Stanford University

NIH Research Projects · FY 2025 · 2018-09

The NIA is committed to mentor promising scientists in the biomedical sciences for sustained and impactful behavioral and social science research careers focused on aging research, and AD-related dementias (ADRD). The Stanford Medicine Center for Longevity and Healthy Aging was founded in 2018 to advance translational longevity and healthy aging research using emerging methodologies. Guided by our multi-stakeholder advisory board, we successfully expanded into the multi-organizational research consortium, which now includes Stanford University, the VA Palo Alto Health Care System, other partner organizations including Palo Alto University, San Jose State University, and several community partners. We are primarily focused on chronic diseases and ADRD. Our goals are to: (i) expand the research workforce by recruiting, retaining, and mentoring new leaders in translational longevity and healthy aging research and (ii) promote new advances and methodologies in biobehavioral and social sciences in longevity and aging research. By providing pilot funds, methodological and recruitment support, ongoing mentoring, and leadership and professional development opportunities, we will create and support a deep bench of investigators who are equipped to lead the next generation of the longevity and healthy aging research workforce. Our specific aims are to: 1) Train and mentor the next generation of the research workforce with the knowledge and skills in clinical and translational longevity and healthy aging research. 2) Conduct rigorous and reproducible research using data-driven artificial intelligence/machine learning approaches, virtual reality, and emerging methodologies  to improve longevity and healthy aging for all. 3) Maximize community engagement and coordinate consortium-wide efforts to advance innovative longevity and healthy aging research. 4) Expand the Longevity and Healthy Aging Research Consortium, deepen existing and forge new partnerships with other research organizations including resource-limited institutions (RLI), to jointly recruit, mentor, and retain junior investigators in clinical and translational aging research.

NIH Research Projects · FY 2025 · 2018-09

PROJECT SUMMARY The Center for Undiagnosed Diseases at Stanford, a member site of the Undiagnosed Diseases Network (UDN), works to improve the lives of patients with undiagnosed and rare diseases and their families. In a sustainable and inclusive manner, we offer cutting-edge diagnostic strategies and technologies to patients who continue a diagnostic odyssey after clinical options have been exhausted. In addition to pioneering innovative diagnostic methodology, we seek to deeply understand the needs and experience of the undiagnosed patient community to inform the design and implementation of best practices with regard to participant experience and the inclusion of underserved populations. The impacts of underinsurance and reduced access to subspecialty care and advanced diagnostics fall disproportionately on underserved populations, making it critical to build community partnerships in the conduct of rare disease studies. The Center for Undiagnosed Diseases (CUD) at Stanford will continue our efforts toward sustainability, refinement of methods, and collaboration with clinicians providing the standard of care. Here, we propose a program of study that will develop a deeper understanding of barriers to UDN enrollment faced by patients from underserved communities and implement mitigation strategies. To inform our work in studying barriers to participation and in building community partnerships, in Aim 1, we will establish an advisory board with representatives from the patient community as well as community health and social service providers. In Aim 2, we will work in collaboration with clinical partners in our region to identify, recruit, and diagnose a cohort of underserved, undiagnosed patients of diverse backgrounds, and empower community providers to participate in the UDN process through strategic partnering. In Aim 3, we will further enhance the diagnostic capabilities of the UDN by leveraging innovations in molecular diagnostics and advanced informatics. This work will include innovative approaches to transcriptomics, 2) long-read genome sequencing, 3) proteomics, and 4) the implementation of new strategies for the computational prioritization of candidate diagnosis and novel disease entities.

NIH Research Projects · FY 2026 · 2018-09

Project Summary/Abstract The BRAIN Initiative is supporting a broad portfolio of neuroscience research aimed at revolutionizing our understanding of the brain. The sharing of data obtained from this research is critical both to leveraging this major public investment and to ensuring the rigor and reproducibility of NIH-funded research. We propose a renewal of support for the OpenNeuro data archive, which provides a platform for the storage, processing, and sharing of neuroimaging data collected as part of the BRAIN Initiative. OpenNeuro enables researchers to easily share a broad range of neuroscience data types, based on the Brain Imaging Data Structure standard for organizing datasets. The platform shares data openly and provides researchers with several avenues to access and reuse the data. In the renewal period we propose to continue supporting a high level of performance for the archive, and to extend the work done in the initial grant period. First, we will provide a specialized portal for BRAIN Initiative investigators, which will help more clearly link their research to funding sources, and to provide them with the ability to more flexibly select an appropriate data use agreement. We will also implement enhanced user profiles, linking shared datasets to standard researcher identities through the ORCID system. Second, we will enhance the ability to search for datasets by improving the ability for researchers to specify metadata that is linked to standard ontologies. Third, will improve the reusability of OpenNeuro datasets by providing support for the sharing of derivative data as well as statistical models, and by providing preprocessed data and quality control reports. Together, these improvements will sustain the success of the OpenNeuro archive and provide neuroscientists with increasingly usable data to address fundamental problems of brain function and health.

NIH Research Projects · FY 2025 · 2018-09

PROJECT SUMMARY Over 230 million people undergo surgery annually. The experience of postsurgical pain varies among individuals, but a significant proportion (20-30%) of patients experience surgical site pain lasting at least a year postoperatively. Such Persistent Post-Surgical Pain (PPSP) causes physical and mental suffering and disability and lengthens exposure to opioid analgesics, potentially placing patients at risk of addiction. Despite excellent research in basic research indicating potential mechanisms involved in the transition of acute to chronic pain, little success at translating these findings to actual prevention of persistent postoperative pain in human patients has been realized. My research program has developed a working human model of this transition, by systematic and longitudinal studying pain before, during and after a variety of surgeries. We have identified several patient-level risk factors that predict who is high-risk for developing PPSP, allowing more efficient study of this problem, as well as insight into relevant mechanisms, in humans. A crucially important factor in determining the trajectory of PPSP appears to be the tendency for the pain signal to be amplified. While pain amplification may be protective in the short term, it becomes dysfunctional if excessive or persistent. In our psychophysics lab, we study measures that indicate excessive amplification response of the nervous system in some individuals in response to standardized pain testing. We also measure psychosocial factors such as stress, sleep disruption, and catastrophizing (a mental process by which rumination, magnification, and worry increase salience and importance), which can also amplify the pain signal. Importantly, pain amplification is more prominent in some individuals, and accounts for a sizeable amount of the variation in pain resulting from surgery (and far more than the surgical extent). We have developed a system to easily and non-invasively test this “amplification phenotype” in individuals BEFORE surgery, using modified bedside quantitative sensory tests, and brief, validated psychosocial questionnaires. My research program has optimized measurement of our patients’ preoperative amplification phenotype, to help target both known and novel non-opioid preventive treatments to these high-risk individuals. Our goals for the next 5 years of this R35 award are: (1) to efficiently target the prevention of persistent pain and opioid use after surgery in high-risk individuals, (2) to understand and target the underlying mechanisms contributing to the development of PPSP, including understanding how pain amplification relates to the inflammatory response to surgery, (3) to more widely apply preventive strategies, understanding their differential efficacy among diverse samples of patients. As an Anesthesiologist with formal training in pain neuroscience, psychophysical and psychosocial assessments, and practical experience in conducting translational studies, I am well-situated to conduct such well-designed mechanistic studies.

NIH Research Projects · FY 2026 · 2018-08

Project Summary/Abstract Mathematical cognition provides a foundation for the development of quantitative skills critical for functioning in the 21st century. Yet, math difficulties are widespread in children, adolescents, and college students, and one in five adults in the USA is functionally innumerate. Low numeracy is associated with poorer health outcomes, reduced health literacy, and improper use of health resources. Characterizing neurocognitive developmental trajectories and risk factors of mathematical disabilities (MD) is critical for addressing the public health burdens of innumeracy. Building on an innovative and high-impact line of research, we propose to investigate neurocognitive longitudinal trajectories and outcomes in MD. We focus on two key cognitive domains impaired in MD: (1) number sense, including representations of quantities, numbers, and their mental manipulation, and (2) arithmetic skills, including numerical problem solving and fluent retrieval of math facts from memory. Our central hypothesis is that, relative to typically developing (TD) controls, individuals with MD will exhibit atypical developmental trajectories of brain response, representations, and connectivity in two functional brain systems: (1) the parietal visuo-spatial attention system, which supports quantity representations, and (2) the medial temporal (MTL) declarative memory system, which supports arithmetic fact retrieval. We will test (1) core and access deficit models of atypical number sense development and (2) a memory deficit model of weak fact retrieval. Using state-of-the-art multimodal brain imaging and three innovative longitudinal designs, we will test these models by (1) characterizing developmental trajectories in children and adolescents, spanning elementary, middle, and high school years (ages 7 to 16), with an accelerated longitudinal design; (2) identify brain measures that predict longitudinal 2-year early math trajectories and outcomes in young children prior to formal instruction or MD diagnosis (ages 5-7); and (3) identify brain measures that predict longitudinal 10-year long-term math outcomes in adolescents (age 17) who were previously characterized in childhood. Three innovative longitudinal designs will address critical gaps in our understanding of neurocognitive systems impacted over development in MD. Findings will inform our understanding of the etiology of MD and the development of targeted cognitive interventions that may ultimately reduce the public health burden of low numeracy.

NIH Research Projects · FY 2026 · 2018-08

PROJECT SUMMARY The Stanford Stroke Center, one of the first comprehensive multidisciplinary centers of its kind, was established in 1992 to develop new approaches to diagnose and treat stroke. The mission of the Stroke Center is to be the best comprehensive organization in the United States focused on stroke diagnosis, treatment, research, and education. In 1992, the Center was established by a team of neurologists, neurosurgeons, neuroradiologists, nurse specialists, basic scientists, and clinical researchers. This multi-disciplinary team has met regularly to continually refine the program for 30 years. In 2012, the Joint Commission and the American Heart Association/American Stroke Association announced that the Stanford Stroke Center was the first hospital in the United States to meet The Joint Commission's standards for Disease-Specific Care Comprehensive Stroke Center Certification. Stanford was chosen to be one of the original StrokeNet Regional Coordinating Centers (RCCs). During the initial grant period, Stanford developed the DEFUSE 3 study, which became the first clinical trial to be funded and executed by StrokeNet. This 40-site trial that tested the efficacy of endovascular therapy in the delayed time- window among patients selected with advanced neuroimaging techniques was extremely successful; enrollment rates were substantially ahead of projected targets and the trial stopped early for efficacy. The publication of the DEFUSE 3 trial results instantly changed practice guidelines and clinical practice around the world. It is now standard of care to treat patients with endovascular therapy in the delayed time-window if they meet DEFUSE 3 imaging criteria. This change in practice has nearly doubled the number of patients that can be treated with endovascular therapy. Stanford’s regional network is one of the highest enrollers in StrokeNet studies and Stanford faculty have made major contributions to key StrokeNet committees. The Stanford-RCC will continue to provide high volume enrollment of diverse patient populations into NINDS funded stroke trials. The Stanford RCC will also continue to offer an innovative multidisciplinary fellowship program that provides comprehensive training in clinical trial design, implementation and analysis. In addition, Stanford faculty members will continue to propose new clinical trials for implementation through StrokeNet.

NIH Research Projects · FY 2025 · 2018-08

PROJECT SUMMARY Tyrosine kinase inhibitors (TKIs) have been shown to significantly decrease a variety of malignancy-related mortality in the past two decades. However, concerns have been raised due to their potential vascular toxicity that could lead to hypertension, myocardial infarction, stroke, and peripheral arterial diseases. Despite these safety concerns, the mechanisms underlying TKI-induced vascular toxicity (TKI-VT) are poorly understood. To overcome this challenge, we propose to leverage human iPSCs, state-of-the-art multi-omics methods, and CRISPR screening to investigate molecular and cellular mechanisms of TKI-VT and identify druggable targets that can be further tested in animal models. Specifically, in Aim 1, we will comprehensively profile human-induced pluripotent stem cell-derived cardiac pericytes (iPSC-PCs), an important but rarely explored cardiac cell type, to define cellular mechanisms of TKI-VT. In Aim 2, we will evaluate how TKIs induce disrupted cellular crosstalk between iPSC-PCs and iPSC-derived endothelial cells (iPSC-ECs) by performing integrative omics on a 3D vessel-on-chip (VoC) model. Finally, in Aim 3, we will perform CRISPR screening on TKI-treated iPSC-PCs and iPSC-ECs to identify potential druggable targets and validate their therapeutic efficacy in mice. Successful completion of these studies will lead to novel mechanistic insights into TKI-VT pathogenesis and help develop promising therapeutic strategies that can prevent and/or treat TKI-VT in cancer patients. Moreover, this proposal will help define the role of TKIs in vascular pathophysiology, which may have broad scientific and clinical implications beyond cardio-oncology.

NIH Research Projects · FY 2026 · 2018-07

PROJECT SUMMARY Gene and chromatin regulation are at the core of many human biological processes such as development and aging, and play an important role in disease, including during immune response and cancer progression. Much work was done over the last few decades to catalogue transcription factors and chromatin regulators, determine the gene regulatory elements where they act, and measure the chromatin states associated with them across different cell types. However, there are over a thousand transcription factors and chromatin regulators controlling gene expression in human cells. Similarly, on the DNA side, there are tens of thousands of gene regulatory elements in the human genome. Moreover, the function of these regulatory proteins (and hence of the DNA elements they bind to) can change over time in response to signals such as cell differentiation or immune responses to viral infections. These processes also show cell-to-cell heterogeneity that is important in cell-fate decisions. Consequently, our efforts to understand the general principles of gene and chromatin regulation in human cells and the type of dynamical responses they enable are severely limited by the fact that most experimental methods can only study a handful of proteins at a time, generally use methods that average across cell populations, and often only measure correlations at a given point in time. In order to address these challenges, we combine high-throughput synthetic biology, single-cell measurements of gene expression dynamics using fluorescence microscopy and flow cytometry, and mathematical modelling for both a systematic and in-depth understanding. We use these tools to answer essential question about gene and chromatin regulation in human cells: (1) How do transcription factors work: what are the biophysical rules governing their effector domains and interactions with coactivators and corepressors, and what type of dynamic responses do they enable? (2) How does the dynamics of gene silencing, activation and epigenetic memory depend on the architecture of gene regulatory elements such as enhancers, promoters, terminators and insulators? (3) What are strategies that viral proteins have evolved to interface with and perturb gene and chromatin regulation in human cells in order to increase viral gene expression and disrupt immune responses? Together, answering these questions quantitatively will help uncover the basic principles of gene regulation in human cells in the context of a dynamic chromatin environment, will provide new tools for genetic, epigenetic and cellular therapies, and will inform treatments of viral infections and immune disorders.

NIH Research Projects · FY 2026 · 2018-07

Summary Dilated cardiomyopathy (DCM) is a leading cause of heart failure and death. Despite the progress in unraveling the genetic basis of DCM, there is a lack of disease-modifying therapies that target the underlying genetic etiology. In preliminary studies, we identified the transcription factor 4 (ATF4) as a potential target for therapeutic interventions in genetic DCM. ATF4 is a critical factor mediating the integrated stress response; an adaptive pathway activated in response to stress. ATF4 is selectively translated in response to specific forms of cellular stress to induce the expression of genes involved in adaptation to stress. Here we propose a multidisciplinary approach to explore the potential role of ATF4-mediated regulation of one-carbon metabolism in cardiac physiology and develop novel mutation-agnostic gene therapy for DCM. In Aim 1, we will test whether ATF4 overexpression can rescue the contractility deficit, a hallmark of DCM, in a mutation-agnostic manner using iPSC-CMs derived for patients carrying DCM-causing mutation in diverse gene ontologies. In Aim 2, we will examine the potential role of ATF4-mediated regulation of one-carbon metabolism gene expression in cardiomyocyte function. In Aim 3, we will use AAV-mediated overexpression of ATF4 in vivo and test whether ATF4 signaling could reverse or halt the progression of DCM in vivo. Unlike conventional gene therapies, our approach does not replace a faulty or missing gene. Instead, our approach aims at triggering a cardioprotective effect by bolstering the ATF4-dependent one-carbon metabolism gene expression in the heart. We hope to provide proof-of-concept for a new clinically relevant therapeutic strategy, paving the way for mutation-agnostic treatments for genetic DCM. Such treatments are likely to apply to other types of cardiac diseases such as heart failure.

NIH Research Projects · FY 2024 · 2018-07

Project Summary/Abstract The objective of Stanford's Health Services Research Training Program (HSRTP) is to develop independent, diverse, well-trained researchers who conduct rigorous, innovative, reproducible, and responsible health services research (HSR) with the goal of improving the U.S. healthcare system. The program is motivated by our view that excellent HSR requires a strong grasp of core methodological skills and the ability to apply them to important real-world problems, diversity in its practitioners and in its practice, inter- and multidisciplinary engagement, and interaction with both traditional and emerging research questions. We thus incorporate strong training in our core disciplinary areas of health economics, decision science, and outcomes research and evaluation methodology; training in key foundational content areas like health equity and social determinants of health, healthcare delivery, and healthcare systems; exposure to cutting-edge data science and methodologies; and engagement with a range of academic and non-academic settings. We emphasize the presence of diverse perspectives in our trainees, mentors, and research environment. Trainees work in a rich multidisciplinary environment, frequently side-by-side with trainees and faculty from areas like clinical medicine, economics, engineering, ethics, informatics, and law. Mentored research experiences are central to our program. Trainees pursue independent research in their area(s) of interest, working with multiple mentors with complementary expertise including at least one mentor focused on career development. The program includes 42 faculty mentors, with diverse backgrounds, drawn from 16 departments or programs. Trainees will find opportunities to engage with experts in a wide variety of areas, including AHRQ priority areas of quality, safety, equity, access, affordability, and value. Our program takes advantage of collaborations with delivery systems including Stanford Medicine and its learning health care system, Kaiser Permanente, the Veterans Administration, and Intermountain Healthcare; our location in Silicon Valley and connections to leading private sector settings doing health- related research like Google, Apple and Facebook; and major investments in cutting-edge data and computing resources to support HSR along with leading investigators in advanced computing, machine learning, artificial intelligence, textual processing, and their application. The program will support 7 pre- and 3 postdoctoral trainees per year, providing 2–3 years of full-time support for each trainee. Predoctoral trainees earn a PhD in Health Policy or a related field and postdoctoral fellows with a professional degree (e.g., MD) commonly earn an MS in Health Policy. Postdoctoral trainees with a research degree focus on research complemented by our core curriculum and targeted electives. Our aim is that these trainees will strengthen the next generation of diverse HSR leaders, equipped to generate, translate, and disseminate the evidence needed to improve health care delivery in the United States.

NIH Research Projects · FY 2026 · 2018-07

Project Summary Ductal carcinoma in situ (DCIS) is the most common form of breast cancer, with 50,000 women diagnosed with DCIS annually in the U.S. Although only 20-30% of DCIS lesions will progress to the invasive disease (IDC), 97% of DCIS patients will undergo surgery with or without radiation. Therefore, markers of DCIS progression to IDC are urgently needed to prevent overtreatment. However, the events leading to DCIS progression are unknown, and previous studies have shown that they cannot be explained by genetic and transcriptomic changes in tumor cells. This suggests that elements of the tumor microenvironment (TME) other than cancer cell-intrinsic events might play a role in the transition from in situ to invasive breast cancer. Macrophages are one of the most abundant immune cell type in the TME, that survey the tissue, react to its changes, and orchestrate the immune response, making them ideal biomarker candidates. In the previous funding cycle, we demonstrated that several macrophage subtypes endowed with different functions and relations to cancer exist. We established the first human macrophage subtype-specific markers that, combined with novel formalin-fixed paraffin-embedded (FFPE) tissue-compatible profiling technologies, enable the study of the contribution of individual macrophage subtypes to tumor immunity using archival tissue specimens with known clinical outcome. In addition, we have extensive prior experience with breast carcinoma research and have access to well-studied cohorts of DCIS and IDC with long clinical follow-up. To this end, we found that a higher overall abundance of macrophages in DCIS predicts tumor progression to IDC. In addition, in the preliminary data to this renewal, we reveal a novel and previously overlooked human intraepithelial tissue-resident macrophage population located between the basal and luminal layers of the breast gland and show that it acquires distinct transcriptional signatures upon transition from normal breast epithelium to DCIS, supporting the notion that changes in macrophage compartment might be leveraged as markers of breast cancer development. Aim 1 will study how different macrophage subtypes change in the early events that lead to DCIS tumor formation and progression to IDC, while Aim 2 will seek to identify macrophage-specific markers of tumor progression from DCIS to IBC. Aim 3 will reveal the cellular interactions and molecular signaling shaping different macrophage functions by studying macrophage crosstalk with other tissue cell types, focusing on macrophage interactions with the most abundant TME cells—fibroblasts. The studies in this proposal will improve our understanding of the biology of breast cancer development and identify new prognostic markers and predictors of DCIS progression. Therefore, the proposed research is relevant to the NIH’s mission to develop fundamental knowledge that will help reduce the burdens of human disability and disease.

NIH Research Projects · FY 2025 · 2018-05

PROJECT SUMMARY LMNA-related dilated cardiomyopathy (DCM) is among the most prevalent forms of inherited heart disease, characterized by severe systolic dysfunction and ventricular chamber enlargement. Major hallmarks of LMNADCM also involve features of non-myocyte dysfunction including myocardial fibrosis and endotheliopathy. However, precise mechanisms of intercellular communication in the heart remain unclear, in part because the human cardiac secretome to date has been poorly defined. To overcome this challenge, we propose to leverage human iPSCs, genome-editing technology, and state-of-the-art omics methods to identify and investigate crosstalk signaling pathways potentially involved in LMNA-DCM pathogenesis. In Aim 1, we will comprehensively profile the baseline secretomes of each cell type by employing high-throughput aptamer-based proteomics methods, and perform trans-well co-culture assays to systematically evaluate the downstream functional consequences of cellular crosstalk. In Aim 2, we will complement these studies with further investigation into intercellular communication mechanisms in engineered heart tissues (EHTs) of varying LMNA-DCM / control cell type compositions. The EHTs will be subsequently analyzed by single-cell RNA sequencing (scRNA-seq) to predict cell-cell crosstalk modalities and construct a list of unique and shared ligand receptor pairs across conditions. In Aim 3, we will perform large-scale high-throughput screening of >4,000 compounds using multicellular iPSC-derived cardiac organoid (iPSC-CO) differentiated from tri-lineage reporter lines. Selected candidates will be validated and further investigated using proteomics and targeted gain/loss-of function studies. We anticipate that the successful completion of these studies will lead to new mechanistic insight into DCM pathogenesis, and help develop novel therapeutic strategies that can impede and reverse aberrant crosstalk signaling between cardiac cell types in the diseased heart.

NIH Research Projects · FY 2025 · 2018-05

PROJECT SUMMARY This program will renew the NEI T32 Stanford Vision Training Program. Based on excellence in postdoctoral training among our vision science faculty, our goal is to provide a vision-specific research training program with integrated clinical experience to the talented trainees aiming for careers as vision scientists and clinician-scientists. Specifically, we seek training support for 4 postdoctoral fellow slots per budget year for the next five years. The 38 primary vision research faculty in the Stanford Vision Training Program includes 21 PhDs, 4 MDs, and 13 MD/PhDs of all academic ranks, with strengths in diverse areas, including molecular and cellular vision biology, vision encoding and circuitry, development and genetics, in vivo imaging, higher order visual behavior and perception, mechanisms of diseases, and different approaches to the treatment of diseases. Together, the core vision faculty is currently funded by 140 grants totaling over $36M annually, of which 38 grants are from the NEI, 60 grants are from the NIH (including NEI), and the rest are from the Department of Defense, National Science Foundation, and various foundations. These are supplements with strong institutional support and commitment. Following the success from our first program cycle, developments to strengthen the next cycle of the Stanford Vision Training Program include leveraging the Stanford Ophthalmology Advanced Research Residency Program and enhancing our Executive Committee, External Advisory Committee, and Trainee Mentoring Committees. Efforts will continue towards the recruitment of a highly skilled cohort of vision research faculty to Stanford; unparalleled institutional resources committed by the department and by the Stanford University School of Medicine; formal classroom, clinical and laboratory training under the auspices of carefully crafted training plans; and ongoing semi-monthly and annual vision research symposia. Together with a consistently large, productive and diverse applicant pool, these will allow the Stanford Vision Training Program to produce future leaders in eye and vision research who are able to tackle the most interesting and important questions and open new horizons at Stanford and beyond.

NIH Research Projects · FY 2026 · 2018-05

PROJECT SUMMARY HIV drug resistance (HIVDR) is a threat to the success of antiretroviral (ARV) therapy (ART) and a major barrier to the elimination of AIDS as a public health problem. Persons with HIV who develop virological failure (VF) during ART are at high risk of developing HIVDR and transmitting a drug-resistant virus to others while persons primarily infected with a drug-resistant virus are at high risk of developing VF and a further increase in HIVDR. Comprehensive, accurate, and publicly available HIVDR data are essential for population-based monitoring of acquired and transmitted HIVDR, for the management of HIV-infected patients, and for identifying overall drug-development needs. A public database that curates, annotates, synthesizes, and disseminates data from HIVDR studies will make it possible to identify and characterize the HIVDR mutations most relevant to surveillance, clinical management, and drug development, and will expedite research into the mechanisms of HIVDR and the predictors of response to the newest ARV regimens. The Stanford HIV Drug Resistance Database (HIVDB) provides a unique conceptual framework for addressing data-intensive questions about the main molecular targets of HIV therapy: reverse transcriptase, protease, integrase, and capsid. HIVDB’s sequence analysis programs have also become integrated into the workflows of many research laboratories worldwide. Accomplishing the Aims of this proposal will assist researchers engaged in HIVDR surveillance, ART clinical trials, and ARV development by enabling them to identify gaps in the published literature, incorporate contributions from HIVDB into novel analyses, and discover new knowledge. Our first Aim will involve expanding HIVDB as a resource that provides the scientific foundations of the clinical and epidemiological significance of HIVDR mutations and that address gaps in HIVDR knowledge including the correlates of resistance to recently approved ARVs, established ARVs used for new indications, and the long-acting ARVs that will be used for prevention and treatment. We will implement strategies to increase data sharing to help ensure the long-term sustainability of this project. Our second Aim will involve extending the logic of HIVDB’s genotypic resistance test interpretation program to predict the virological response to ARV combinations and common ART regimens. We will demonstrate and promote the use of our sequence analysis software for the analysis of other pathogenic viruses for which antiviral therapy is available. Our third Aim will involve converting HIVDB into a fully open source and transferable project. Accomplishing this aim will support researchers using HIVDB to advance their research by enabling them to seamlessly integrate HIVDR data into their research. Accomplishing this aim will also foster the long-term sustainability of the HIVDB project.

NIH Research Projects · FY 2025 · 2018-04

Developmental biology is now both a molecular and systems-level science. Forward- and reverse-genetic technologies have identified individual genes that regulate tissue formation and contribute to their oncogenic transformation later in life. High-throughput sequencing has revealed the “omic” features that differentiate cellular states. Translating this knowledge into mechanistic understanding will require new scientific approaches, and chemistry can help bridge this gap. Chemical synthesis and protein engineering can empower us to interrogate tissue biology in new ways, and the resulting technologies and insights can lead to innovative treatments for human disease. With these goals in mind, our research group has explored the interface of chemistry and developmental biology. Over the past four years, we have developed an optogenetic system for targeted cell ablation, identified novel small-molecule inhibitors of Gli transcription factor function, and discovered the first specific inhibitors of aldehyde dehydrogenase 1B1 (ALDH1B1), a mitochondrial enzyme that is expressed in multipotent cells of the adult intestine and pancreas and promotes colorectal and pancreatic cancer. We have also used high-throughput and systems-level approaches to establish a regulatory model for ARHGAP36, a non- canonical Gli activator that controls motor neuron specification and can induce medulloblastoma. We now seek to build upon these accomplishments and explore new scientific directions. One focus of our research program will be the creation of new optogenetic tools that act through inducible allostery rather than proximity. To facilitate the discovery of such constructs, we have established a transposon-based platform that recapitulates the evolution of natural photoreceptors. Using this approach, we will develop optogenetic regulators of the Hedgehog pathway, focusing on light-oxygen-voltage (LOV) domain-functionalized forms of Smoothened and GLI1. We will elucidate the mechanistic basis of their light-dependent activities, optimize their functionality, and apply these reagents to study Hedgehog pathway-dependent patterning in zebrafish models. We will also extend this platform to other developmental pathways such as bone morphogenetic protein signaling. Our second research focus will be ALDH1 isoforms that are highly expressed in normal stem cells and integral to tumor initiation and progression. We will investigate the roles of ALDH1B1 in pancreatic cancer and develop specific inhibitors of ALDH1A3, a cytoplasmic enzyme that promotes breast cancer, melanoma, and glioblastoma, and other malignancies. In addition, we will pursue small molecules that target ALDH1A1 and/or ALDH1A2, motivated by the roles of these enzymes in spermatogenesis and their potential as non-hormonal male contraceptive targets. Collectively, our studies will open new windows into developmental biology and new doors to clinical therapies.

NIH Research Projects · FY 2026 · 2018-04

Unraveling the genetic basis of complex traits is a crucial step toward advancing human genetics and precision medicine. Despite significant progress, gaps remain in the molecular mechanisms underlying GWAS findings. My group has developed novel statistical and computational approaches for post-GWAS functional characterization and for individualized genetic risk assessment. These methods facilitate the systematic characterization of the genetic architecture underlying phenotypic variation, with a strategic emphasis on improving biological resolution and statistical generalizability. In parallel, we have developed and applied statistical tools to uncover regulators of human proteomic variation, generating one of the most comprehensive catalogs of protein quantitative trait loci (pQTL) in non-disease human tissues. Beyond providing novel insights on regulatory mechanisms, these pQTLs point to plausible genes and functions underlying complex trait GWAS associations that elude other omics analyses, such as eQTLs. Our long-term goal is to decode complex traits at molecular, individual, and population levels. The field of human complex trait genetics is entering a transformative era, fueled by advances in biobank-scale population cohorts, precise single-cell technologies, and revolutionary AI/ML tools. Inspired by these developments and building upon our expertise, we propose three innovative directions: (1) generating cell type-specific proteomic profiles by computational deconvolution of tissue-level data, thereby addressing experimental limitations in single-cell proteomics; (2) developing protein-prediction models informed by regulatory landscapes to enhance proteome-wide association studies (PWAS); and (3) constructing AI-assisted polygenic risk scores (PRS) that leverage biobank cohorts and capture complex allele interactions, producing generalizable and individualized PRS. Methodological innovation lies in the adaptive integration of heterogeneous data, while conceptual innovation incorporates biological insights into AI/ML-driven models. By leveraging emerging resources and computational advancements, the proposed research offers exciting opportunities for scientific discoveries that ultimately enhance clinical utility and precision health models across complex diseases.

NIH Research Projects · FY 2026 · 2018-04

Program Summary Our research is aimed at understanding the molecular and cellular mechanisms underlying the faithful inheritance eukaryotic chromosomes. Our primary focus is on elucidating the events required for the orderly segregation of homologous chromosomes during meiosis, the crucial process by which diploid germ cells generate haploid gametes. These events are of central importance to sexually reproducing organisms, since failure to execute them correctly leads to chromosomal aneuploidy, one of the leading causes of miscarriages and birth defects in humans. During meiotic prophase, chromosomes undergo a dramatic and dynamic program of structural reorganization in preparation for the meiotic divisions. Moreover, chromosome inheritance during meiosis relies on the formation of double-strand DNA breaks (DSBs) and repair of a subset of these DSBs as inter-homolog crossovers (COs). Because the DSBs that serve as the initiating events of meiotic recombination pose a danger to genome integrity, the success of genome inheritance during meiosis requires cells to maintain a balance between the beneficial effects of COs and the potential harmful consequences of the process by which they are generated. A major goal of our research is to understand the mechanisms that operate during meiosis to achieve this crucial balance. An inter-related goal is to understand how meiosis-specific chromosome organization is established, maintained, and remodeled to bring about successful segregation of homologous chromosomes. We are approaching these issues using Caenorhabditis nematodes, simple metazoan organisms that are especially amenable to an integrated application of powerful cytological, genetic, genomic, and biochemical approaches, and in which the events under study are particularly accessible. Our goal under the MIRA program is to pursue a systems-level understanding of meiosis, based on the recognition that multiple distinct aspects of the meiotic program are intimately interconnected, and that robustness of the system is an emergent property of this interconnectedness. Our approach will build on recent technical advances and new discoveries in the well-established C. elegans experimental system, in combination with opportunities afforded by a newly-introduced Caenorhabditis interspecies hybrid model, to interrogate the meiotic program at multiple levels. Planned areas of investigation will include: Elucidating mechanisms that ensure reliable formation of CO- based connections for all chromosome pairs; Exploring how different events and developmental transitions in the meiotic program are temporally and spatially coordinated; Investigating the functional organization of meiosis-specific chromosome structures that promote and regulate meiotic recombination and enable chromosomes to sense and respond to events occurring at distant positions; Pursuing a new approach aimed at understanding the fundamental basis of homolog recognition.

NIH Research Projects · FY 2026 · 2018-01

Severe maternal morbidity (SMM), which encompasses conditions that put pregnant women most at risk of dying (e.g., hemorrhage, sepsis, organ failure), doubled in the last two decades. The most common precursors to SMM – anemia, hypertensive disorders of pregnancy (HDP), and cesarean birth – are also increasing. This Renewal proposal builds on our prior work to address maternal outcomes. Via the Parent Grant, our team enhanced current understanding of the contribution of social context and maternal pre-pregnancy health to SMM risk, using a unique data resource we built of California (CA) births. This Renewal addresses several remaining gaps in our understanding of maternal health in the U.S. that were illuminated by the Parent Grant. We will build a unique resource of 14 million births in four states from 1997-2022. The dataset longitudinally links vital records (live birth and fetal death certificates) with hospital discharge data for mother and baby; includes residential census tracts; and links data for repeat pregnancies to the same person over time, thus providing the type of large-scale data with high-quality information on maternal health and social context that the field needs to advance population-level research on maternal health. All phases of the research will be guided by a community advisory board (CAB). Aim 1 will examine joint impacts of multiple risk factors on risk of SMM, its subtypes (i.e., hypertension-, hemorrhage-, and sepsis-related SMM), and its precursors (i.e., HDP, anemia, mode of birth). Risk factors include education, health care payer, and census tract-level markers of social disadvantage (e.g., unemployment, rurality). Using a reproductive life-course framework, Aim 2 will determine the cumulative impact of risk factors across successive pregnancies on maternal health (i.e., SMM, SMM subtypes, SMM precursors). We will examine how factors related to social context (e.g., persistently high census tract unemployment), morbidity (e.g., persistent hypertension), and mode of birth (primary cesarean birth) affect subsequent occurrence and recurrence of the study outcomes. Aim 3 will use findings from Aims 1 and 2 to identify and prioritize strategies to improve maternal health. We will use a) causal inference methods (mediation and g-computation) to understand mechanisms and compare the potential impact of selected hypothetical interventions on study outcomes, and b) community-engaged prioritization methods to synthesize our findings and prioritize next steps. By understanding risks across multiple risk factors and successive pregnancies, and guided by rigorous analytics and patient input, our work will contribute to advancing the next generation of actionable population-level SMM research.

NIH Research Projects · FY 2026 · 2018-01

Genome wide association studies (GWAS) have identified the transforming growth factor-b (TGFB) pathway as a prominent causal mechanism of coronary artery disease (CAD) risk. Through support provided by this funding mechanism, we have shown that disease protective TGFB canonical signaling factors SMAD3 and ZEB2 promote formation of disease-related transition smooth muscle cells (SMC) to a fibroblast-like phenotype, producing cells we term “fibromyocytes” (FMC) and inhibit SMC transition to a “chondromyocyte” (CMC) phenotype that is advanced by disease promoting genes such as PDGFD and TWIST1. In this renewal application we propose to extend these studies by investigating upstream signaling mediated by two TGFB superfamily members that link the BMP and TGFB pathways in a causal CAD regulatory network. Specifically, in this application we will pursue investigation of functional cellular interactions that are mediated by CAD associated factors BMP1 and TGFB1, which are linked in a feed-forward autoregulatory loop that impacts extracellular matrix (ECM) components and growth factors to mediate CAD risk through previously unexplored disease mechanisms. BMP1 is the primary regulator of TGFB1 bioavailability through post-translational prodomain processing, and as a metalloproteinase also directly activates other TGFB growth factors and extracellular matrix molecules such as collagens and lysyl oxidases that can promote stability of the fibrous cap. In keeping with previous studies, causal gene TGFB1 is expected to mediate SMC disease transition phenotypes through canonical signaling, but is also expected to mediate SMC cell state changes through unexplored non-canonical signaling pathways. We hypothesize that protein products of these two prominent CAD genes, BMP1 and TGFB1, regulate each other’s expression and function to modulate SMC phenotype transitions, ECM composition, and thus lesion integrity in the context of a CAD gene causal nexus. Thus, to better understand how BMP1 and TGFB1 interact to modulate the function of other growth and matrix factors that determine structure and stability of the plaque and fibrous cap, we propose the following Aims. Aim 1 studies will investigate the cellular anatomy of vascular lesions, as well as genome wide transcriptomic effects of SMC-specific Bmp1 modulation, in a mouse atherosclerosis model. In Aim 2, we will perform identical studies investigating genetic manipulation of Tgfb1 and compare transcriptional and lesion features of these two linked CAD causal factors. In Aim 3, we will use in vitro SMC models to further investigate how BMP1 regulates TGFB1 bioavailability and function of other ECM molecules involved in SMC- specific disease processes. These studies will significantly expand our understanding of genetic CAD mechanisms and identify targetable genes and pathways for new approaches to the treatment of CAD.

NIH Research Projects · FY 2025 · 2017-12

Skin, muscle, joints, and internal organs encapsulate specialized sensory neurons that detect mechanical cues in the form of touch and movement. The ability to perform most, if not all of the essential activities of daily living depends on information from these somatosensory, proprioceptive, and visceral sensory neurons. Thus, a better understanding of their function and sensitivity to mechanical and chemical stress is of vital importance for health. This research program focuses on the skin-neuron composite tissues responsible for touch and seeks to decipher how mechanical force is translated from the skin surface to embedded sensory neurons and converted into electrical signals that give rise to tactile perceptions. The work combines genetic dissection in a simple invertebrate (C. elegans nematodes) with electron microscopy, high-performance tools (self-sensing cantilevers) for delivering mechanical stimuli under feedback control and for optically monitoring tissue deformation and neuronal activation with electrophysiology and calcium imaging. The research team includes biologists, engineers and physicists and integrates experimental work with theory and simulation. In addition to seeking a comprehensive understanding of mechanosensation by skin-neuron composites, the research program will also address the outstanding question of how neurons bend without breaking. Based on preliminary work, we also plan to leverage our knowledge of touch sensation and its molecular basis to investigate how chemical stressors linked to diabetes (glucose) and chemotherapy (paclitaxel) affect the function and morphology of skin-neuron composites. The knowledge we seek to acquire is relevant to all animals, including humans that rely on skin-neuron composites for touch sensation.

NIH Research Projects · FY 2025 · 2017-12

Pulmonary arterial hypertension (PAH) is a life-threatening disorder characterized by elevated pulmonary pressures and right heart failure. A hallmark of PAH pathology is progressive loss and inappropriate regeneration of pulmonary and right ventricular (RV) microvessels. Pericytes are highly specialized mural cells that interact with endothelial cells to provide structural support and facilitate vessel maturation during angiogenesis. Our studies show that inability to establish proper endothelial-pericyte (EC-PC) interactions is associated with pulmonary small vessel loss and insufficient angiogenesis in PAH, leading us to speculate that targeting the mechanisms that orchestrate EC-PC interactions could open new therapeutic opportunities for PAH. We have demonstrated that dysfunctional Wnt/planar cell polarity (PCP) signaling contributes to small vessel loss in PAH by disrupting lung EC-PC interactions. We found that pulmonary microvascular endothelial cells (PMVECs) release Wnt5a to recruit lung pericytes via ROR2-dependent Wnt/PCP activation in pericytes. Compared to healthy donors, both Wnt5a production and ROR2-dependent Wnt/PCP activation are significantly reduced in PAH PMVECs and pericytes, respectively. We also found that endothelial-specific Wnt5a deletion in mice was associated with decompensated RV failure characterized by disrupted EC-PC interactions and reduced RV capillary density. Based on our findings, we hypothesize that loss of Wnt/PCP signaling contributes to lung and RV vessel dysfunction in PAH by disrupting the establishment of EC-PC interactions and angiogenesis. In this renewal, we plan to: (Aim 1) Elucidate the mechanisms responsible for inappropriate Wnt5a expression by PAH PMVECs, (Aim 2) Elucidate the mechanisms responsible for dysfunctional ROR2 activity in PAH pericytes, and (Aim 3) Demonstrate that Wnt5a/ROR2 signaling plays a key role in RV remodeling and angiogenesis in response to PAH. Understanding how Wnt/PCP orchestrates endothelial-pericyte interactions will provide insight into the PAH pathogenesis and open new therapeutic opportunities to promote regeneration of lost vessels, prevent progression and improve clinical outcomes for patients afflicted with this devastating disease.

NIH Research Projects · FY 2025 · 2017-09

SUMMARY - OVERALL The Stanford vision research community is comprised of an impressive array of faculty bridging all levels of vision research, from molecular to cellular to circuits to systems, from development to adult to disease. The Stanford Vision Research Core grant will bring 4 modules to this community: (1) Advanced Computing/Computational Core, (2) Device Design and Development, (3) Neurogenetics of Vision, and (4) Imaging Structure and Function. These cores will be positioned to amplify the considerable resources Stanford University is devoting to the growth of vision research, including new faculty recruiting in the Department of Ophthalmology and the Stanford Neurosciences Institute and new space allocation to wet- and dry-lab vision research, as well as commitments from the Department of Ophthalmology for additional administrative capacities. Bringing these 4 cores to this community will help us achieve a number of specific outcomes. 1) We will extend the reach of vision research among the NEI-funded investigators at Stanford: by providing core resources and services to investigators, this grant will centralize specialty capacity, allowing faculty to benefit from the ready availability of such expertise. 2) We will accelerate discoveries in these laboratories: the availability of new resources that specifically target areas of need across the vision research community at Stanford will allow research to move more quickly into new, cutting edge areas of innovation. 3) We will promote inter-disciplinary collaboration that bridges molecular through systems level vision research: The selection of these 4 cores also carries a specific intention to bring vision research at Stanford into a “next-generation” position bridging across disciplines. Offering these tools, with cell- and species-compatible vectors, device development, advanced imaging, and the computational power to extract relevant data from these, will facilitate this bridging. Finally, 4) We will attract new faculty at junior through senior levels into vision research: by providing tools specific to vision research, and making these tools available broadly to the Stanford research community, we will facilitate entry into vision research by both seasoned investigators in other fields, and newly recruited junior investigators poised to become the next generation of leaders in vision research.

NIH Research Projects · FY 2025 · 2017-09

PROJECT SUMMARY The cerebrovasculature is a highly specialized vascular bed where cellular and molecular components of the blood-brain barrier (BBB) stringently regulate entry into the central nervous system (CNS). BBB disruption occurs in diseases such as stroke, brain tumors and multiple sclerosis and thus improved mechanistic understanding and directed therapies are urgently needed. Through convergent genetic and biochemical studies, we and others have defined a GPR124/RECK/WNT7 pathway that is essential for BBB function during embryogenesis and during pathologic states such as stroke and glioblastoma. In the prior granting period, we demonstrated that the GPI-anchored membrane protein RECK binds and stabilizes newly secreted WNT7 for presentation to Frizzled (FZD), the canonical WNT receptor. Remarkably, the GPCR-like 7-pass transmembrane protein GPR124 synergizes with RECK to potently amplify signaling by WNT7A/WNT7B but not by the other 17 WNTs. While GPR124 function in the BBB has been unequivocally established by in vivo knockout (KO) and in vitro transfection studies, its molecular mechanism remains an enigma and clinical translation has been elusive. Here, we pursue both mechanistic and translational investigations into the GPR124/RECK/WNT7 pathway, building upon substantial preliminary data. Aim 1 investigates the hypothesis that GPR124 is crucially required for coupling of the ligand WNT7 and receptor RECK to the downstream FZD/LRP signaling complex. We utilize doxycycline-inducible WNT7 expression to initiate WNT7 signaling, surmounting historical difficulties with WNT7 protein solubility and production, overlaid upon isogenic brain endothelium with and without GPR124 expression, to defining signaling complex dynamics with RECK, FZD and LRP by co-immunoprecipitation and single molecule resolution live imaging studies. Aim 2 explores the hypothesis that WNT7- and GPR124- dependent signaling can induce human cerebral angiogenesis and neurovascular unit (NVU) formation, leveraging our novel adult human brain organoid system that develops extensive vascular networks and accurately recapitulates NVU cellular interactions within a neuronal context. These adult-derived brain organoids, developed in the previous granting period, contrast strongly with conventional avascular iPSC-derived brain organoids. Lastly, Aim 3 investigates the translational potential of the GPR124/RECK/WNT7 pathway through the hypothesis that agonistic GPR124 ectodomains with and without novel bioengineered FZD4 agonists, administered post-stroke, can improve outcomes in the transient middle cerebral artery occlusion stroke model. In all, this renewal application leverages substantial progress in the prior granting period to pursue a comprehensive and multidisciplinary approach to GPR124/RECK/WNT7 mechanism and preclinical translation, towards the development of BBB-targeted stroke therapeutics.

NIH Research Projects · FY 2025 · 2017-09

Abstract For this CIMAC renewal, the Stanford Cancer Immune Monitoring and Analysis Center (CIMAC) will continue to collaborate with NCI and the CIMAC/CIDC network to identify and, where appropriate, lead correlative studies for trials testing novel immunotherapy regimens. We will participate in working group calls, network meetings, and coordination with clinical teams. The Stanford CIMAC performs highly comprehensive assays of immune phenotype and function for NCI-identified clinical trials. These will include already validated and harmonized Tier 1 assays, validated Tier 2 assays, and newly proposed exploratory Tier 3 assays. For Tier 1 assays, we propose CyTOF, singleplex IHC, Olink, TCRseq and RNAseq. For Tier 2, we propose single-cell TCRseq, MIBI, ATACseq, and CyTOF proteomics. For Tier 3, we propose single-cell glycan imaging (by MALDI-ToF), spatial transcriptomics (Nanostring DSP platform), and single-cell genomics/proteomics (Mission Bio Tapestri and BD Rhapsody platforms). We will use longitudinal reference materials for tracking inter-batch and inter-project consistency. We will assess quality control measures on all assays before uploading data to the Cancer Immune Data Commons (CIDC) according to their specifications. We will also perform biostatistical analysis of results for all assays performed, in relation to clinical outcome data. For those trials where Stanford is the lead CIMAC, we will perform integrative analysis across assays, using appropriate machine learning techniques and multivariate regression algorithms such as LASSO or Elastic Net. We will work closely with the clinical teams to obtain standardized clinical data, and to disseminate and publish results in accordance with NCI guidelines.

NIH Research Projects · FY 2025 · 2017-09

CENTER OVERVIEW: PROJECT SUMMARY/ABSTRACT The Stanford Diabetes Research Center (SDRC) embodies the culmination of a strategic plan by the Stanford University School of Medicine to create a premier program founded on a base of superb, collaborative investigators studying basic, clinical and translational problems in diabetes research. The SDRC mission is to foster innovation, new knowledge, and training in diabetes-related research, leading to improved diagnosis, treatment, and ultimately, prevention and cure of diabetes and its complications. Renewal of this P30 application will leverage diabetes research at Stanford University by providing crucial resources dedicated to supporting investigations and enrichment activities focused on diabetes. Stanford has a strong tradition of academic excellence, innovation, and clinical care, united in a true University on a single campus that fosters interactions between scientists and clinicians from different disciplines. Stanford is in the heart of Silicon Valley, an epicenter of innovation and calculated risk-taking, whose companies partner with SDRC faculty in unique and growing collaborations to advance diabetes research and care. Stanford neighbors two Universities of California (UC) at Berkeley, and at Davis, both elite research centers with a growing diabetes research base unconnected to a NIDDK DRC. The SDRC is comprised of 124 members from 3 Schools at Stanford, and from multiple Schools at UC Berkeley and UC Davis. SDRC members at Stanford currently have $65,044,250 in annual direct costs for diabetes-related research. SDRC members are organized by affinity groups focused on (i) Islet & Pancreas Biology, (ii) Metabolism & Signaling, (iii) Immunology, Transplantation & Stem Cell Biology, and (iv) Bioengineering & Behavioral Sciences. The SDRC consists of: (1) Administrative Component that coordinates scientific, organizational, enrichment, training and outreach activities, (2) Biomedical Research Component that recruits and selects members, and supervises 4 Research Cores that facilitate and enhance their research, and (3) a successful SDRC Pilot and Feasibility (P&F) Award Program that promotes the diabetes research of early stage investigators, and established scientists new to diabetes research. We propose to expand this Program to include a Regional P&F Program that supports research at UC Davis and Berkeley. NIH support for the SDRC is amplified by (1) Stanford’s sustained commitment to provide space and significant financial resources, (2) a comprehensive array of institutional research cores, which allow NIDDK funds to support specialized SDRC research cores devoted to diabetes research, (3) collaborative efforts with other Stanford research centers, and (4) SDRC member leadership of high-profile national diabetes research efforts. Since P30 funding began in 2017, the SDRC has evolved, including growth of its investigator base, intensified focus on translational research, and modification of core services to provide indispensable support for diabetes research. By multiple metrics, the SDRC is a force multiplier of innovation, whose members make seminal scientific contributions related to basic and translational diabetes, obesity, and metabolism research.