genome, the majority of which fall outside protein coding sequences. Decoding the significance of these variants in gene function represents a major challenge. Untranslated regions of mRNAs play an important role in gene regulation, and single nucleotide changes in these regions can have remarkable effects on protein expression and gene function. The goal of this proposal is to develop new and generalizable genomic and computational approaches to understand the functional effect of genetic variation in the 5’ and 3’ UTRs and its impact on protein output and gene function. We propose two aims to achieve this goal. First, we will identify all the variants in the human 5’ and 3’ UTRs, characterize their conservation and association with disease, and develop a high throughput parallel method (NaP-TRAP-seq) to quantify the regulatory activity of each variant on mRNA translation and protein output across different cell types (Aim 1). This aim will generate extensive quantitative data for the effect of each UTR variant on protein output. Second, we will develop a computational model to predict the impact of each variant on protein output and develop a new constraint model to analyze how variant conservation relates to the effect on protein output and translation (Aim 2). This model will predict the functional effects of known and novel variants on the translation of the downstream coding sequence and how sequence variants affect gene function. Together, these aims will provide a generalizable method to understand the regulatory significance of each variant in the UTR, will provide the principles to interpret variants of uncertain significance in the UTR, and will help predict the functional consequences of sequence variants across trait- and disease-associated genes.

NIH Research Projects · FY 2026 · 2025-02

PROJECT SUMMARY/ABSTRACT Acquired tick resistance (ATR) occurs when ticks can no longer feed on a host. This proposal will determine whether ATR can be induced against Amblyomma americanum - the first step in a novel vaccine to prevent red meat allergy. A. americanum tick bites are associated with IgE mediated type I hypersensitivity reactions to galactose-α-1,3-galactose (alpha-gal). Alpha gal is an oligosaccharide unique to many non-primate animals and added during post-translational protein modification. Old world primates including humans (catarrhines) have lost the enzyme and therefore do not possess alpha-gal modified proteins. Once sensitized by an A. americanum tick bite, some humans experience a hypersensitivity response to alpha-gal, known as alpha gal syndrome -- upon consuming specific types of meat or its derived products. Patients who avoid tick bites have been shown to have a decrease in their alpha-gal IgE levels suggesting that inhibiting tick feeding could decrease the production of alpha gal antibodies. ATR, therefore, is a novel strategy to prevent alpha gal syndrome. We demonstrated ATR in guinea pigs against Ixodes scapularis ticks. Further, our group also showed that ATR induced by I. scapularis results in ATR against A. americanum. In addition, we have also reported that a lipid nanoparticle containing the mRNAs for 19 I. scapularis salivary proteins (19ISP) was sufficient to induce ATR against I. scapularis. We have demonstrated that immunity against I. scapularis cement antigens also elicit ATR against I. scapularis in guinea pigs. Our initial observations suggest that lipid nanoparticles containing the mRNAs for 19ISP or predominant cement antigens of I. scapularis may induce ATR against A. americanum. These observations support our hypothesis that an mRNA vaccine can be developed to induce ATR against A. americanum – the first step towards a unique vaccine to prevent alpha gal syndrome. Our hypothesis will be evaluated comprehensively in this proposal.

NIH Research Projects · FY 2026 · 2025-02

PROJECT SUMMARY (See instructions): Despite the necessary role of dopamine in nicotine reinforcement, it is not sufficient to explain the complexity of addiction. Additional processes, particularly the ability of cues associated with nicotine exposure to develop control over behavior, are essential for ongoing drug seeking. Both human subjects and rodents experience reward-enhancement when exposed to nicotine. This has led to the idea that one of the primary factors driving nicotine addiction is its ability to potentiate the value of other appetitive stimuli and to accelerate cue-reward learning. The major achievement arising from this grant is the discovery of a VT A-to-VP GABA circuit and a MS-to-BLA ACh circuit that increase responding for rewards and reward-paired cues. We have now published manuscripts on characterization and manipulation of these novel, potentially interacting, circuits, as well as on proteomic approaches to identify intracellular pathways downstream of nAChRs in the VTA that contribute to cellular and morphological plasticity following nicotine administration. Our new and updated Aims will expand on this progress by identifying the role of nAChRs in these circuits, exploring cholinergic inputs to the VTA-to-VP GABA neurons, identifying nicotine-dependent proteomic changes in BLA, and determining whether these pathways interact to promote cue-reward behaviors. Together, these proposed studies will go beyond initial steps of nicotine reward mediated through DA signaling to identify circuits and signaling pathways involved in the ability of nicotine to potentiate rewarding responses, processes that likely contribute to long-term susceptibility to nicotine addiction and relapse.

NIH Research Projects · FY 2026 · 2025-02

SUMMARY The ability of an animal to successfully navigate the world and carry out goal-directed behavior is dependent on the hippocampus and entorhinal cortex but is also strongly shaped by visual information derived from external cues. Indeed, manipulation or elimination of visual input can significantly disrupt ongoing activity in these regions and impair tasks that require accurate internal representations of the local environment. Considerable anatomical data indicate that the occipital cortex, including primary and higher-order visual areas, sends projections to the medial entorhinal cortex (MEC). However, the ability of MEC neurons to encode visual cues and the specific circuits mediating this function are largely unknown. Whether the MEC can respond to low-level visual features or primarily represents complex, behaviorally salient relationships between stimuli has not been examined. Furthermore, how visual inputs interact with ongoing network activity within the MEC is unclear. In the present study, we propose a combination of electrophysiology, anatomical tracing, optogenetic manipulation, and ex vivo synaptic physiology to (1) determine the capacity for visual stimulus representation by MEC neurons, (2) identify the afferent pathways and specific subpopulations of MEC neurons that encode visual input, (3) determine the microcircuit organization of connections within the MEC that shape visual responses, and (4) link visually-evoked MEC activity to virtual navigation for reward. Our overall goal is to understand the pathways by which visual information guides complex behaviors such as navigation through the environment. We expect that our results will generate new avenues for exploring both the cellular and circuit foundations of visual behavior and the mechanisms underlying coordination of activity between different brain regions.

NIH Research Projects · FY 2026 · 2025-02

Project Summary Anxiety disorders are the most common mental illnesses in the world. One in 14 people worldwide currently suffer from dysregulated anxiety. People with dysregulated anxiety report poor quality of life, loss of independence and are at an increased risk of suicide attempts. A key component of anxiety disorder is a persistent and disruptive state of aversion, high arousal, and negatively valenced perception even in the absence of threat. Remarkably, up to 30 percent of those who suffer from anxiety disorders do not respond to currently available pharmacologic and behavioral therapies. Part of the reason for this treatment gap is because we do not have a mechanistic understanding of anxiety related brain circuits in humans. Noninvasive neuroimaging techniques, mainly fMRI, have been used to study anxiety related brain circuits. However, fMRI may not capture dynamics and other aspects of the neural mechanisms of anxiety that require greater temporal and spatial resolution. Extensive work in rodent models has identified brain circuits associated with anxiety, in the context of simple experiences. Causal manipulations at the level of specific brain regions and individual neurons have defined their contributions to anxiety-like behavior with potential implications for the treatment of dysregulated anxiety. However, studies in rodent systems may not capture the relationship of anxiety to human subjectivity or the complexities of higher-order human cognition. Circuit-level work in humans is required. The goal of this proposal is to mechanistically uncover neuroanatomical substrates of anxiety related brain circuits that will be candidates for neural circuit reprogramming in future studies. Two reciprocally connected brain regions that have been implicated in top down and bottom-up control of anxiety are the dorsal Anterior Cingulate (Area 24) and the anterior insula. Here we propose a theoretical model where safety assessment and aversive outcomes are dissociably represented in the dorsal Anterior Cingulate Cortex and anterior Insula, respectively. To determine how this circuit operates in humans requires causal manipulations which are difficult due to their deep location. We will take a two-level approach in dissecting these anxiety related brain circuits in epilepsy patients implanted with intracranial depth electrodes, for the sole purpose of seizure onset localization and functional brain mapping. First, using multiregional invasive neurophysiology, we will outline the individual and complementary roles these brain regions play in safety assessment and outcomes response as subjects engage in a spatial avoidance of threat task. This will be done at single neuron, population activity, and network oscillation levels. Next, transient disruption of key nodes of this network, using direct electrical brain stimulation, will provide a mechanistic understanding and causal relationships across these brain regions. This scientific approach—linking single neuron activity to behavior through large scale brain oscillations will set the stage for outlining the fundamental circuit level organization of anxiety in humans.

NIH Research Projects · FY 2026 · 2025-02

PROJECT SUMMARY Excessive alcohol use is a pervasive condition impacting millions of people. To alleviate this significant burden, previous research has aimed to define neural mechanisms underpinning risky drinking. A large body of literature has revealed altered brain responses in individuals with problematic alcohol use while they are presented with alcohol-related information. However, how individuals disengage from such alcohol exposure has received relatively little empirical attention. Notably, persistent processing after tasks is a hallmark of maladaptive thought processes like craving and can promote stronger memory for these experiences, which in turn may drive later motivation to drink. For instance, persisting in processing positive drinking experiences may promote alcohol craving and positive alcohol memories, thus motivating future decisions to consume alcohol. Together, this work suggests that persistent processing may play an etiological role in risky alcohol consumption and present a novel intervention target. Using a combination of secondary data analysis on functional neuroimaging (fMRI) data collected from individuals with alcohol use disorder (AUD), light and risky drinkers as well as a novel behavioral task, I will rigorously identify neural and cognitive markers of persistent processing and investigate their potential contributions to problematic alcohol use. This proposal builds on my prior experience in computational neuroimaging techniques and behavioral task paradigms. Additionally, this proposal will provide me with personalized trainings in advanced statistical methods, neurobiology of alcohol use, persistent or perseverative thinking in psychopathology, and experimental task designs from leading experts. In Aim 1, I will leverage an advanced brain dynamic approach to broadly examine whether individuals with AUD demonstrate an inability to disengage from salient information and express persistent processing at the neural level. In Aim 2, I will elucidate the behavioral consequences of neural persistent processing. I will focus specifically on persistent processing of alcohol-related information and examine whether persistent processing at the neural level in light and risky drinkers influence memory of alcohol events and subsequent real-life drinking. Aims 1 and 2 infer persistent processing at the neural level. To supplement this neural marker, I will introduce a novel behavioral task combining naturalistic stimuli and thought sampling (Aim 3) to develop and validate a cognitive marker of persistent processing and study whether it predicts alcohol-related memory and drinking behaviors. The successful completion of this proposal will address critical gaps in my training and prepare me well for a career in the alcohol field. By examining the ability to disengage from alcohol-related information, this proposal has the potential to refine our understandings of how risky drinking occurs, present actionable intervention targets, and mitigate risks for problematic alcohol consumption.

NIH Research Projects · FY 2026 · 2025-01

Project Summary / Abstract We live in a multisensory world. Our brains must integrate relevant information across modalities to understand our environment and survive. How the brain combines and processes these multiple streams of information within cells and across circuits remains elusive. A major barrier to understanding how sensory information alters neural code and signal processing is the lack of experimental models that allow precise control of multiple sensory modalities and the manipulation of their cellular and circuit mechanisms. To bridge this gap, I will explore how odor and temperature information intersect in the brain of the fruit fly, Drosophila melanogaster. This project aims to uncover how dedicated thermosensory processing compensates for or collaborates with temperature-induced changes in neuronal functions to help understand how sensory information is transformed in the early stages of sensory processing. Specifically, the goals of this project are to establish how temperature modifies olfactory processing at the cellular, synaptic, and circuit level. I will use extracellular recordings to examine the biophysical effects of temperature on sensory transduction and spike generation in olfactory receptor neurons (ORNs). I will use intracellular whole-cell patch-clamp recordings from projection neurons (PNs) to characterize the impact of temperature on cellular and synaptic properties, revealing temperature’s influence on the transformation of information between ORNs and PNs. Finally, I will combine PN recordings with pharmacological and genetic manipulations of local inhibition to elucidate how active temperature encoding in the thermosensory system regulates the transformation of odor information across the first layer of sensory processing. This project will provide foundational knowledge about the cellular, synaptic, and circuit mechanisms transforming of raw sensory stimuli under dual sensory input. This proposal furthers my knowledge and skill set in sensory neuroscience. It provides me the opportunity to develop new expertise, including in vivo patch-clamp and single sensillum extracellular recordings, while expanding my grasp of genetics and temperature manipulation. Further, this proposal firmly supports the NIDCD’s stated priority “to enhance our understanding of how individuals gather information about their environment”.

NIH Research Projects · FY 2026 · 2025-01

ABSTRACT Adverse social determinants of health constitute major barriers to type 1 diabetes (T1D) management and drive disparities in diabetes outcomes. Young adults with T1D tend to have the worst glycemic control levels of all age groups, with Black and Hispanic young adults experiencing the highest complication rates and mortality. While social risk factor screening-and-referral services could improve health outcomes, convincing data on their effectiveness are largely lacking. Results from the Accountable Health Communities Model found this intervention ineffective with respect to addressing social needs. As opposed to classifying people by social risk factors and assisting them in accessing generic services, a personalized intervention, fully responsive to the complex, problematic situation of each person may be required, especially to address the unique needs of young patients with T1D. However, such an approach remains untested against care as usual. To fill this knowledge and care gap, we propose a pilot randomized trial to test the feasibility and preliminary efficacy of T1CARE: Comprehensive Assessment Responsiveness and Engagement. T1CARE includes in-depth assessment of social and clinical needs and a hybrid community health worker-patient navigator approach to address social and clinical needs of young patients with T1D. We have partnered with a community-based organization (Project Access-New Haven), which has an established record of removing barriers to clinical care and addressing social needs for underserved populations. Our specific aims are: Aim 1: Determine the feasibility of implementing screening for adverse social determinants of health (SDOH) for young patients with T1D and randomly linking patients who report ≥1 adverse SDOH to either T1CARE or usual care: (1.1): Characterize what is the usual care these patients receive during the experimentation period to determine what aspects of the intervention are present usually, including “dose” and intensity. (1.2): Evaluate the feasibility of recruitment and retention of trial participants, rates of SDOH screening and identification of adverse SDOH, acceptability of the intervention, completion of study procedures, and collection of clinical outcome data. (1.3): Assess the extent to which screening for SDOH and T1CARE can be integrated into clinical practice routines using Normalization Process Theory and its Toolkit. Aim 2: Estimate preliminary signals of the efficacy of T1CARE vs. usual care for the following outcomes at 6 months post intervention: (2.1) resolution of adverse SDOH; (2.2) patient-reported outcomes, including diabetes distress (measured using the Diabetes Distress Scale), illness intrusiveness (Illness Intrusiveness Scale), and global quality of life (evaluated using a 1-item analogue scale); and (2.3) clinical outcomes, specifically changes in HbA1c levels. This study will establish a robust partnership model with Project Access-New Haven, and estimate feasibility, normalization, and efficacy of an innovative approach, T1CARE, for testing in future larger hybrid effectiveness-implementation trials.

NIH Research Projects · FY 2026 · 2025-01

PROJECT SUMMARY Telomeres are TTAGGG repetitive DNA-protein complexes at chromosome ends required to solve three significant problems critical for the maintenance of genome stability. The “end replication problem” is due to the inability of DNA polymerase to completely copy the lagging strand of chromosome ends, necessitating telomerase to synthesize the 3’ G-strand. The CTC1-STN1-TEN1 complex recruits DNA primase-polymerase alpha to promote fill-in synthesis of the 5’ C-strand. A major gap in our knowledge is how G- and C-strand synthesis are coordinated to maintain telomere length. We have previously shown that the POT1 protein participates in both G- and C-strand synthesis at mouse telomeres. To determine whether human POT1 coordinates telomere length maintenance, we will use state-of-the-art biochemical, structural, cellular and genetic approaches to explore the possibility that a phosoho de-phopho switch occurs on hPOT1 to coordinate the recruitment of telomerase and CST to telomeres to maintain telomere length. The telomere “end protection problem” is due to the fact that telomere ends resemble DNA double-strand breaks, which must be protected by the shelterin complex to prevent the activation of a DNA damage response. We have previously shown that shelterin components TRF2-RAP1 represses telomere homology directed repair (HDR). To determine mechanistically how TRF2-RAP1 protects telomeres from engaging in HDR, we conducted genome-wide CRISPR screens and IP-mass spectrometry. We identified BLM and ADAR1p110 as potential candidates proteins involved in telomere HDR. Using purified proteins, we developed a novel telomere D-loop strand invasion assay and a telomere D-loop unwinding assay to address how BLM participates in telomere HDR. We also developed a telomere R-loop assay to determine mechanistically how telomere R-loops are resolved by ADAR1p110. The “end replication problem” stems from the observation that telomeres are difficult to replicate regions in the genome. To address the gap in knowledge of what novel proteins are involved in telomere replication, we used BioID to identify Claspin as a TRF2 interacting protein involved in DNA replication. We will determine mechanistically how Claspin resolves telomere replication stress, using a telomere single-molecule analysis of replicated DNA to measure the speed of telomere replication fork progression. Using this system, we will also test whether TRF2 binding proteins identified in our CRISPR screens are required for telomere replication. We invented an innovative technique called COMET-FISH that combines strand-specific chromosome-orientation (CO)-FISH with immuno-metaphase-FISH, to visualize C- or G-strand-specific localization of Claspin to telomeres during replication stress. Our proposed research will yield new mechanistic insights into how telomeres are protected, maintained and replicated, with broad future implications for understanding the treatment of human diseases including cancer and aging.

NIH Research Projects · FY 2026 · 2025-01

Project Summary/Abstract The formation and maintenance of membranes is essential for the health of the nervous system. Consistent with the unique sensitivity of the nervous system to lipid dynamics, each of the four mammalian paralogues in the VPS13 family of proteins, which were recently proposed to function as bridges that connect lipid synthesis in the ER to recipient membranes for the nonvesicular transfer of lipids (Leonzino et al., 2021), are associated with neurodegenerative and neurodevelopmental disease. Of the four VPS13 paralogues, VPS13D is the only one essential for life. While full loss of function is not compatible even with cellular life, partial loss of function of VPS13D leads to neurodegenerative diseases, such as spastic ataxia, which motivates this proposal to investigate mechanisms of VPS13D-dependent neurodegenerative disease. Previous studies showed that exogenous, and thus overexpressed, VPS13D resides at the Golgi apparatus and also at contacts between the ER, via VAP, and both mitochondria and peroxisomes via an interaction with Miro (Guillen-Samander et al., 2021). This proposal seeks to understand VPS13D’s still-unknown role at the Golgi complex, in spite of its prominent localization at this organelle using cellular models. The first aim is to elucidate the precise localization of VPS13D within the Golgi complex, where preliminary data suggests an association of overexpressed VPS13D with the trans Golgi/TGN. I established an endogenously tagged VPS13D^V5 line that I find localizes at the Golgi apparatus, wherein I propose to investigate its precise localization using nocodazole ministacks, superresolution, and immune-electron microscopy. The second aim focuses on how VPS13D is recruited to the Golgi complex. Proteomics screens based on proximity labeling will be used to complement co-immunoprecipitation of endoVPS13D^V5 towards the identification of binding partners on membranes of this organelle. In preliminary proximity labelling mass spectrometry experiments, I identified candidates at the TGN, which I propose methods to test. In the final aim, my preliminary data show that VPS13D depletion leads to a selective dispersion of TGN46 and impaired trafficking of its associated cargo, Lysozyme C, implicating VPS13D, and thus its putative lipid transport function, in the maintenance of the TGN. Furthermore, I find that VPS13D loss leads to decreased ability of membranes to form ordered raft- like domains, which are critical for sorting at the TGN. Proposed experiments include investigating the effect of VPS13D loss on purified Golgi with lipidomics, and how my findings from cell lines translate to conditional knockout mice and cells derived from them.

NIH Research Projects · FY 2026 · 2025-01

PROJECT SUMMARY – CORE A: ADMINISTRATIVE Thoracic aortopathy – aneurysms, dissection, and rupture – is increasingly responsible for significant morbidity and mortality in Americans of all ages, independent of sex. Despite many seminal discoveries since 1991, when the genetic basis of Marfan syndrome was uncovered, much remains unknown and therapeutic strategies remain limited. We submit that significant new understanding and new actionable therapeutic targets will stem from coordinated and comprehensive testing of the compelling overall hypothesis that aberrant cell-extracellular matrix interactions that compromise tissue homeostasis are primary drivers of thoracic aortic disease. Here, we bring together 5 leading laboratories to address 5 critical contributors to compromised homeostasis, or its treatment, in the thoracic aorta; importantly, these labs have made significant prior contributions to understanding thoracic aortopathy and have a track-record of successful collaborations as evidenced by papers and grants. Core A: Administrative will nonetheless work to seamlessly coordinate all activities – those with the NIH, those across institutions (Yale and UT-Health), those amongst the 5 laboratories, those with the External and Internal Advisory Boards, those with the trainees, and those with the PPG-specific and university-sponsored cores. We propose, in this Core, what we feel will be a highly effective administrative structure (with a consensus-driven Executive Committee providing oversight) and a similarly effective Yearly Calendar with associated monthly, semi-annual, and annual activities to promote interactions, emphasizing both the science and opportunities for training amongst our overall team. Importantly, Core A will ensure the use of consistent and authenticated methods to collect, analyze, synthesize, and share complementary data sets, addressing 5 of the key factors that contribute to thoracic aortopathy. Core A will also ensure timely presentation and publication of results and will ensure appropriate documentation, reporting, data management, and resource sharing, including data availability. Finally, Core A will ensure compliance with all federal and state requirements. We expect this Administrative core to ensure that our highly integrated approach will yield unique insights into thoracic aortopathy and its potential treatment

NSF Awards · FY 2025 · 2025-01

This grant supports student participation in the 4th Symposium on Computer Science and Law (CSLaw), sponsored by the Association for Computing Machinery (ACM), to be held March 25-27, 2025, in Munich, German. The event brings together computer scientists and law scholars and policymakers to discuss the latest research, developments, and trends in the developing intersection of Computer Science and Law. Students will attend invited talks, technical paper presentations, poster sessions, and panel discussions. The topics discussed include cybersecurity and privacy, and more generally, the legal aspects of computer and software technology in all aspects of society, which has become especially critical as societal functions and capabilities are increasingly relegated automation by computers and software. The symposium allows computer scientists and legal scholars to work together to solve problems that require their combined expertise. Computer science and law have long existed in parallel, with occasional overlaps in areas such as export controls. However, computer technologies are now performing functions for which people used to be responsible, and now that computers are taking over these functions, new legal frameworks are needed to deal with the new roles of automated systems, applications and agents. Legal and regulatory aspects need to be implemented correctly to meet new types of requirements in order for users (citizens) to be served effectively. 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 · 2025-01

PROJECT SUMMARY Type III secretion systems (T3SSs) are widely distributed among important gram-negative pathogenic bacteria. These complex specialized machines have evolved to transfer multiple bacterial-effector proteins into host eukaryotic cells to modulate a variety of cellular functions and they are essential for pathogenicity. The central component of T3SSs is a multi-protein structure known as the “injectisome”. This structure is composed of the envelope embedded needle complex (NC), and a cytoplasmic sorting platform (SP) that selects the substrates and energizes the secretion process. This research project focuses on the structural and functional characterization of the sorting platform. Through a multidisciplinary approach involving bacterial genetics, biochemistry, super-resolution microscopy, cryo-EM and cryo-ET, we intend to investigate the sorting platform structure and function, and in particular, the mechanism by which client proteins are selected and sorted. These studies will provide insight into poorly understood aspects of T3SS function. Importantly, given the high degree of conservation of this machine in many important pathogenic bacteria, knowledge gained with these studies will contribute to the understanding of T3SS in general, and therefore, generate knowledge that could be leveraged in fighting bacterial pathogenesis.

NIH Research Projects · FY 2026 · 2025-01

ABSTRACT There is an urgent need to understand the health impacts of alternative air quality policies. Such policies can impact various source sectors (e.g., transportation), fuel type and chemical composition of fine particulate matter (PM2.5). Detailed characterization of the health consequences of exposure to PM2.5 sources and chemical composition will provide timely guidance to develop the most cost effective interventions for air pollution mitigation. The National Academy of Sciences, Health Effects Institute, US EPA, and Global Burden of Disease have all identified understanding health outcomes of air pollution sources as a critical research need. Prior studies suffer from the inability to identify relative contributions of sources and fuel types to pollutant mixtures, quantify uncertainties, or apply rigorous cross-validation, often due to lack of appropriate data and approaches. Most past analyses have inherently assumed that all PM2.5 mass is equally toxic, regardless of source or composition; in fact, PM2.5 is the only air pollutant regulated without regard to chemical form. To address this knowledge gap, we will conduct a nationwide analysis to determine which types of PM2.5 (e.g., source sectors, fuel types) are most associated with cardiovascular and respiratory hospital admissions. We will employ 2 large, well-characterized datasets (Medicare: >60 million participants ≥65 years, and Medicare Current Beneficiary Survey: >200,000 participants with detailed data on >100 individual-level variables). Using multiple approaches, including causal inference, we will test the hypothesis that health impacts of PM2.5 vary by pollution source and/or combustion type for cardiovascular and respiratory hospital admissions. We will estimate and validate PM2.5 exposure by chemical components (e.g., sulfate, organics, black carbon), source sectors, and fuel types for the continental US for 2000-2023 at monthly, ZIP code-level resolution by harmonizing data from satellites, air quality models, emissions inventories, and monitors (Aim 1). We will apply well-established approaches, modified for our analysis, to estimate exposure-response curves (ERCs), with causal interpretation, for PM2.5 and components (Aim 2). We will ensure computational scalability and account for uncertainty in estimated exposures, unmeasured confounding bias, and co-pollutants. We will estimate ERCs for cause-specific (cardiovascular, neurological, asthma, other respiratory) hospital admissions by PM2.5 type (Aim 3). This work will help air quality and health policymakers prioritize mitigation efforts to maximize health benefits. Findings will inform assessments of health effects of PM2.5 exposure. We will disseminate new exposure data, causal inference applications, and statistical code.

NIH Research Projects · FY 2026 · 2025-01

Summary - Noninvasive imaging of disease progression is a critical component in the management and treatment plan of brain tumors. To evaluate tumor growth and treatment response anatomical magnetic resonance imaging (MRI) scans are acquired on regular intervals to detect changes in lesion size. However, the need to acquire multiple MRI scans over several months to be certain about tumor growth can correspond to a waste of time, particularly for patients with glioblastoma (GBM), the most aggressive and most common primary brain tumor, who face an overall survival of less than 2 years. An imaging method that can detect active tumor much faster would be a significant improvement for patients and help clinicians make treatment decisions. In tumors outside of the brain metabolic imaging with 18F-fluoro-deoxy-glucose positron emission tomography (18FDG-PET) can quickly characterize disease progression by detecting increased glucose uptake. However, 18FDG-PET is rarely used for brain tumor imaging because healthy brain also takes up high amounts of glucose which can negate image contrast and make it problematic to distinguish tumor from normal brain. As an alternative we propose to extend our work on the MR-based deuterium metabolic imaging (DMI) combined with simple, oral intake of non-radioactive deuterated glucose, to characterize brain tumors based on the altered metabolic fate of glucose. While both healthy brain and tumors can have high glucose uptake, aggressive tumors differ by metabolically converting a high fraction of glucose to lactate, a phenomenon known as the Warburg effect. DMI has an advantage over 18FDG-PET because it can directly detect various metabolites, including lactate, and generate multiple types of metabolism-based image contrast from a single scan. Preliminary data show high image contrast based on glucose metabolism in GBM at diagnosis and at recurrence after treatment, detected with DMI. Furthermore, DMI is highly robust, safe, and has already been implemented on 3T and 7T clinical MRI scanners. Concerns about long additional scan time have been mitigated by acquiring DMI and MRI simultaneously. Because of these features and the ease of use of the method, glucose DMI can become the robust metabolic imaging method for brain tumors that so far has been missing. The primary significance of this proposal is fulfilling the need for key studies required before DMI can be translated from a promising research-only method to where it can be used in clinical imaging trials to fully establish its diagnostic and prognostic utility. In Aim 1 we will validate the specificity of DMI for detecting active tumor by comparison with histopathology of excised tumor tissue from patients with GBM. In Aim 2 we will perform test-retest studies in patients with GBM to establish the repeatability of glucose DMI. Aim 3 is focused on the use of DMI to detect true disease progression in a clinical setting. These aims will potentially have a high impact on clinical research and could shift disease management of GBM by providing a robust and specific method for imaging tumor progression that can be integrated -without time penalty- in standard MRI protocols.

NIH Research Projects · FY 2026 · 2025-01

Type 1 diabetes (T1D) is an autoimmune disease with a metabolic outcome. A number of agents can change the course of the disease when given to patients with new onset (Stage 3 T1D) and teplizumab, the anti-CD3 mAb has been approved to delay the clinical diagnosis in patients at risk, prior to the clinical diagnosis. Two clear unmet needs have emerged from the clinical trial experience. First, the successful immunologic treatments do not last indefinitely and do not restore normal β cell function. Second not all patients respond to treatments. In this proposal, we plan to study the features of β cells between clinical cohorts that show different rates of progression to clinical T1D and in response to immune therapy (i.e. teplizumab) in the successful TN10 prevention trial. New York Stem Cell Foundation (NYSCF) Research Institute has developed robust, high- throughput robotic cell culture systems that have successfully been applied to induced pluripotent stem cells (iPSCs) reprogramming and differentiation into pancreatic organoids. Importantly, these procedures minimize technical variation, allowing the detection of complex, subtle disease phenotypes and responses to perturbation. Our overarching hypothesis is that there are β cell intrinsic features that determine the effects of immune mediators, progression of T1D and responses to therapies. Our overall goal is to identify the β cell intrinsic features that determine progression of T1D, their interactions with immune cells, and the responses to therapies. In the UG3, Phase 1 part of this program, we will characterize and analyze pancreatic organoids from 16 existing iPSCs (10 from patients with T1D and 6 healthy controls) and reprogram iPSCs and develop pancreatic organoids from 20 additional patients. We will also prepare autologous islet autoantigen reactive CD8+ T cell lines from the iPSC donors that will be used in responses with the organoids. We will validate our models for detection of β cell killing in vitro and in vivo and obtain preliminary data on the differences between the cohorts and with primary islets which we can determine our statistical power for studies in Phase 2. In the Phase 2 UH3 program, we will analyze and compare the responses of the islet organoids between cohorts and to primary islets including a detailed analysis of metabolic function. We will determine the changes in the islet organoids when they are exposed to inflammatory mediators and specifically analyze protein modifications and development of neoantigens that may be targeted by antigen reactive CD8+ T cells. We will test whether deletion of TET2 in the islet organoids, that we have shown is required for inflammatory responses of β cells, will prevent immune mediated killing of the organoids. Finally, we will use the NYSCF automated platform to screen molecules for their ability to prevent organoid damage and death from inflammatory mediators. Understanding mechanisms of β cell failures in this context will direct therapies to prolong efficacy of immune treatments to arrest autoimmunity, and permit restoration of metabolic function for individual patients.

NIH Research Projects · FY 2026 · 2025-01

PROJECT SUMMARY The arginine methyltransferase PRMT5 has been identified as a potential target in cancers with loss of the metabolic enzyme MTAP, which occurs in ~15% of all malignancies including several (such as glioblastoma, pancreatic ductal adenocarcinoma, and esophageal cancer) that are refractory to standard therapies. MTAP loss partially impairs PRMT5 activity and sensitizes MTAP-deleted cancer cells to pharmacologic PRMT5 inhibition. As a result, the development of PRMT5 pathway inhibitors has accelerated, including two PRMT5 inhibitors recently reported to have clinical activity in patients with various MTAP-deleted solid tumor malignancies. While PRMT5 is a well-established regulator of multiple cellular pathways including transcription, RNA processing, and DNA repair, how it regulates these pathways and which processes are critical for maintaining cell viability is unclear. To address this knowledge gap, a genome-scale CRISPR activation platform has been leveraged to identify genes that modulate sensitivity to PRMT5 pathway inhibition in MTAP-deleted cancer cell models. Among the top-scoring gene products that reduce sensitivity of MTAP-deleted cells to PRMT5 pathway inhibition are previously unrecognized regulators of DNA damage response (DDR) and potential new PRMT5 substrates. The overall objective of this proposal is to define key components of the PRMT5 axis that impair cell viability upon PRMT5 inhibition and to define pathways that can restore viability. The central hypothesis is that the top- scoring gene products that reduce sensitivity to PRMT5 pathway inhibition represent previously unrecognized regulators of DDR, activate DDR pathways that protect cells from PRMT5 pathway inhibition, and may represent core PRMT5 pathway components. This hypothesis will be tested by pursuing 2 specific aims: 1) Determine how top-scoring proteins mediate responses to DNA damage and 2) Define mechanistic connections between top- scoring proteins and the PRMT5 pathway. The project will examine the impact of these gene products on generation of double-strand DNA breaks, R-loop formation, and homologous recombination (HR) pathways. Proteomic, biochemical, and genetic approaches will be leveraged to gain mechanistic insights about how these proteins intersect with the PRMT5 axis. The proposed work is significant because it will define genes and pathways capable of restoring viability of MTAP-deleted cells exposed to PRMT5 pathway inhibition and will inform a molecular and functional annotation of downstream effects of PRMT5 and compensatory pathways. The approach is innovative and distinct from prior studies because it builds on functional genomic insights to focus squarely on the therapeutically relevant functional roles of PRMT5. Successful completion of these aims will identify processes dysregulated by PRMT5 inhibition that impair cell viability, delineate molecular mediators of these processes, and provide fundamental insights about mechanisms of DDR regulation. The work may also identify additional therapeutic targets in the PRMT5 axis.

NSF Awards · FY 2025 · 2025-01

Large Language Model (LLM) has become an emerging tool for complex reasoning tasks in data modalities such as image and video, by efficiently harnessing rich unlabeled data. Yet, few researcher have focused on time series data, which is widely used in critical applications with limited amount of annotation. Time series data poses three key unresolved challenges: 1) there is a lack of high-quality text information for help with identification that aligns with time series data; 2) deep learning models to reason with both time series and text data are under-researched; and 3) novel explainable artificial intelligence (AI) tools to ensure the trustworthiness of such models and give users confidence in model predictions are lacking. This project aims to address these challenges and develop a time series text-based cross-modality Question Answering (QA) system. The project will also promote close collaboration between UTRGV and Yale University to encourage Hispanic undergraduate students to pursue higher education and build UTRGV's capacity to conduct research on advanced AI topics including LLM, time series, foundational model, and trustworthy AI at UTRGV. This project aims to develop a time series text-based QA system that can accelerate a wide range of research by providing expert-level explanations. The technical aims of this research project can be divided into three key components: 1) Develop an automated high-quality time series annotation pipeline by designing a multi-view prompt-based QA generation framework to build training data and labels. 2) Develop a novel text and time series cross-modality pre-trained model to better enable knowledge extraction from time series data and fuse information across two modalities. 3) Enhance transparency and interpretability of the built model by developing a combination of time series-oriented explanation and text-oriented explanation. Collaborating with Idaho National Lab, the system will be evaluated by analyzing and forecasting extreme weather that can cause energy infrastructure damage, using the associated time series and text information. 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 · 2025-01

The list price of insulin has increased dramatically over the past two decades, hindering access to this essential medication, contributing to insulin rationing and ultimately worsening health outcomes for people living with type 1 (T1D) and type 2 diabetes (T2D). To address insulin affordability for Medicare beneficiaries, the Inflation Reduction Act (IRA) capped out-of-pocket (OOP) payments for one month’s supply of insulin to $35 for all Medicare beneficiaries enrolled in Medicare Part D plans effective 2023. Understanding the impact of IRA provisions on patients' OOP payments for insulin, diabetes management, and health outcomes in diabetes care is crucial to advancing effective solutions to barriers in diabetes care. Accordingly, we propose to evaluate the real-world implications of the IRA by leveraging rigorous quasi-experimental methods applied to data from OptumLabs Data Warehouse linked with Medicare fee-for-service (100% sample) claims from 2021-2022 (pre-IRA) and 2023-2024 (post-IRA). These data include both utilization and clinical information for beneficiaries in traditional Medicare and Medicare Advantage plans across the U.S., as well as those who are commercially insured (for comparison), with characteristics of each prescription plan (benefit design, including Senior Savings Model participation prior to IRA), OOP payments for each medication, and clinical data (diagnoses, procedures, clinical encounters, prescription medication fills, and even laboratory data such as hemoglobin A1c levels). Using this rich and comprehensive nationwide data asset, we will address the following aims: AIM 1: To examine the association between IRA implementation and patient OOP payments for insulin by comparing pre- and post-IRA trends among Medicare beneficiaries (separating those who participated in the Senior Savings Model vs. those who did not), then comparing them to corresponding trends among commercially insured patients 60-64 years. AIM 2: To examine the association of IRA implementation and clinical outcomes in the same patient subgroups, including rates of insulin use, type(s) of insulin used, insulin adherence, utilization of non-insulin guideline-recommended T2D diabetes medications (e.g., SGLT-2 inhibitors and GLP-1 receptor agonists for those with T2D), hemoglobin A1c levels, and rates of hospitalizations and emergency department visits for hypoglycemic and hyperglycemic emergencies. AIM 3: To examine whether IRA implementation is associated with changes in outcomes from Aims 1 and 2 across demographic, socioeconomic, and clinical patient subgroups. By evaluating the effectiveness of this landmark policy, we aim to inform future healthcare policy decisions about prescription drug affordability and contribute to improving the lives of individuals living with T1D and T2D in the United States.

NIH Research Projects · FY 2026 · 2025-01

Project Summary We propose to address the causal link between Asn and sex-specific differences in colorectal cancer (CRC) tumor growth. We have compelling preliminary data which shows sex-specific metabolism in CRC, whereby tumors from female patients have a nutrient deplete metabolic phenotype characterized by increased asparagine (Asn) production, and a positive association between elevated Asn and poorer prognosis for females only. We show that asparagine synthetase (ASNS), the enzyme that catalyzes Asn production within the tumor, is positively associated with female patient prognosis and specifically for stage III-IV patients. Knockout of ASNS in CRC cells and xenograft in mice results in smaller tumor volume for female mice, and longer tumor-specific survival. We have identified a potential mechanism for this sex-related difference through an estradiol-mediated stress response, which activates G-protein coupled estrogen receptor 1 (GPER1) signal transduction and ASNS. ASNS and GPER1 are part of a coordinated response to a nutrient stressed tumor microenvironment that increase cell survival and tumor growth, i.e. at advanced stages of cancer growth. Even though the canonical relationships that link GPER1 and ASNS are well established, the association between GPER1 and ASNS and their effects on cancer growth are novel. Moreover, GPER1 associates with poorer survival in female stage III- IV patients, and not males, supporting the sex-specificity of GPER1 in advanced CRCs. In addition to intracellular production of Asn, Asn can be taken up by the tumor from exogenous sources (i.e., diet, microbiome). We show that Asn supplementation to ASNS knockout CRC cells rescues depleted growth, and analysis of cecal contents from 100 germ-free mice inoculated with distinct microbiota show that they can metabolize Asn, thus could contribute to Asn supply in the colon for tumor growth. Therefore, we hypothesize that: intracellular (GPER, ASNS) and extracellular (microbiota and diet) regulation of Asn contribute to CRC growth in a sex- specific manner. In Aim 1 of this proposal, we will use samples from two large clinical cohorts to determine whether ASNS and GPER1 act as sex-specific prognostic biomarkers in male and female patients with advanced stage CRC, we will also examine stool from CRC patients to identify microbiota that are Asn consumers or producers and determine how treatment for CRC modulates Asn-metabolizing microbiota. In Aim 2 we will determine how GPER1 and ASNS promote CRC primary tumor growth and metastasis in colonoscopy-guided orthotopic mouse models in a sex-specific manner. In Aim 3, we will determine the impact of dietary Asn on sex- specific differences in CRC growth and use gnotobiotic CRC mouse models inoculated with microbiota that express ASNS, to determine whether microbial production of Asn directly contributes to cancer growth. In this proposal, we have a high level of innovation, using colonoscopy-guided orthotopic models, assessments of sex- differences, and translation using large clinical cohorts. We anticipate that we will be able to translate such knowledge to target this patient subgroup and improve clinical outcomes.

NIH Research Projects · FY 2026 · 2025-01

PROJECT SUMMARY Parkinson's Disease (PD) is characterized by the progressive loss of dopaminergic (DA) neurons within the substantia nigra (SN), resulting in debilitating motor impairments. To develop therapeutic interventions that can be administered prior to extensive DA neuron loss, early pathomechanisms at the DA synapse must be explored. Central to PD pathology is the dysregulation of dopamine neurotransmission, which is in part mediated by the dopamine transporter (DAT). Interestingly, DAT surface levels are controlled by the endolysosomal system, which includes several proteins mutated in familial and sporadic PD. For example, loss-of-function (LOF) mutations in the clathrin uncoating chaperone, auxilin, cause early-onset PD, whereas the D620N mutation in VPS35, a retromer protein, causes familial PD that is phenotypically similar to sporadic PD. My lab's study of auxilin knockout (KO) mice suggests that disruptions in DAT function and trafficking precede DA neurodegeneration, which is further supported by changes in DAT expression and function in VPS35 D620N knockin (KI) mice. Determining whether DAT dynamics are impaired across genetic etiologies of PD will be pivotal to the field's understanding of early PD pathology and DA vulnerability. This study will test the hypothesis that DAT recycling and trafficking defects occur in forms of PD involving endolysosomal mutations by using cutting-edge live and super-resolution imaging techniques and in vitro PD models. To measure DAT endo- and exocytosis with high temporal resolution in Aim 1, I developed a DAT-pHluorin that I will express in primary SN DA neurons from auxilin KO and VPS35 D620N KI mice. To account for species differences, I will also validate my results in induced pluripotent stem cell (iPSC)-derived DA neurons from PD patients with auxilin LOF and VPS35 D620N mutation. I hypothesize that auxilin PD models will display delayed DAT vesicle reacidification after endocytosis, and both auxilin and VPS35 PD models will exhibit reduced magnitudes and rates of DAT reinsertion following endocytosis, signifying impaired DAT recycling, due to distinct mechanisms. To further explore these mechanisms, Aim 2 will utilize DAT-PRIME imaging, which fluorescently labels surface DAT in live cells, to track DAT post-endocytic fate in the aforementioned models. Using stimulated emission depletion microscopy paired with immunofluorescence staining, I will assess the colocalization of DAT with various endolysosomal markers to understand the role of auxilin and VPS35 in controlling post-endocytic fate of DAT. I predict that loss of clathrin uncoating by auxilin will stall DAT trafficking at the early endosome stage, leading to reduced DAT trafficking to recycling endosomes and retromer compartments. On the other hand, VPS35 D620N neurons are likely to show enhanced lysosomal trafficking of DAT due to retromer LOF. This study will shed light on mechanisms underlying early DA dysfunction in PD and provides me with the opportunity to further my scientific training through mentorship by experts in synaptic biology, neuronal cell culture, and microscopy.

NIH Research Projects · FY 2026 · 2025-01

Abstract This project will define mechanisms that coordinate late endosome and lysosome functions across the extreme size and polarity of neurons. Although multiple proteins have been implicated in this process, there is a significant lack of understanding concerning how the network of proteins that control of lysosome function is integrated in support of the unique demands of neurons. This is a bottleneck to understanding the mechanisms whereby variants in genes encoding lysosome proteins contribute to multiple neurodegenerative diseases. In particular, this is a barrier to understanding the relevance of abnormal lysosome accumulations that occur within neurons that contact amyloid plaques in Alzheimer’s disease as it results in a lack of tools to modulate neuronal lysosomes for scientific and therapeutic purposes. Our proposed research will address these problems by building on extensive preliminary data related to the JIP3 and JIP4 proteins (encoded by the MAPK8IP3 and SPAG9 genes respectively). JIP3 and JIP4 control multiple aspects of lysosome function by acting as scaffolds that link lysosomes to motors and signaling proteins in order to regulate their subcellular distribution as well as the budding of vesicles from them. Our preliminary data indicates that there are major differences in the regulatory mechanisms that control the subcellular activities of JIP3 and JIP4 in neurons. We now seek to determine the basis for the compartmentalized differential activation of JIP3 and JIP4 and to use new insights into JIP3 and JIP4 regulation as tools to test the lysosomal contributions to Alzheimer’s disease pathogenesis. To this end, we will use experimentally tractable human cell lines to define fundamental relationships between JIP3, JIP4 and their regulatory proteins along with assays in human iPSCs and neurons derived from them and genetically modified mice to establish the physiological relevance of our discoveries. Through this research we aim to achieve the following goals: 1. Define pathways that differentially regulate JIP3 and JIP4-dependent control of lysosome subcellular distribution. 2. Determine mechanisms whereby JIP3 and JIP4 control signaling and vesicle budding events that control the protein composition of lysosome membranes. 3. Establish the in vivo impacts of JIP3 and JIP4-dependent processes on neuronal lysosomes with a focus on Alzheimer’s disease related proteins.

NIH Research Projects · FY 2026 · 2025-01

Project Summary Catalysis is an enabling technology for selective synthesis in organic chemistry. In the majority of transformations, catalysts are based on distinct homogeneous, heterogeneous, or enzymatic platforms, enabling high chemo- and site-selectivity for a particular transformation. However, when substrates become more complex, including for the functionalization of natural products, traditional catalytic methods can become incompatible with the functional group complexity of these molecules. Therefore, there is motivation to develop site-selective catalysts that are compatible with the molecules at the frontier of human health efforts. One approach to achieving enzyme-like selectivity is the use of synthetic peptide catalysts. Similar to enzymes, synthetic peptides have chirality, can participate in a variety of covalent or non-covalent interactions, and can also have a secondary structure to create an active site for catalysis. To date, peptide catalysts have been developed for organo-catalyzed transformations but are in the early stages of potential application in transition metal catalyzed reactions. This proposal will develop peptide-containing transition metal catalysts for the site- selective transformations of complex targets. In particular, due to the rapid development of antibiotic resistance, the late-stage functionalization of antibiotics is of particular relevance to human health efforts. To begin our efforts, the potent, structurally complex antibiotic thiostrepton has been selected for this purpose. Thiostrepton is not currently used in the clinic due to poor pharmacokinetic properties; therefore, modification of thiostrepton using these catalysis offers the exciting potential to develop new, more potent antibiotics. We will specifically develop site- selective hydrogenation and additional transition metal catalyzed reactions for the synthesis of derivatives and development of structure-activity relationships that could be used to design new thiopeptide antibiotics. Towards these goals, the following aims have been developed: 1) Identification of Transition Metal Catalysts for the Enantioselective Functionalization of Thiostrepton 2) Development of Peptide-Containing Catalysts for Site-Selective Hydrogenation 3) Expansion of Methods for Site-Selective Modification of Thiostrepton With these Aims, design principles for site-selective catalysis will be uncovered, significantly contributing to known methods for the synthesis of molecules with potentially improved bioactivity. 1