Scripps Research Institute, The

NIH Research Projects · FY 2026 · 2026-06

PROJECT SUMMARY A functional cure for HIV that maintains lifelong suppression of viremia without antiretroviral therapy (ART) remains an urgent unmet need. Broadly neutralizing antibodies (bnAbs) can control HIV, but vaccines have failed to induce them because they require unusual structural features that are not readily generated by natural B cell maturation. Genome engineering now allows mature bnAb genes to be inserted into the immunoglobulin heavy chain (IgH) locus of primary B cells, where they function as antigen receptors capable of undergoing germinal center maturation and forming memory responses. In mice, IgH-reprogrammed B cells generate durable bnAb titers near therapeutic levels after vaccination. However, the in vivo behavior of genome-engineered human B cells has not been tested due to the lack of an appropriate model. The recently developed Truly Human Xenograft (THX) mouse supports robust antigen-dependent human B cell responses and thus provides a unique opportunity to establish a preclinical platform for engineered B cell therapies. In Specific Aim 1, we will determine whether IgH-reprogrammed human B cells can participate in germinal center reactions and generate memory and long-lived plasma cells following vaccination in THX mice. In Specific Aim 2, we will establish an HIV infection and treatment model in THX mice, adapting mucosal challenge, ART suppression, and analytical treatment interruption protocols to evaluate viral rebound and reservoir establishment. Completion of these aims will demonstrate feasibility of eliciting vaccine-responsive bnAb memory responses from genome-engineered human B cells in vivo, while also establishing the THX mouse as a physiologically relevant platform for HIV infection and treatment studies. Together, this work will provide a critical foundation for advancing engineered B cell vaccines as a potential functional cure for HIV.

NIH Research Projects · FY 2026 · 2026-05

PROJECT SUMMARY Protein–protein interactions (PPIs) govern nearly every facet of cellular function and represent a key axis for therapeutic targeting. Yet, the vast majority of the ~650,000 predicted PPIs in the human proteome remain uncharacterized, largely due to limitations in technologies that can map interactions in live cells. Existing approaches rely on genetic tagging or in vitro systems and lack the resolution to detect transient, low-abundance, or state-specific interactions—especially in pharmacologically or disease-relevant contexts. This proposal aims to overcome these challenges by developing a next-generation crosslinking mass spectrometry (XL-MS) platform that enables quantitative, proteome-wide interactome mapping in live cells. Current XL-MS methods are limited by narrow residue reactivity, short and inflexible spacer geometries, inefficient enrichment strategies, and poor quantitative compatibility. Here, we will build a modular crosslinker platform that enables: (i) orthogonal residue reactivity and tunable spacer designs to access a broader spectrum of interaction interfaces; (ii) isotope-encoded handles for robust MS1-based quantitation; and (iii) cleavable enrichment handles that allow gentle, MS- compatible peptide recovery. In Aim 1, we will synthesize and benchmark a chemically diverse crosslinker library, systematically evaluating how spacer length, geometry, and residue reactivity affect proteome-wide PPI coverage in cells. In Aim 2, we will develop isotopically encoded variants and optimized workflows for quantitative PPI comparison across biological states, applying the platform to two high-impact systems: unbiased mapping of small molecule–modulated PPIs (stabilizers and disruptors) and dynamic PPI remodeling during human T cell activation. Together, these studies will establish a versatile XL-MS platform and reagents that addresses key limitations of current technologies, enabling quantitative, proteome-scale PPI discovery in native cellular contexts with unprecedented sensitivity, coverage, and versatility.

NSF Awards · FY 2026 · 2026-05

This REU Site award to The Scripps Research Institute, located in La Jolla, CA, will support the training of 10 students for 10 weeks during the summers of 2026-2028. It is anticipated that a total of 30 students, primarily from schools with limited research opportunities and first-generation college students, will be trained in the program and contribute to development of the US STEM workforce. To compete in today's global, high-tech economy, the US increasingly depends on STEM-trained workers; yet too few students gain the hands-on research experience needed to enter this workforce. This program addresses that gap by providing an immersive summer research experience that enables undergraduates to investigate fundamental biological processes at one of the nation's leading biomedical research institutions. Students are embedded in cutting-edge laboratories and receive structured mentoring and professional development that build their critical thinking, communication skills, and confidence as emerging scientists. In addition to learning how research is conducted, many students will present the results of their work at scientific conferences. Assessment of this program will be done through surveying participants and mentors as well as tracking participant career outcomes. Students apply to the REU site using NSF ETAP (Education and Training Application: https://etap.nsf.gov). The training students will receive is aligned with the NSF priority in Biotechnology. The scientific focus of this REU Site is the investigation of molecular and cellular structure and function using interdisciplinary approaches drawn from chemistry, biology, biophysics, computation, and neuroscience. Students are matched with a laboratory from one of Scripps Research's six academic departments according to their interests and work alongside leading scientists on hypothesis-driven research projects. Active research areas include identifying genes that predispose individuals to immunologic disease; defining the structure and function of key proteins in the innate and acquired immune systems; integrating computational and biophysical techniques to determine protein structure; exploring the molecular basis of brain function; and developing new functional molecules for novel strategies and technologies. In conjunction with their interdisciplinary laboratory research, students participate in skill-building workshops on science communication and responsible conduct of research, professional development seminars, individual and small-group mentorship, and career exploration sessions that support their growth as well-rounded scientists. The program concludes with an institute-wide Summer Intern Symposium at which all participants present their research findings. Program outcomes are assessed through pre- and post-program surveys, including the Undergraduate Research Student Self-Assessment (URSSA), and longitudinal tracking of participants' career trajectories. 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 · 2026-05

ABSTRACT The lens of metabolic zonation is extremely pertinent to liver pathophysiology, and can be applied to both acute and chronic/progressive conditions like acute liver damage and MASLD/MASH. The long term goal is to better understand the role of microRNAs in liver physiology, microRNA dysregulation in pathophysiology, and to improve clinical outcomes for patients with acute and chronic liver diseases. The overall objective of this application is to unravel the specific mechanism by which microRNAs maintain metabolic zonation by mapping and validating microRNA-target interactions across the lobule with high fidelity to identify new biomarkers and inform therapeutics in the context of the healthy and diseased liver. The central hypothesis is that the phenomenon of metabolic zonation is at least partially controlled by miRNA-target networks that can be taken advantage of both therapeutically and diagnostically. The central hypothesis will be tested by pursuing two specific aims: 1) Mapping and validation of miRNA-target interactions in liver cells along the lobular axis with high fidelity and 2) Assessing dysregulation of miRNA-target networks in a model of acute and chronic liver disease. Under the first aim, we will use Spy3-Ago2-pulldown and sequencing (SAPseq) in mice with a Cre-inducible Spy3-tag on microRNA effector protein Ago2 (Cre +iSpy mice) to create a single high-fidelity map of differential miRNA-target regulation in spatially sorted hepatocytes, validate miRNA zonation using miRNA-sensing reporter constructs and independently validate node-level and global miRNA-target interactions using N-acetylgalactosamine conjugated miRNA sponging ASOs and vectors that deliver miRNA-blocking peptide ddT6B. For the second aim, we will use spatial sorting and SAPseq to evaluate miRNA-target changes in response to pericentral toxin APAP and periportal toxin allyl alcohol over time in Cre+ iSpy mice, miRNA-target changes in Cre+ iSpy mice fed a choline-deficient, L-amino acid defined, high fat diet over time (induces MASLD/MASH), and use serum SAPseq to evaluate circulating miRNA changes in both conditions. Our proposal is innovative as it utilizes technical advances in microRNA biology and Ago2 structure to expand our understanding of liver physiology with applications in addressing pathologies. Ultimately, this work will have a significant, direct, and positive impact in improving treatment options for patients with chronic liver diseases and diagnostics for acute liver diseases. Beyond the liver, it will have wide-reaching effects in the fields of cell, gene, and immunotherapy. The proposed work will be conducted at The Scripps Research Institute, under guidance of mentors in RNA biology, liver biochemistry, and clinical care. This proposal will be vital to supplement my dual-degree training to become an independent physician-scientist and domain expert in clinical RNA biology.

NIH Research Projects · FY 2026 · 2026-04

Our autonomic regulation of respiration, digestion, circulation, and immune functions is closely coupled with emotional states. Anxiety elevates blood pressure, stress induces sighing, and anger suppresses digestion, while slow breathing promotes calmness. Despite these well-documented phenomena, the neural mechanisms underlying the tight coupling between emotion and autonomic control remain poorly understood, limiting the development of complementary therapies for emotional disorders, such as anxiety, phobia, and depression, and autonomic disorders, including hypertension, diabetes, gastroparesis, tachycardia, pulmonary diseases, sleep apnea, and many others. The interoceptive system continuously monitors visceral organ status. Many bodily cues are transmitted via the vagus nerve to the nucleus of the solitary tract (NTS) in the brainstem, the primary sensory gateway for interoception. The NTS processes interoceptive information and distributes it, via its ascending pathways, to multiple brain regions, including autonomic motor nuclei, the hypothalamus, and limbic structures, to orchestrate coordinated whole-body autonomic, emotional, and behavioral responses. The goal of this proposal is to pinpoint the neural substrate that mediate bodily signal-evoked emotional and autonomic responses respectively. Using viral-genetic tracing, our preliminary study shows that single NTS neurons extend highly collateral projections to multiple targets. In particular, we identified a group of NTS neurons that jointly innervate brain regions implicated in aversion/anxiety and autonomic control. This previously uncharacterized ascending interoceptive pathway forms the basis of our hypothesis that axonal collaterals from the same neurons jointly regulate autonomic and emotional responses. Using a portfolio of genetic tools that enable us to precisely record and manipulate genetically defined NTS pathways, we will, through three specific aims, determine the anatomical signatures that underlie the tightly associated emotional and autonomic responses. The completion of this proposal will help establish an anatomical-functional blueprint of ascending brainstem interoceptive circuits, laying the foundation for future investigations. By revealing the multisystem interactions of the interoceptive network, this proposal will provide insight into how complementary approaches, such as meditation and breathing-based therapies, holistically improve autonomic emotional well-being.

NIH Research Projects · FY 2026 · 2026-04

Project Summary: This proposal evaluates how the obligate TLR coreceptor cluster of differentiation 14 (CD14) regulates NLRP3 signaling pathways relevant for ischemia/reperfusion injury (IRI). IRI occurs commonly in the setting of vascular compromise. In substantial work from our lab and others it is now well-established that signals generated by molecules released from IR injured renal tuble epithelial cells (RTECS) in the kidney activate innate immune signaling pathways that in turn trigger a robust inflammatory/cell death cascade. Injured RTECs release damage activated molecule patterns (DAMPs) that potently activate injurious inflammatory signaling pathways by binding to pattern recognition receptors (PRRs) constitutively expressed on parenchymal cells in the kidney. Work from our lab, and others, has established that blocking specific PRRs (namely toll-like receptors 2 or 4 or the cytoplasmic NOD like receptor NLRP3) can prevent kidney IRI. Clinical therapeutics are not yet available to target these TLRs or NLRP3 but a promising approach is monoclonal antibody blockade of CD14, as it is the key proximal regulator of these pathways. Broad/long-term objectives: The long-term goals of the proposed research are to define how CD14 contributes to injurious tissue responses in the setting of IRI and how it’s signaling can be effectively and selectively targeted. Specific Aims: The overall hypothesis is that CD14 regulates NLRP3 inflammasome activation in RTECs. Elucidating how CD14 regulates NLRP3 inflammasome activation, including whether its triggering of NLRP3 depends on TLR engagement, is essential hypothesis will be tested in two specific aims. Aim 1 tests whether CD14 must engage with TLR2 or TLR4 to trigger NLRP3 signaling in RTECs. Aim 2 tests whether CD14 can bypass TLR engagement and directly activate NLRP3 signaling pathways in RTECs. Research Design and Methods for Achieving the Stated Goals: Aim 1 employs a combination of knockout mouse models and small-molecule inhibitors to dissect the key signaling pathways linking CD14 to NLRP3 activation to determine whether CD14 engagement with TLR2 (canonical pathway) or TLR4 (noncanonical pathway) drives NLRP3 activation in RTECs and to assess whether CD14 blockade alone is sufficient to attenuate both pathways or if additional interventions, such as TLR inhibitors, are necessary. Aim 2 uses RTECs that express CD14 but lack TLRs, stimulating them with ligands known to induce CD14/TLR-independent NLRP3 activation. We will then determine whether CD14 directly activates NLRP3 in RTECs by examining DAMP/CD14 endocytosis and direct cytosolic activation of NLRP3. Health Relatedness of Project: If the aims of this proposal are met, our studies will provide a platform on which to discover the link between IRI and CD14-mediated signals and will set the stage for future clinical studies directed at pharmacologic blockade of this master regulator of PRR signaling. This knowledge is crucial for the development of rational targeted therapies for prevention or amelioration of IRI, a syndrome that causes significant morbidity and enormous healthcare expenditures.

NIH Research Projects · FY 2026 · 2026-04

The overarching goal of this collaborative program is to understand how circuits in the mammalian brain are reorganized to encode new memories. We address this problem through detailed reconstruction of neuronal connectomes, single synapses, and glia at nanometer resolution using 3D Electron Microscopy (3D-EM). We combine 3D-EM with chemogenetic techniques for labeling cellular ensembles recruited for specific cognitive tasks and Artificial Intelligence (AI)-based computational tools for image segmentation. Using this interdisciplinary approach, we began to identify the morphological hallmarks of long-term associative memory in the mouse hippocampus. Our recent studies of the canonical CA3-CA1 pathway revealed principles by which pyramidal glutamatergic neurons (PNs) engaged during fear learning modify their local wiring diagrams, synaptic weights, and membrane organelles essential for energy metabolism and intracellular calcium buffering. Despite their broad physiological implications, these structural correlates of information storage share three features: (1) Their induction requires presynaptic activity elicited by sensory stimuli with negative valence; (2) Their manifestation transcends co-activated neurons; and (3) They involve multi-synaptic boutons (MSBs), atypical connections capable of simultaneously relaying neurotransmitter signals from one axonal terminal to several independent dendritic spines. Contrary to common dogma, we found that the initial cellular substrates of memory traces expand their connectivity via MSBs, thereby recruiting new neurons into the network while preserving the stable arrangements of individual synaptic sites on axons and dendrites. Taken together, these observations support the hypothesis that MSBs are pivotal for memory storage and that the structural plasticity of neural ensembles representing engrams does not adhere to traditional Hebbian rules. Our studies provide the first mechanistic explanation for representational drifts, a non-Hebbian phenomenon suggesting that population coding of a particular experience is not fixed over time. We will test out central hypotheses in the following specific aims: Aim 1. Investigate the spatiotemporal dynamics of non-Hebbian network remodeling via MSBs. We will determine if the synaptic architectures of an associative memory engram are reconfigured through MSBs globally or in a circuit-specific manner and will investigate the temporal dynamics of this process. Aim 2. Explore the physiological mechanisms of MSB morphogenesis. We will determine how the organization of MSBs reflects memory strength and will test if MSB morphogenesis is regulated by de novo protein synthesis, transcription, and synaptic activity. Aim 3. Define the composition of MSBs and their local microenvironment. We will comprehensively dissect the fine-scale architecture of MSBs and their postsynaptic partners. These analyses will involve reconstructions of active zones, PSDs, vesicles, other intracellular membrane organelles, astrocytes, and microglia.

NIH Research Projects · FY 2026 · 2026-04

ABSTRACT The long-term objective of this research is to develop a long-acting injectable (LAI) therapy for hepatitis B virus (HBV) in individuals co-infected with human immunodeficiency virus (HIV). This project is of significant health relevance as approximately 10% of the 1.2 million people living with HIV in the United States are co-infected with HBV. Effective management of both infections is crucial to prevent accelerated liver damage, improve health outcomes, and enhance the quality of life for this population. As LAI therapies have improved HIV management, to improve management of HIV/HBV co-infections there is a need to develop a complementary LAI for HBV. The proposed research aligns with the mission of NIH and NIAID to advance innovative therapeutic approaches and improve public health. In the R61 phase, the specific aims are to optimize the current lead entecavir prodrug (mCMQ657) to achieve sustained release and maintain therapeutic levels for up to three months. This will involve pre-formulation and formulation development to ensure the stability and bioavailability of the long-acting entecavir prodrug. Preclinical pharmacokinetic (PK) and pharmacodynamic (PD) studies will be conducted to determine safety, efficacy, and optimal dosing regimens in animal models. Additionally, toxicology and safety pharmacology assessments will be performed to support the identification of a development candidate and transition to the R33 phase. The R33 phase will focus on Investigational New Drug (IND)-directed development activities, including the development of good manufacturing practice (GMP) processes, good laboratory practice (GLP) toxicity studies, and preparation for future clinical trials. This phase will involve engaging with regulatory authorities to schedule and complete a pre-IND meeting with the FDA. The research design and methods for achieving these goals are comprehensive and rigorous. The project will leverage the expertise of the research team and include collaboration with translational advisors and regulatory advisors. Pre-formulation studies will involve characterizing the physicochemical properties of mCMQ657, while formulation development will focus on creating a stable and effective LAI formulation. PK and PD studies in relevant animal models will assess the prodrug’s pharmacological profile and therapeutic potential. In summary, the successful development of an LAI for HBV in HIV/HBV co-infected individuals aims to reduce the burden of daily medication adherence from a daily oral pill to a once-monthly injection, enhance patient compliance, and ultimately improve clinical outcomes by providing a more effective and convenient treatment option. This approach is expected to significantly impact the treatment landscape for HBV and HIV co-infections and contribute to the advancement of long-acting therapies in infectious diseases.

NIH Research Projects · FY 2026 · 2026-04

The long-term objectives of this program are to contribute to therapeutic progress for vascular, thrombotic, and inflammatory diseases by advancing knowledge through both basic and translational research. Available therapeutic solutions for cardiovascular diseases where vascular dysfunction underlies the disease etiology are limited and mortality rates remain unacceptably high. Despite recent advances, major gaps in knowledge remain about the physiological and pathophysiological mechanisms that are affected when vascular and inflammatory pathways intertwine with abnormal coagulation, which includes both hypercoagulation (thrombosis) and hypocoagulation (bleeding). Activated protein C (APC) is a naturally occurring anticoagulant plasma serine protease that has been translated to the clinic as a recombinant wild type or mutant biologic. Endogenous and pharmacologic APC has multiple beneficial effects in a diverse collection of preclinical animal injury models where unbalanced regulation of vascular, inflammatory, and coagulation pathways contribute to pathogenesis. These beneficial effects of APC are primarily mediated by the cytoprotective activities of APC that involve the endothelial protein C receptor (EPCR) and non-canonical activation of PAR1 at Arg46 and of PAR3 at Arg41, which induce biased signaling pathways contributing to rebalancing tissue homeostasis and host defense systems. Despite recent insights, there is a major gap in knowledge about protein-protein interactions between APC and its cellular receptors. Knowledge gathering on the Protein C pathway has a high likelihood for paradigm-shifting discoveries and for stimulating new basic and translational research directly relevant to NHLBI’s mission. This OIA program seeks a broad approach to advance basic knowledge possessing translational potential to fill major knowledge gaps. Building on our prior success, studies will continue our longstanding research focus in three related focus areas. The objective of focus areas 1 and 2 is to fill the major gap in knowledge about protein-protein interactions between APC and its substrates and cellular receptors. Mapping APC’s receptor specificities and understanding the structural requirements of the receptors will not only enable deciphering which receptors play critical roles on cells in vitro or in animals in vivo but also may lead to translation for novel APC mutants, APC mimetic peptides or other cytoprotection-promoting biologics. In focus area 3, we take a step back to consider the protein C pathway as the integrated part of hemostasis in the regulation of and response to thromboinflammation in the setting of a heightened prothrombotic state following a prior bacterial or viral infection. Succesful completion of this program will advance the field of blood and vascular disorders relevant to the mission of the NHLBI, will provide novel mechanistic insights for the protein C pathway biologics, and may aid translations of new biologics to the clinic.

NIH Research Projects · FY 2026 · 2026-02

Project Summary The envelope (Env) glycoprotein of HIV is the only viral protein on the surface of virions, making it the sole target of B cell-based HIV vaccines. While Env is natively a transmembrane protein, most vaccine development relies on soluble versions of the trimer. These versions lack the membrane-proximal external region (MPER) epitope, the native bilayer environment, and the transmembrane (TM) and C- terminal (CT) domains. Broadly neutralizing antibodies (bnAbs) targeting MPER have remarkable breadth, reaching near-complete coverage of all circulating HIV strains, thus making MPER an attractive target for vaccine development. Recent progress in MPER-targeted vaccine development has been notable on two fronts. First, in the HVTN133 clinical trial, MPER peptide presented in a liposome formulation induced a B cell lineage for bnAbs and their precursors and reached 15 % neutralization breadth of a global tier 2 panel. Second, two studies described the development of a germline targeting immunogen for 10E8-class MPER bnAb, and affinity maturation process of the primed antibodies in pre-clinical mouse models. Characterization of new and improved MPER- targeting immunogen candidates and responses they elicit will require biophysical and structural analysis. Challenges in handling Env as a recombinant transmembrane protein therefore persist. This project incorporates engineered transmembrane Env vaccine candidates into stable lipid nanodiscs using membrane scaffold proteins and a selection of lipid molecules. This solution enables scalable and reproducible in vitro characterization and optimization of engineered transmembrane Env-based immunogens and evaluation of in vivo responses from MPER-targeting immunizations. Env nanodiscs allow using transmembrane Envs under identical conditions that have been established for soluble Envs in commonly used iterative vaccine development methods. In the first specific aim of this proposal, Env nanodisc structures are solved in complex with MPER-targeting antibodies to give guideposts for vaccine development. In the second, nanodiscs are assembled with controlled lipid compositions to elucidate the contribution of the bilayer surface to MPER antibody binding. Lastly, the third specific aim establishes conditions for utilizing Env nanodiscs in electron microscopy- based polyclonal epitope mapping (EMPEM). All aims will collectively contribute to improved nanodisc assembly pipeline that can be scaled to serve multiple HIV MPER targeting vaccine development projects. This pipeline can also serve the development of any transmembrane Env immunogen that targets other epitopes. Ultimately, the tools will be made available for other virus glycoprotein vaccine development projects beyond HIV.

NIH Research Projects · FY 2026 · 2026-02

ABSTRACT Cortical inhibitory interneurons (cINs) are critical for circuit function. Despite tremendous advances in single cell technologies that have painted high-resolution transcriptomic maps of their developmental trajectories, we still don’t fully understand the mechanisms driving cIN migration and specification, suggesting that post-transcriptional mechanisms might be at play. Indeed, microRNAs (miRNAs) are necessary for cIN development, as demonstrated by defects in migration and specification after knockout of the miRNA biogenesis enzyme Dicer. However, miRNA mechanisms underlying these phe- notypes remain to be discovered because current tools are inadequate to address the complexity of cIN development. We engineered new tools to fill this gap. Using a peptide that rapidly and reversibly blocks the miRNA machinery, we find that during miRNA LoF during late embryonic development leads to impaired cIN migration at E18 and an altered ratio of parvalbumin (PV) to somatostatin (SST) cINs at P21, without altering overall cIN abundance. Mapping of miRNA- target interactions in developing cINs identified ‘miRNA hotspots’, the genes most heavily regulated by miRNAs. Through a CRISPR activation screen, we found that hotspots play critical roles in cIN migration. In particular, de-repression of Ist1 increases neuronal branching and alters migration dynamics in vitro and in vivo. In this proposal, we will identify mecha- nisms by which miRNA hotspot de-repression leads to cIN migration defects. For example, we will elucidate how elevated Ist1 expression leads to aberrant activity in the endosomal sorting complexes required for transport (ESCRT) pathway and how Armcx2 de-repression perturbs mitochondrial motility to affect cIN migration. Further, will investigate how transient miRNA LoF during late embryonic stages or miRNA hotspot de-repression shifts the PV to SST ratio, either by selective apoptosis or by class fate plasticity. Successful completion of this proposal will define, for the first time, the mechanistic links between miRNA-mediated post-transcriptional regulation and the essential processes of cIN migration and the determination of PV to SST ratio. This is particularly significant because defects in cIN development have been linked to multiple psychiatric disorders, but the mechanisms instructing these processes are still largely unknown. This proposal will yield critical advancement, providing evidence that key aspects of cIN development are regulated post-transcriptionally. It will also provide a new toolbox for interrogating miRNA-target networks in specific neuronal cell types, and innovative methodologies to dissect miRNA mechanisms. The combination of technical and conceptual innovations will be transformative for the field, and we predict that the approach outlined here will be widely adopted.

NIH Research Projects · FY 2026 · 2025-09

ABSTRACT Mounting evidence suggests mitochondrial decline is an early driver of Alzheimer’s disease and related dementias (ADRD) but the underlying mechanisms remain unclear. Single-cell RNAseq experiments revealed profound differences in the expression of nuclear DNA-encoded mitochondrial genes between neuronal subtypes, suggesting a cell type-specific control of mitochondrial gene expression depending on mitochondrial energy demands. Studying the role of ATP synthase in aging and ADRD, we recently discovered a brain-specific mito-nuclear feedback loop that controls mitochondrial gene expression in response to acetyl-CoA signals from the mitochondria. This mito-nuclear feedback loop is activated by reducing ATP synthase activity, activating AMPK, and subsequently blocking fatty acid synthesis by inhibiting acetyl-CoA carboxylase 1 (ACC1). The block of fatty acid synthesis leads to an accumulation of acetyl-CoA, H3K9 histone acetylation, and increased expression of nuclear-encoded mitochondrial proteins by a mechanism that requires TAF1, the largest component of the transcriptional initiation complex TFIID. Treatment with J147, a partial inhibitor of ATP synthase and an AD drug candidate, increases acetyl-CoA and restores the expression of mitochondrial and synaptic genes, known targets of TAF1. Conducting longitudinal electroencephalogram (EEG) recordings in PS19 mice, an FTD mouse model expressing proteotoxic tau, we observed neuronal hyperexcitability and non-convulsive seizure activity, specifically during slow-wave sleep (SWS). Activation of the mito- nuclear feedback loop by treating the PS19 mice with J147 suppressed the neuronal hyperexcitability and the observed pathological EEG features, revealing that they are likely the consequence of early mitochondrial damage. Here, we hypothesize that age and pathological tau destabilize the mito-nuclear feedback loop by lowering the mitochondrial acetyl-CoA synthesis and export that is required for TAF1 to control synaptic and mitochondrial gene expression. Due to their high mitochondrial energy demands, inhibitory neurons are preferentially susceptible to mito-nuclear insults by tau, resulting in preferential damage to inhibitory neurons. Thus, we further hypothesize that this preferential damage to the mitochondria of inhibitory neurons reduces inhibitory tone and results in early hippocampal hyperexcitability and sleep loss, which can be rescued by treatments that re-activate the mito-nuclear feedback loop.

NIH Research Projects · FY 2025 · 2025-09

ABSTRACT Antivirals that are currently in clinical use target a limited number of viruses or viral subgroups, have moderate efficacy and are prone to resistance. Current approaches for antiviral development mainly target viral proteins with enzymatic activity. A disadvantage of this approach, especially for RNA viruses, is that their small genomes offer few drug targets and high mutation rates lead to rapid emergence of drug-resistant strains. The discovery of potent, broad-spectrum antivirals with a high barrier to resistance therefore remains an urgent, unmet medical need for the treatment of endemic and emerging viral infections. Agents with these properties will most likely target host factors that are required for replication of multiple viruses and/or innate immune circuits that govern endogenous cellular defense mechanisms. SMAC mimetics, first developed to induce immunogenic death of tumor cells, are now emerging as such pan-antivirals. These agents simulate the activity of endogenous SMAC to block the action of inhibitor of apoptosis proteins (IAP). Although best known for their regulation of caspases during inflammation and cell death, IAPs also influence ubiquitin (Ub)-dependent signaling pathways that modulate innate immune responses. Several SMAC mimetics have already entered clinical trials for cancer treatment. As for antiviral therapy, research thus far has focused on SMAC mimetics for treatment of chronic viral infections, such as Hepatitis B virus and as latency reversal agents (LRAs) of HIV-1 infection. A recent report described the antiviral activity of a potent, monovalent SMAC mimetic against flaviviruses, SARS-CoV-2 and influenza A13. We have generated similar findings with SARS-CoV-2, Dengue 2 and influenza A using SMAC mimetics developed by our group. Owing to our current HIV-1 LRA program, we have novel compounds in hand that feature a range of activity profiles. We hypothesize that SMAC mimetics can be developed into potent pan- antivirals because they preferentially kill infected cells, which are sensitized to death due to activation of innate immune circuits. We recognize that SMAC mimetics may also affect cellular processes universally required for or inhibiting viral replication. This project will focus on RNA viruses with pandemic potential, including influenza A, flaviviruses (Dengue, Zika and West Nile), and SARS-CoV-2 variants. In Aim 1 we propose to investigate the breadth and potency of the antiviral activity of SMAC mimetics. Here, we will also delineate the stage of the viral replication cycle that is affected by SMAC mimetics and/or that triggers their antiviral properties. Aim 2 will rely on systems biology approaches to identify the host factors that are implicated in SMAC mimetic antiviral activity. Overall, the proposed studies will identify the mechanisms and pathways that are responsible for the antiviral activity of SMAC mimetics and enable their further optimization as broad-acting antivirals.

NIH Research Projects · FY 2025 · 2025-09

PROJECT SUMMARY Antibodies capable of neutralizing the global diversity of HIV strains are difficult to elicit in humans. This is because such antibodies require unusual features deriving from rare precursor B cells that must undergo extensive affinity maturation. To date, only a small number of potent broadly neutralizing antibodies (bnAbs) have been isolated after screening thousands of patients responding to unsuppressed infection. Passive immunization with recombinant monoclonal HIV bnAbs however, can maintain suppression of viremia in patients after anti-retroviral treatment (ART) interruption for as long as serum titers remain above threshold effective serum concentrations. This suggests that establishing durable bnAb titers above these thresholds could result in an HIV functional cure, defined as life-long suppression of viremia. Since HIV bnAbs cannot be elicited through vaccination, gene therapies are being considered as an approach to deliver such long- lasting bnAb titers in vivo. Of these, genome-edited B cells are a novel and promising approach that may hold several key advantages. Primary B cell antigen receptors (BCRs) can be reprogrammed to express novel specificities by inserting antibody transgene cassettes into the IgH-locus downstream of endogenous heavy chain (HC) immunoglobulin (Ig) variable region exons. These modified cells can be expanded and differentiated in vivo by vaccination into memory and long-lived plasma cells that can durably secrete the new antibody specificity in wild type immunocompetent mice by independent research groups. The overall purpose of the PlanB consortium is to accelerate the pre-clinical development of safe and effective IgH- reprogrammed B cell-based therapies that would provide life-long bnAb titers capable of maintaining suppression of the viral reservoir, allowing patients to discontinue ART therapy. Our aim is to develop and compare two distinct options from which one could be selected for clinical development upon completion of the program. The first is an ex vivo reprogrammed B cell product that can be autologously transferred and vaccinated in patients. The second is an in vivo B cell targeting and IgH-reprogramming system that will be used in conjunction with vaccination. In both cases, durable HIV broadly neutralizing antibody memory responses must be elicited from the engineered cells.

NIH Research Projects · FY 2026 · 2025-09

SUMMARY Myelination is essential to efficient action potential propagation and neuron survival. The bulk of myelination occurs during development, but new myelin sheaths continue to be added throughout adulthood, especially in white matter tracts. Chronic alcohol exposure alters the expression of myelin genes/proteins and reduces the volume and microstructural integrity of white matter tracts both in humans and in animal models. However, the molecular and cellular mechanisms driving these effects are poorly understood. The present project seeks to address the structural and functional correlates of myelin protein changes in a mouse model of alcohol use disorder that combines voluntary alcohol drinking and chronic intermittent alcohol vapor inhalation. One goal is to tease apart the effects of alcohol on oligodendrogenesis vs. preexisting myelin using in vivo genetic labeling of newly formed myelin and in vitro assays of oligodendrocyte precursor cell differentiation. In all experiments, we will test the role of ethanol's action at large conductance, voltage- and calcium-activated potassium channels (BK channels) using knockin mice that express ethanol-resistant BK channels. Potential sex differences will be considered throughout the project. The first Aim will use untargeted quantitative proteomics to determine whether chronic alcohol and withdrawal impact the abundance of myelin proteins differentially in female vs. male brain samples. The second Aim will use electroencephalography to measure the functional integrity of myelin over time and electron microscopy to analyze the ultrastructure of myelin sheaths at timepoints of peak deficit and recovery onset. The third Aim will use a mouse reporter line to quantify the formation of new myelin and oligodendrocytes during alcohol exposure. The fourth Aim will use primary cultures to determine whether the effects of alcohol on oligodendrogenesis are caused by a direct action on oligodendrocyte lineage cells or via extrinsic mechanisms involving other brain cell types. This project builds on rigorous evidence of the pervasive effects of alcohol on myelin. It is innovative because the molecular target of ethanol responsible for myelin disruption is unknown and the role of BK channels in oligodendrogenesis is uncharted. The proposed research will enhance our mechanistic understanding of alcohol's effects on myelination and may in turn create unprecedented opportunities for prevention and/or restoration strategies.

NSF Awards · FY 2025 · 2025-09

With the support of the Chemical Synthesis and Chemical Mechanism, Function, and Properties Programs in the Division of Chemistry, Professor Ryan Shenvi of The Scripps Research Institute is studying the chemical synthesis and modification of new anti-fungal and anti-malarial medicines based on siccanin, a substance produced by a mold called Helminthosporium siccans Drechsler. The strategy of synthetically altering a naturally-occurring compound to become a human medicine has become common since the beginning of the 20th century. However, many natural product molecules are very complex, and it is difficult to know what chemical structural changes to make and how to make them. Traditional “guess-and-check” synthetic investigations are common, but are costly in terms of labor and resources and can lead to undesired outcomes. The Shenvi laboratory is developing an integrated experimental and computational workflow towards synthetic strategies for complex molecules to avoid trial-and-error approaches. In the current project, they are adapting the anti-fungal compound siccanin to become a human therapeutic by predicting which chemical characteristics are needed and which chemical reactions are required to install desired properties. Aligned with these research goals, Prof. Shenvi and his research team are also continuing to advance their chemistry education game, Synthordle, which allows chemistry students to practice their growing know-how in a Wordle-like format using problems that range from easy (college-level) to advanced degree-levels of difficulty. Pattern recognition is fast but does not have the resolution to distinguish molecular features that lead to success or failure in a chemical reaction. Quantum mechanical calculations are slow, but can identify reactivity differences that are unclear to both computer-assisted synthesis planning (CASP) and human practitioners. To investigate a compromise, the Shenvi group is creating libraries of CASP intermediates that can be triaged by reaction prediction to build a general predictive platform for the synthesis of antifungal meroterpenoid analogs of siccanin that improve the molecular properties of the target. These activities are also providing training opportunities for graduate, undergraduate, and high school students in chemical synthesis, computational chemistry, and computer-assisted synthesis planning. 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 · 2025-09

In biomedical research, effective analysis of new experimental data depends on the contextualization of results using the totality of biomedical knowledge known to date. This existing knowledge is often organized in structured knowledge bases (KBs). These KBs are instrumental in interpreting new data, and subsequent conclusions are often integrated back into the KBs to stimulate future discoveries. This positive-feedback loop has benefited multiple areas of biomedical research, given the rich availability of both high-throughput data and derived knowledge in recent decades. While development of technologies for data generation remains a primary way to drive research forward, improvements to the efficiency of making available data/knowledge Findable, Accessible, Interoperable and Reusable (FAIR) also has a significant impact for the future advancement in biomedical research. In this proposal, we propose to build a distributed ecosystem of biomedical Application Programming Interfaces (APIs) for promoting FAIR data-sharing and knowledge integration. This ecosystem contains a framework for API creation; an API registry for API management and discovery; and a semantic annotation and integration framework to create cross-API interoperability for their reuse. Beyond promoting the FAIR principles, the distributed nature of this API-based data ecosystem also allows distributed implementation and maintenance efforts for its long-term sustainability. The utility of the ecosystem will be demonstrated in broad areas of research use-cases.

NSF Awards · FY 2025 · 2025-09

With the support of the Chemistry of Life Processes program in the Division of Chemistry, Professor Donna G. Blackmond from Scripps Research is studying how exclusively homochiral biological polymers emerged from the chiral building blocks of life. Homochiral molecules exist in only one of two possible mirror-image forms, analogous to our right and left hands. Understanding how homochirality emerged will help us understand the origin of life on Earth. Homochirality is also a critical feature of many modern pharmaceuticals, where administering the incorrect “hand” of a drug may result in unintended biological effects. The current research intends to study how molecular building blocks assemble into homochiral chains of proteins and nucleic acids. The results of this work will shed light on chemical processes that occurred billions of years ago, provide insights into the production of modern pharmaceuticals, and underlie key science teaching moments. The concept of mirror image molecules is fascinating to students and laymen alike because the two molecules that are mirror images of each other can exhibit different properties, such as taste and smell. Demonstrations of homochirality – ranging from the shapes of seashells and the smells of spearmint and rye bread to the search for life in interstellar space – represent an exciting means of bringing fundamental and practical chemistry concepts into the lives of young scientists. A key current challenge is to combine the findings from Blackmond's previous studies on monomeric building blocks with investigations focused on prebiotic reaction networks that assemble biological polymers. These studies will combine experimental organic synthesis and kinetic measurements with computational modeling to determine whether there is a specific chain length at which homochiral chains begin to dominate, leaving heterochiral residues behind. This work will also explore whether peptide-forming reactions may be combined with the peptide-catalyzed kinetic resolution of amino acids to create the first known prebiotically relevant autocatalytic feedback network exhibiting chiral amplification. Finally, these investigations will be expanded to the ligation of nucleic acid monomers in prebiotic processes to form RNA oligonucleotides. 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 · 2025-09

Summary The abuse of drugs is associated with treatment non-compliance, greater risk of viral transmission, and more rapid clinical progression of HIV disease. The overarching hypothesis behind the present project is that the exploration of gene regulatory networks in single cells will elucidate key pathogenic mechanisms that underlie the effects of HIV and substance use disorder (SUD) and their detrimental interactions that will indicate novel therapeutic targets for neuroinflammation, neurodegeneration, virus expression and persistence, and cognitive impairment in the setting of HIV and SUD. To test the present hypothesis, we propose a data mining campaign centered on a comparative analysis of cell type-specific gene regulatory networks or interactomes reconstructed from the human and animal model single cell/single nucleus RNA-Seq (sc/snRNA- Seq) and single nucleus assay for transposase-accessible chromatin-sequencing (snATAC-seq) from the SCORCH program. To this end we will use a validated systems biology strategy for the reconstruction and interrogation of a genome-scale gene regulatory network that proved exceptionally effective in deconvolving molecular interactions in cancer, Alzheimer's disease, development, substance abuse (by our group), as well as in the identification of therapeutic targets, mechanisms of action and synergistic activities of therapeutics. The occasional but limited use of a drug is clinically distinct from dependent drug use, which is characterized by the emergence of dependence and a negative emotional state when access to the drug is prevented that drives negative reinforcement, a powerful source of motivation for drug seeking. Therefore, we will validate the key genes identified both in vitro and in vivo in a state-of-the-art paradigm of voluntary intravenous drug self-administration under long access (LgA) conditions, which leads to escalated (dependent) drug intake that we implemented in HIV transgenic rats. Escalated drug intake in this paradigm is highly relevant to human SUD as it has been suggested that it models all 7 of the criteria for drug addiction in the Diagnostic and Statistical Manual of Mental Disorders (DSM)-IV and 7 of the 11 criteria in the DSM-V. HIV Tg rats self-administering drugs in this paradigm display increased neural injury and neuroinflammation. Overall, this collaborative interdisciplinary proposal integrating systems biology data mining centered on the deconvolution of the gene regulatory networks at the single cell level, hierarchical validation strategies including state-of-the-art behavioral paradigms of volitional drug intake, single cell level transcriptomics, and state-of-the-art behavior methods in HIV Tg and wild-type rats, will elucidate key mechanisms that underlie the detrimental interactions of HIV and SUD on disease progression, virus expression and persistence. The results will indicate transformative new mechanistic hypotheses that may lead to novel therapeutic concepts for SUD in the setting of HIV and will establish key resources for the neuroHIV field to be made publicly available through the SCORCH data coordination center and other public repositories.

NIH Research Projects · FY 2025 · 2025-09

Project Summary Post-transcriptional RNA modifications are a ubiquitous feature of the stable RNAs of the translation apparatus, with attributed functions including biogenesis, stabilization of rRNA structure, and promoting the fidelity of translation. There is recent mounting evidence that rRNA and tRNA modifications play an important role as a second layer of the genetic code, tuning gene expression in response to cellular cues, and in particular altered modification states have been implicated in many types of cancers. This proposal seeks to understand the fundamental biology of rRNA and tRNA modifications as they contribute to altered gene expression supporting tumorigenesis, exploring a critical link between modifications and methionine metabolism. The overall goal of this work will be to identify correlations in modification state of the translation apparatus with changes in codon occupancy and translation rate, and to map these correlations across cancer cell lines to uncover the key link to methionine starvation. These data will offer further insights into how methionine starvation might mediate or limit cancer cell growth, informing ongoing efforts to target this pathway therapeutically. There is certain to be a fundamental relationship between the availability of methyl groups for RNA modification and gene expression patterns, and the work outlined in this proposal will serve as a strong foundation for subsequent studies on the roles of the many other types of modifications in altered programs of gene expression.

NIH Research Projects · FY 2025 · 2025-08

PROJECT SUMMARY The HIV pandemic has been raging for nearly forty years, and despite immense effort we have yet to discover a vaccine that can induce durable, protective immunity. HIV remains an urgent global health crisis, with 38 million people living with HIV and 1.5 million people newly infected each year. For most infectious diseases but particularly HIV, vaccines are preferable to other forms of prevention or prophylaxis because of their potential durability. Ideally, a single immunization induces protective immunity that lasts for years or even decades. Antibodies are the primary mechanism of protection for nearly all available vaccines, so when considering vaccine durability, an important measure is the length of time that neutralizing antibodies can be maintained at a functional level. In this proposal, we will systematically study the effects of different vaccine parameters on antibody durability. In Aim 1, we will evaluate immunogen affinity and valency. In Aim 2, we will investigate adjuvants and vaccine platforms, including mRNA delivery. In Aim 3, we will explore dosing regimens, including promising escalating-dose strategies.

NIH Research Projects · FY 2025 · 2025-08

PROJECT SUMMARY / ABSTRACT The modulation of autophagy is a promising target for drug discovery due to its role in various diseases. Current approaches often result in drugs with unanticipated effects due to the complexity of autophagy signaling networks, highlighting the need for novel strategies. Biomolecular condensates (BMCs), membrane-less organelles formed by phase separation, play a key role in selectively disposing of unwanted proteins via autophagy. Selective autophagy receptors (SARs) function as BMCs, recruiting degradation-bound cargo to phagophores. For example, p62/SQSTM1 forms BMCs to regulate autophagosome biogenesis by stabilizing phagophores, a biophysical regulatory mechanism that correlates the physicochemical properties of BMCs with autophagy efficacy. Despite advances, the regulatory mechanisms of BMCs in autophagy remain largely unexplored due to their compositional complexity and transient nature. This poses a barrier to systematically studying the biophysical interactions during autophagic engulfment. We propose to engineer a novel BMC-based tool with tunable physicochemical properties using PopTag, a synthetic BMC platform developed in our lab. This will create an orthogonal SAR-like BMC capable of supporting autophagosome biogenesis and selective cargo recruitment. Our approach involves leveraging PopTag's modular domain architecture, which includes the 'condenser' (drives condensation), the 'tuner' (modulates properties), and the 'actor' (enables recruitment). This platform allows us to disentangle signaling-based regulatory mechanisms from biophysical ones, enabling detailed investigation of BMC properties and autophagy. We will first Investigate the physicochemical properties of p62/SQSTM1. Using confocal microscopy, fluorescence recovery after photobleaching (FRAP), and microelectrophoresis, we will establish the homeostatic range of surface tension, viscosity, and surface electrostatics for p62/SQSTM1-mediated autophagosome biogenesis. We will also assay disease-relevant mutations to identify abnormal physical properties (Aim 1). Next, we will engineer an orthogonal BMC-based platform for selective autophagy. Using rational protein design, we will create an autophagy-targeted PopTag (AutoPop) and optimize its physicochemical properties to enhance autophagosome biogenesis and cargo recruitment (Aim 2). This proposal aims to establish the foundational physicochemical properties required for autophagosome biogenesis and develop an orthogonal BMC-based tool for investigating the cellular biophysics of autophagic engulfment, paving the way for innovative therapeutic strategies targeting the biophysical aspects of autophagy.

NIH Research Projects · FY 2026 · 2025-08

Project Summary/Abstract Somatosensory neurons are well-known for innervating skin and muscle and transmitting sensations such as touch, pain, itch, and proprioception to the brain. However, these same type of heterogeneous set of neurons also innervate internal organs and are responsible to convey information of the internal state of our body. These interoceptive signals include both conscious (bladder fullness) and subconscious (blood pressure) senses. Despite their importance, we do not know their projection patterns and physiological roles. Here, we propose to use a set of innovative tools that will allow us to specifically label, visualize, and isolate sensory neurons innervating various internal organs. Using a variety of state-of-art molecular, imaging, and genomic techniques, we will build an anatomical database of these neurons and use snRNAseq to establish the molecular identities of individual sensory neurons based on their innervating organs. Finally, the anatomical, cellular, and molecular maps will be standardized, indexed, and integrated into an atlas that will allow the community to freely access the data.

NIH Research Projects · FY 2025 · 2025-08

Type 1 diabetes (T1 D), a prototypic CD4 T cell mediated autoimmune disease, is believed to have a prolonged pre-clinical phase that lasts many years. Therapeutic intervention during that period of the disease has demonstrated effectiveness in a small subset of patients and for a limited time. Towards finding a cure, we have decided to investigate the very early phase of the disease in mice and human. Our focus has been closely linked to the genetics of the disease and its association to MHC class II genes and products. Because the evidence put CD4 T cells as initiators of the autoimmune process, defining the antigen presenting cells (APCs) that control pathogenesis is essential. We have recently described a non-hematopoietic CD45- cell associated to the efferent post-capillary collecting venule that expresses MHC-II and spontaneously presents islet antigens to CD4 T cells. Further characterization of this cell showed that it is fibroblastic and epithelioid in nature. More importantly, it coexpresses PD-L 1 with MHC-II but no coreceptors, and can anergize pre-activated T cells. We hypothesize that this cell protects islets from immune attacks but is overwhelmed by blood derived APCs when local inflammation persists and disease progresses. In Specific Aim 1, we will perform a time course characterization of CD45- and CD45+ APCs that are associated to the islets and control anti-[\-cell autoimmunity. This landscape of APCs will be defined in normal pancreatic islets, and islets of pre-diabetic mice. Traditional methods of immunocytochemistry and more sensitive methods of cell tracking will be used to characterize every MHC-II+ cell type associated with the normal pancreatic islet and the islet progressing towards autoimmunity. Transgenic mice expressing eGFP MHC-II, optimized high affinity anti-islet TCRs as well as spatial transcriptomics will be other tools used for this aim. In Specific Aim 2. we will further characterize the MHC-II+ PD-L 1+ tolerogenic fibroblast This aim will focus on: the nature and pathways of antigen presentation in those cells, their embryologic origin, the definition of their function at the initiation of T1 D, and their potential utilization for the prevention of T1 D? To overcome their very small numbers in the islet, mouse and human cell lines have been established. In addition, mouse to human translation will be facilitated by our ability to differentiate a similar cell from ES and iPSC cells. In Specific Aim 3. the regulation of MHC-II expression on non-hematopoietic cells associated with the islet, endothelial cells and fibroblasts, will be studied. In addition to IFNy, the main driver of MHC-II expression, new molecules such as a fragment of gasdermin D will be examined in vitro and in vivo. This proposal focuses on two aspects of T1 D that urgently need to be studied: the initiation of autoimmunity and its control, and the nature of the APCs that are at the center of these processes. As such, the work has the potential of being paradigm shifting and is likely to make new therapeutic approaches emerge. Project Summary/Abstract

NIH Research Projects · FY 2025 · 2025-08

Project Summary/Abstract Scripps Research is a leader in the field of chemical biology. This leadership is established on three core strengths: the high quality of its faculty, its top ranked graduate program, and the excellent interdisciplinary nature of our research programs. Scripps Research exemplifies itself as a research institution where ideas in the basic sciences can be seamlessly translated to drug candidates and clinical trials. Likewise, our institution also boasts the ability to take observations from the clinic and extract meaningful molecular information from them to innovate on basic principles. Our program is not bounded by departments, and interdisciplinary work is found in commonplace at Scripps. The overall mission of our graduate program is to coordinate our established pre-doctoral training program with the translational drug discovery mission and activities across the Institute. With this Chemical Biology Training grant, our objective is to train a cadre of elite Scripps Research students with emphasized and specialized training in translational chemical biology. Under this newly coordinated program, students will be equipped with advanced chemical biology and translational drug discovery skills that prime them for successful transition to competitive spots within the biomedical research workforce. These skills will be developed via our chemical biology didactic curriculum that will be infused with advanced courses in drug discovery and pharmacology, seminars and trainee presentations, a chemical biology-specific alumni matching program, an internship program that exposes trainees to local companies that have been highly successful at translating chemical biology technologies, and a transformative set of career development activities that are design to teach collaboration as a skill. This training is designed as a two-year program that commences following the first year of laboratory rotations and the selection of a graduate advisor who is a member of our molecular-focused 41 Participating Faculty. A projected number of ten trainee slots will be supported via this program.