Stanford University

NIH Research Projects · FY 2024 · 2023-08

While there have been great advances in HIV therapies over the past decades, the only true cure so far has been through hematopoietic stem cell transplant (HSCT) of cells naturally lacking the HIV co-receptor CCR5. Due to the toxicity of conditioning regimens prior to HSCT and significant morbidity due to graft-verses-host disease (GVHD), allogeneic HSCT is not a viable option for most patients. With the advent of CRISPR, modification of a patient’s own cells to prevent GVHD is now possible, but thus far the efficiency at which cells have been modified was not enough to prevent viral rebound in the absence of anti-retroviral therapy. In line with the rationale for combination anti-retroviral drug therapy to target multiple steps in replication, we have developed a multi-factor knock-out/knock-in strategy for editing CD34+ hematopoietic stem and progenitor cells which allows greater than 90% deletion of CCR5, as well as up to 50% allelic knock-in of two inhibitory peptides targeting either fusion (C46V2o) or uncoating (a human-rhesus chimeric TRIM5a). When using this strategy to edit primary human CD4+ T cells, the efficiency of knock-out/knock-in is sufficient for complete inhibition of CCR5-tropic virus (BaL), and an average of more than 700-fold inhibition of CXCR4-tropic virus (NL4-3) when tested across 5 different primary human T cell donors. While these data are extremely promising, there was a large disparity in the efficiency of inhibition of CXCR4-tropic replication by the human- rhesus TRIM5a, with some T cell donors showing greater than 1,000-fold inhibition in the hRhTRIM5a knock- in condition, and some showing little or no significant inhibition of replication. This observation was in spite of sustained levels of allelic knock-in and hRhTRIM5a RNA expression throughout the course of the infection, and no resistance mutations observed in the infectious virus at endpoint. We therefor propose here to study the underlying T-cell/TRIM/virus interactions which may be uniquely donor specific and influence viral replication including T cell cytokine expression, viral reactivation, and expression of endogenous cellular factors that may act as a dominant negative to our inhibitory hRhTRIM5a in addition to investigation of other TRIM-related factors for inhibition such as TRIMCyp. Although the final goal is to develop a therapy through transplantation of edited hematopoietic stem and progenitor cells, this proposal is entirely based on editing and investigating the mechanisms of restriction in differentiated primary human target cells such as CD4+ T cells, monocytes, and macrophages in order to better understand the biology within our editing platform and allow eventual improvement of the platform. Successful completion of this proposal will allow a better understanding of mechanisms of restriction in primary cells where often these mechanisms have been predominantly studied in immortalized cell lines. In addition, completion of this proposal to improve our therapeutic platform will widen the pool of patients potentially able to be treated using genetically modified autologous HSCT such as patients later in infection that may have predominantly CXCR4-tropic virus.

NIH Research Projects · FY 2025 · 2023-08

PROJECT SUMMARY This comprehensive training program described in this five-year proposal is designed to prepare Dr. Staudt to transition to a career as a productive independent investigator focused on deciphering the molecular mechanisms underlying diastolic heart disease. Over the course of the described studies, Dr. Staudt will expand his skills in induced pluripotent stem cell-derived cardiomyocyte phenotyping at the single-cell level, as well as acquire new skills in biophysical analysis of pathogenic myosin mutations and high-throughput assay design and analysis. Further, he will obtain substantial experience and training in mentorship, scientific presentation, and grant writing. These skills will be crucial for his successful transition to independence. This proposal assembles an impressive team of world-renowned experts in cardiovascular biology to guide him, including his co-mentors, Drs. Mark Mercola and Euan Ashley, as well as the members of his mentorship committee, Drs. Joseph Wu, Marlene Rabinovich, and Don Bers. Their support will provide the resources and mentorship that Dr. Staudt needs to succeed in an independent academic career at the conclusion of the K08 award. The scientific aim of this project is to uncover mechanisms leading to diastolic dysfunction, an abnormal stiffness of the ventricular muscle that contributes to nearly half of heart failure cases. Specifically, this proposal focuses on Pediatric Restrictive Cardiomyopathy (RCM), a severe genetic disorder characterized by isolated, profound diastolic dysfunction. Patients with this disease have few treatment options, stemming from a relative lack of understanding of the molecular mechanisms underlying this disease. This proposal leverages novel stem cell models of RCM combined with high-throughput measurement of diastolic function to probe these mechanisms. In Aim 1, multiple cellular models of RCM will be characterized and compared to determine whether different classes of RCM mutations act via similar or divergent mechanisms. Aim 2 uses a functional genomics approach to determine whether different mutations evoke distinct pathogenic mechanisms that converge on a similar clinical presentation. Aim 3 focuses on a unique line from a patient with severe, pediatric onset RCM caused by a de novo mutation in cardiac myosin. In this aim, a novel multi-scale approach links the biophysical effects of this RCM mutation on myosin molecules to the physiologic changes in whole cells, and compares this to a comparable, previously characterized myosin mutation that causes Hypertrophic Cardiomyopathy, a more common but generally less severe disease.

NIH Research Projects · FY 2025 · 2023-08

7. Project Summary / Abstract. Prolonged sitting and inadequate moderate to vigorous intensity physical activity (MVPA) are pervasive risk factors for cardiovascular disease (CVD).1–6 CVD is the leading cause of death globally, prematurely taking 655,000 American lives annually.7 Recent research has shown that some benefits of moderate to vigorous physical activity can be accrued in motivationally accessible, short, 2-5 minute bouts throughout the day rather than needing to be a single, longer, continuous bout.8–13 Identifying an effective intervention to interrupt prolonged sitting throughout the day with short, 2-5 minute bouts of MVPA, “exercise snacks,” can provide an accessible way for adults with sedentary jobs to change two CVD risk factors. The current R34 proposes to user-test and pilot the acceptability, feasibility, and clinical signal detection of a novel intervention, MOV’D, to interrupt prolonged sitting with short bouts of MVPA, compared with a Fitbit-only control. Preliminary evidence from an NHLBI K01-funded proof-of-concept study found that evidence-based behavior change technique (BCT) texts to a private, social-media based support group increased steps throughout the day compared to a Fitbit-only control group, but the effects did not last. MOV’D significantly adds to this initial work by: adding videos teaching exercise snacks and BCTs to increase initial and maintained change; adding a peer-coach feature to increase engagement; targeting exercise snacks instead of single exercise bouts; and targeting an at-risk, understudied population (receptionists and clerical health care staff with CVD risk factors). Our team partnered with upper management of Stanford clerical health care staff (low wage positions with high job constraints on physical activity). Together, we have occupationally-tailored the MOV’D program. Before conducting a fully-powered efficacy trial (ORBIT Phase III), we need to user-test and refine two intervention components with our target population (ORBIT Phase Ib; Aim 1); and conduct the necessary acceptability, feasibility, and clinical signal detection pilot trial (ORBIT Phase IIb; Aim 2), which will obtain recruitment and retention parameters to inform the Phase III trial. The Aim 1 user-testing of both the exercise snack and BCT videos will be done with participants from the target population to ensure learning effectiveness, appropriateness, and acceptability. The Aim 2 pilot will randomly assign n=60 participants from the target population to either MOV’D or a Fitbit-only control for 6-weeks, with a 6-month follow-up. We will compare immediate and 6-month data to a priori benchmarks for acceptability, feasibility, and clinical signal detection in workday prolonged sitting bout length and workday MVPA minutes. Results from the proposed R34 will directly inform the R01 for the Phase III trial of MOV’D to test efficacy and duration of effects. The long-term objective is to have a scalable, widely-accessible, remotely-delivered, low-cost behavioral intervention to decrease CVD risk, and is easily adaptable to different populations. Additionally, we will have a library of vetted exercise snack and BCT videos and a guide for occupational-tailoring and adapting videos for researchers in this space.

NIH Research Projects · FY 2025 · 2023-08

Project Summary/Abstract Chronic low back pain (CLBP) is a pervasive disorder affecting up to one-fifth of adults globally and is the single greatest cause of disability worldwide. Despite the high prevalence and detrimental impact of CLBP, its treatments and mechanisms remain largely unclear. Biomarkers that predict symptom progression in CLBP support precision-based treatments and ultimately aid in reducing suffering. Longitudinal brain-based resting- state neuroimaging of patients with CLBP has revealed neural networks that predict pain chronification and its symptom progression. Although early findings suggest that measurements of brain networks can lead to the development of prognostic biomarkers, the predictive ability of these models is strongest for short-term follow- up. Measurements of different neural systems may provide additional benefits with better predictive power. Emotional and cognitive dysfunction is common in CLBP, occurring at the behavioral and cerebral level, presenting a unique opportunity to detect prognostic brain-based biomarkers. Likewise, improvements in electroencephalogram (EEG) neuroimaging strategies have led to increased spatial resolution, enabling researchers to overcome the limitations of classically used neuroimaging modalities (e.g., magnetic resonance imaging [MRI] and functional MRI), such as high cost and limited accessibility. Using longitudinal EEG, this patient-oriented research project will provide a comprehensive neural picture of emotional, cognitive, and resting-state networks in patients with CLBP, which will aid in predicting symptom progression in CLBP. Through this mentored career development award (K23), I will use modern EEG source analysis strategies to track biomarkers at baseline and 3- and 6-month follow-ups and their covariance with markers for pain and emotional and cognitive dysfunction. In Aim 1, I will identify and characterize differences in resting-state, emotional, and cognitive networks between patients with CLPB and age/sex-matched controls. In Aim 2, I will identify within-subject changes across time and their relationship with clinical symptoms. In Aim 3, as an exploratory aim, I will apply machine- and deep-learning strategies to detect a comprehensive signature of CLBP using EEG features from resting-state, emotional, and cognitive networks. Throughout the award period, I will develop new and advanced skills in understanding CLBP and its comorbidities as well as in EEG signal- processing strategies, machine-/deep-learning algorithms, career development, and grant writing. To accomplish the proposed study and training, I have gathered a world-class team of experts in pain imaging, physiology, psychology, EEG, and statistical learning as mentors. This training will build on my prior experience in psychophysiology to achieve my long-term goal of becoming an R01-funded investigator focused on patient-oriented research in chronic pain and psychophysiology.

NIH Research Projects · FY 2024 · 2023-08

Project Summary/Abstract Ischemic heart disease affects more than 197 people worldwide every year. Despite advances in macro revascularization techniques such as coronary artery bypass grafting and percutaneous coronary intervention, many patients progress to heart failure due to residual microvascular perfusion deficits. Although the adult human heart appears to be unable to significantly regenerate myocardium after injury, neonatal mice and pigs are capable of efficient angiogenesis and myocardial regeneration during the first week of life. Endogenous angiogenic and regenerative pathways are intricately linked to the wound-healing inflammatory cascade, extracellular matrix remodeling, endothelial cell migration, and cardiomyocyte proliferation. Consequently, the infarct border zone, which is the spatial intersection of these cellular processes, has proven to be a complex and dynamic microenvironment to investigate. In this proposal, we describe a novel application of a multiplexed immunofluorescent imaging platform with single cell resolution called CODEX (co-detection by indexing) which was developed here at Stanford. With the guidance and mentorship described in the research training plan, we have compiled an advisory committee of physician and surgeon-scientists, cardiologists, cell biologists, and the experts in CODEX from Stanford's Cell Sciences Imaging Facility. If awarded this Fellowship, this multidisciplinary team is uniquely positioned to execute this first of its kind application of CODEX to myocardial regeneration. CODEX will be used to characterize the longitudinal changes in the spatiotemporal relationship between the resident cells of the myocardium and the paracrine pathways that govern angiogenesis and myocardial regeneration. CODEX is an extension of immunofluorescence microscopy that utilizes antibodies conjugated to DNA barcodes to simultaneously quantify up to 44 antigens in situ. In Aim 1 we will apply CODEX to neonatal mouse and pig LAD ligation models of myocardial regeneration to define novel spatial phenotypes of angiogenic and inflammatory cellular neighborhoods throughout the neonatal period of regenerative potential in comparison to non-regenerating adults. After characterizing the cellular microenvironments and cell-signaling activity of natural angiogenesis in neonatal mammals, in Aim 2 we will investigate the effect of exogenous modulators of angiogenesis and the acute inflammatory response in adult mice and pigs. As an animal model for myocardial regeneration, the regulatory pathways that govern natural angiogenesis and subsequent myocardial regeneration in the mouse and pig are the subject of great interest due to their potential therapeutic benefit in humans. By using CODEX to study the complex interplay between multiple cell types, paracrine signaling pathways, and intercellular processes we hope to advance our mechanistic understanding of natural neonatal angiogenesis and myocardial regeneration and identify new therapeutic targets for ischemic heart disease, which has the potential to advance the treatment of millions of patients worldwide who are suffering from ischemic heart disease.

NIH Research Projects · FY 2025 · 2023-08

Dr. Anisha Patel is a midcareer pediatrician-researcher at Stanford applying for a K24 Midcareer Investigator Award in Patient-Oriented Research (POR). Dr. Patel has excellent training in research (public health, health services research, community-engaged research, health policy). She has built an innovative research program that leverages community-academic partnerships to prevent obesity and cardiometabolic diseases funded by federal agencies, foundations, and institutional support. She also has an extensive history of mentoring in POR. As Associate Professor of Pediatrics at Stanford in many formal mentoring roles and as Director of Community-Engaged Research in Stanford’s Maternal and Child Health Research Institute, Dr. Patel is poised to mentor early and junior clinician-investigators in translational science. Dr. Patel is conducting numerous community-engaged studies to prevent childhood obesity that provide training opportunities for mentees. The first two aims of this application focus on two R01-funded cluster randomized-controlled trials (CRTs) examining the impact of drinking water promotion and access on children’s intake of water and sugar-sweetened beverages, and obesity in elementary schools (Water First, n=1249 students) and childcare centers (Healthy Drinks, Healthy Futures, n=420 children).This K24 award will leverage these two trials by applying the RE-AIM framework to examine the interventions’ reach, effectiveness, adoption, implementation, cost, and maintenance. The Specific Aims are to: 1) Estimate the short-term cost, population reach and effectiveness of Water First and Heathy Drinks, Healthy Futures interventions in increasing water intake, decreasing SSB intake, and preventing overweight, 2) Examine the impact of the interventions among different groups, and 3) Describe how the impact of the interventions differ by fidelity to the intervention implementation strategies. These data will be used to translate evidence into practice and adapt the interventions for “real-world” settings. The research will also provide a platform for training experiences in conduct of CRTs, community-engaged research, dissemination and implementation science, intervention development, mixed methods, dietary assessment, and statistical analysis. The award will also allow Dr. Patel to expand her mentoring of early stage clinical investigators pursing translational POR and support her own career development in 1) gaining and applying mentorship and leadership skills, 2) building novel research with multi-disciplinary investigators, and 3) fostering new research expertise in dissemination and implementation research and economic evaluation at an opportune time in her career.

NIH Research Projects · FY 2025 · 2023-08

Project Summary/Abstract The balance between immune tolerance and activation lies at the heart of most pathologies. Immunological tolerance refers to the set of processes that prevent immune activation against non-pathogenic antigens. The key distinguishing feature of tolerance compared to other forms of immunosuppression is that it operates to inhibit reactivity only to specific antigens and does not render the host immunosuppressed with respect to unrelated pathogens. Immune homeostasis relies upon precise tuning of this tolerance-activation axis, and disruption of this balance results in autoimmunity or malignancy. To date, nearly all our treatments for autoimmune disease result in some form of nonspecific immunosuppression. Conversely, while immunotherapies represent the greatest paradigm shift in oncology in decades, they largely act to induce broad immune activation in a nonspecific manner that often results in adverse events, including autoimmune pathologies. In solid organ transplantation, our inability to induce complete graft tolerance often requires the use of lifelong immunosuppressants. Thus, despite over a half-century of research into immunological tolerance, there remains a pressing need to develop therapies capable of controlling antigen-specific immunological tolerance for a wide range of diseases and clinical settings. In this proposal, we seek to develop a new class of modular immunotherapies that couple intrinsic T cell biology with synthetic biology and genome engineering to reeducate endogenous tolerance programs in the host. We hypothesize that by activating or disrupting aberrant tolerance programs, we can treat autoimmune disease and metastatic cancer. Lymph nodes are the anatomical hubs of peripheral tolerance induction, a feature that is coopted by malignancies as they metastasize throughout the host. Unlike conventional engineered cell therapies whose mechanism of action relies upon cytolysis of pathogenic cells, including tumors or autoreactive lymphocytes, the engineered cell therapies that we propose instead function by trafficking to lymph nodes to alter endogenous tolerance induction resulting in resolution of autoimmunity or treatment of metastatic cancer. To achieve these goals, we will develop a T cell therapy that specifically homes to lymph nodes by coopting intrinsic naïve T cell homing machinery. In the context of metastatic cancer, we will augment this approach with the inclusion of chimeric antigen receptors (CARs) that break immune tolerance and induce activation upon ligation of the CARs following trafficking to LNs. In the context of autoimmunity, our therapies will induce tolerance following recognition of autoantigen presentation by antigen presenting cells in lymph nodes. Thus, at the conclusion of this project, we will deliver a new class of modular immunotherapies that harnesses the endogenous immune response in an antigen-specific manner. This approach has the potential to deliver cures to patients suffering from debilitating autoimmunity and stage IV cancer and is readily extensible to transplantation, pregnancy, and infectious disease settings.

NIH Research Projects · FY 2025 · 2023-08

PROJECT SUMMARY Poverty-related adversities place children at an increased risk for developing behavioral self-regulation difficulties that disrupt their capacity to learn and thrive across the lifespan. With nearly 12 million children growing up in poverty in the United States, this represents a monumental public health concern. Clarifying the environmental determinants and underlying mechanisms that explain associations between poverty and child self-regulation skills is central for the creation of policies that address families’ challenges while leveraging extant strengths. Several complementary theoretical frameworks of early life adversity suggest that the accumulation of economic deprivation and psychosocial threat, and their corresponding patterns of (un)predictability, shape distinct developmental mechanisms that prepare children to meet the demands of their specific environments. This project bridges novel methodological and theoretical approaches to characterize dynamic patterns of change in early-life experiences in the context of poverty, and examine the role such experiences play in shaping children’s self-regulation in early childhood. Early childhood is marked by substantial neurodevelopmental changes that support the emergence of self-regulatory skills needed to meet the learning and psychosocial demands of schooling. Effects of poverty on these developing regulatory systems are present as early as infancy, with more years spent at or below the federal poverty line predicting greater self-regulation difficulties over time. Yet, how poverty leads to such disparities remains largely unknown. The type, timing, and temporal variability in poverty-related experiences, and their respective roles on contextually-adaptive self-regulation skills in early childhood, may be candidate mechanisms underlying the effects of child poverty on long-term outcomes. The current project addresses two aims using data from a large mixed-methods national survey (N~13,000) of predominantly low-income families during the pandemic. Aim 1 will apply innovative psychometric, time-series, and qualitative approaches to understand what, when, and for whom poverty-related experiences are most salient (1a), as well as how and under which conditions such experiences unfold (1b). Aim 2 will leverage quasi-experimental methods (i.e., propensity scores) to test the putative impact of experiences revealed in Aim 1 on children’s emerging self-regulation skills as they transition to formal schooling. Findings will afford novel and timely insights into the complex ways in which early poverty-related experiences affect children’s ability to thrive, with broad implications for public health and well-being during a monumental point in history that calls for much-needed policy reform. Under the guidance of Sponsors Fisher, Obradovi?, and Frankenhuis, the proposed research and training plan will prepare the applicant for a career as an independent researcher focused on the basic, translational, and applied study of child poverty and self-regulation.

NIH Research Projects · FY 2024 · 2023-08

PROJECT SUMMARY / ABSTRACT The devastation wrought by cancer derives primarily from the capacity of tumor cells to evolve. Metastasis, immune evasion, treatment resistance, and even tumorigenesis itself are evolutionary processes. Our understanding of tumor evolution is incomplete, evidenced by the ability of some cancers to evolve more quickly in response to treatment than is compatible with classical genetics. A more comprehensive molecular understanding of how tumors evolve is key to improving cancer treatment. Recent work has shown that oncogene amplification on extrachromosomal DNAs (ecDNAs) is a major driver of tumor evolution, treatment resistance, and poor outcomes in patients. These circular DNAs are acentric and have long been thought to asymmetrically segregate at cell division, leading to intratumoral heterogeneity. We have recently proved this to be the case, but our understanding of the precise mechanisms through which ecDNA drives tumor evolution remains limited. In this project, Dr. John Rose aims to advance our understanding of ecDNAs in cancer evolution through unprecedented, well-controlled experimental studies of ecDNA. First, through a novel approach to image every ecDNA in living cells, I will delineate ecDNA dynamics on the level of single cells and single ecDNAs (Aim 1a), before extending these findings to organoid models and analysis of ecDNA+ patient samples (Aim 1b). Second, I will identify the genes that impact ecDNA, either promoting or inhibiting their accrual in tumor cells, using a high-throughput CRISPR screening strategy (Aim 2). Finally, I will characterize the development of ecDNAs’ uniquely accessible chromatin structure, elucidating its etiology (Aim 3). Together, these studies will dramatically improve our understanding of ecDNA in tumor evolution, while identifying putative avenues for therapeutic intervention. This work will be performed in the world-class training environment at Stanford University, under the mentorship of Dr. Howard Chang, an expert in the application of epigenomics to the study of cancer, and Dr. Paul Mischel, an expert in extrachromosomal DNA. An advisory committee composed of leaders in the fields of tumor evolution, computational biology, advanced cell imaging, high-throughput CRISPR screens, and cancer organoid models will provide additional expertise and mentorship. The first half of each aim will be completed predominantly during the K99 phase of the award, providing a platform for completion of the aims in the R00 phase.

NIH Research Projects · FY 2024 · 2023-08

PROJECT SUMMARY The decreased quality of life and increased morbidity due to oncological drugs such as Tyrosine Kinase Inhibitors (TKIs) is a serious and growing general health problem. In particular, cardiovascular (CV) morbidities are a major detrimental factor affecting the survivorship of cancer patients. The primary roadblock to addressing the toxicity of TKIs is that they inhibit multiple kinases besides those necessary to achieve the anti-cancer effect, but the kinases responsible for CV toxicity are poorly defined. This K99/R00 project supports a productive physician-scientist to identify kinase interaction networks relevant to the anti-cancer and CV toxic effects of TKIs. Preliminary data builds on the candidate’s research leading to the development of analogues of the TKI ponatinib that have greatly reduced toxicity, which can additionally be used as probes of signaling in CV and tumor cells. These studies identified candidate kinases that, when inhibited, are detrimental to cardiomyocyte and endothelial cells, as well as candidate kinases that, when inhibited, elicit potentially protective effects against CV morbidities. By using pharmacological and genetic probes, the broad objectives of the project are 1) determine the comprehensive kinase signaling networks responsible for anti-cancer activity in Chronic Myeloid Leukemia (CML) and the kinases that evoke the CV toxicity in each of the two major CV lineages (cardiomyocytes and vascular endothelial cell) and 2) verify and characterize kinases that, when inhibited, prevent this toxicity. The mentored (K99) phase of the project will focus on elucidating the kinase networks responsible for the anti-cancer effect in CML carrying the drug resistant mutation T315I (K99-Aim1) and for CV toxicity (K99-Aim 1). The independent (R00) phase of the project will examine candidate protective kinases networks (involving inhibition of ROCK1, RAF1 and MAPK11) using xenograft models of CML-T315I treated with ponatinib (R00-Aim1A) and non-small cells lung cancer treated with osimertinib (R00-Aim1B). The proposed research and training plan will prepare the applicant to successfully transition to a productive independent academic career defining mechanisms relevant to the safety and efficacy of oncology drugs. The mentoring plan describes roles of the primary mentor, an Advisory Committee consisting of highly regarded senior PIs at multiple institutions who are experts in clinical and basic science aspects of oncology, drug development and cardio-oncology, and collaborators who are leaders in kinase network mapping, and bioinformatics. The training plan will expand the applicant’s skills in cutting edge technologies such as kinase mapping approaches, mass spectrometry and computational analysis of the high-throughput data, and leadership skills. The training will be a critical factor for R00 independent phase and beyond. Training will take place at Stanford University enabling her to become an independent academic PI and leader in the development of safer and more effective oncology drugs to improve survivorship and life-quality of cancer patients.

NIH Research Projects · FY 2026 · 2023-08

Title: “AddBiomechanics: Automatic processing and sharing of human movement data” Abstract: Movement related injuries and disorders affect most people at some point in their lifespan. Treatments are difficult to develop because we have limited ability to predict how a proposed treatment will change the neuromusculoskeletal dynamics of a patient. Machine learning approaches to predict patient responses to hypothetical treatments would radically shorten the development time for novel treatments, but we lack sufficient clean public data to apply these methods. Biomechanics data is too heterogeneous, decentralized, and small to be useful for modern machine learning techniques. This proposal describes a novel collaborative approach to create a large biomechanics dataset. The main bottlenecks preventing the sharing of biomechanics data are the very large time cost to manually process the data, and the lack of incentives for sharing. We propose to address both of these problems with a cloud-based data processing automation tool, which researchers can use for free if they agree to share the resulting de-identified data. To demonstrate the social viability of our approach, we have developed a prototype to partially automate the processing of biomechanics data, saving researchers some of the time they spend collecting and processing data. We have hosted this tool as a cloud application called AddBiomechanics, available for free if users are willing to share anonymized versions of any data they upload. Despite minimal advertising and including only an initial set of features, since our launch in early July 2022 researchers from over 130 universities already use the tool to process and share data, and have already collectively shared 10,000 motion capture trials totaling more than 80GB of data now in a unified, ML-ready format. The first aim of our proposal is to develop methods to automate more of the processing of biomechanics data, saving researchers up to 90% of the time they spend collecting and processing data. To further encourage sharing of data, our second aim is to improve our cloud-based tools, provide more support to our users, and advertise the tools more broadly within the community. This project has broad support in the biomechanics community, evidenced by letters of support from researchers at 8 institutions in 5 countries, and the resulting dataset will lay the foundation for machine learning breakthroughs in the analysis of human movement and prediction of treatment outcomes by reducing friction to share and aggregate movement data. This will increase innovation and improve the treatment of movement related injuries and disorders, enhancing quality of life for millions of people.

NIH Research Projects · FY 2025 · 2023-08

Enter the text here that is the new abstract information for your application. This section must be no longer than 30 lines of text. The overall objective of the Multidisciplinary K12 Urology Research at Stanford (KUReS) Career Development Program is to develop the next generation of highly qualified MD, MD/PhD, and PhD scientists to emerge as independent investigators capable of obtaining funding to support their research, leading their area of research in benign urology, and ultimately bring meaningful impact to their field. During the program period, Scholars will be given the training, courses, and guidance needed to achieve this goal; key to the Program’s success will be the mentoring provided by our NIH-funded faculty preceptors. Twenty-eight Faculty Preceptors drawn from 3 Schools, 6 Institutes/Centers and 16 Departments at Stanford, 8 Advisory Committee members, and 6 Near-Peer Mentoring Committee members will collaborate to train junior physician scientists and investigators (KUReS Scholars) to acquire the skills and experience needed to transition into productive, independent physician scientists. The KUReS Program bridges clinical care with excellence in basic, clinical and translational research to address the national shortage of qualified investigators in benign urology. The Program includes a structured training plan of sufficient duration to achieve independence, individualized didactic education based on skills, competencies, and needs, extensive team-based mentoring, hands-on research, and protected time with immersion in a vibrant research community. Stanford has robust mentoring systems, strong curriculum, and solid infrastructure in place to prepare KUReS Scholars for research independence. Each Scholar will have a multidisciplinary mentor team as well as access to a wealth of resources including the Stanford U54 O’Brien Center, Stanford CTSA and NIDDK CAIRIBU network. Two KUReS Scholars will be supported each year of the 5-year Program. Duration of support for each Scholar will average 2-3 years. Leveraging on the expertise of the Preceptors and Stanford’s outstanding infrastructure, Scholars will be recruited nationally to pursue one of four research thematic areas: 1) Regenerative Medicine, Interstitial Cystitis/Bladder Pain Syndrome (IC/BPS), and Voiding Dysfunction; 2) Urologic Omics and Lower Urinary Tract Symptoms (LUTS); 3) Urologic Imaging and Engineering and 4) Urinary Stone Disease and Infections. Scholars will develop essential skills and a portfolio of research projects to propel their transition to independence. Research progress and career outcomes of Scholars are evaluated in an ongoing basis by Faculty Preceptors, Program leadership and Advisory Committee members.

NIH Research Projects · FY 2025 · 2023-08

ABSTRACT Screening for prostate cancer (PCa) is highly controversial, as accumulated evidence indicates that widespread, routine prostate-specific antigen (PSA)-based screening reduces PCa mortality but at the cost of significant over- diagnosis and over-treatment. PSA-based risk-stratified screening could capture much of the benefit of screening while greatly reducing over-diagnosis. This promising approach uses men’s baseline PSA values to inform their risk of future aggressive and/or fatal PCa and determine their frequency of further screening. Under this approach, men with high baseline age-specific total PSA levels receive more frequent screening and men with lower levels receive less frequent screening. This efficient approach is currently supported by at least three US advisory agencies, but not by several others, including most notably, the US Preventive Services Task Force. This agency recommends additional “validation studies” with “longer-term follow-up” before considering PSA- based risk-stratified screening. Additional data are also needed to optimize each of the components of PSA- based risk-stratified screening, including the: (1) age at which baseline PSA values should be obtained, (2) length of tailored re-screening intervals, (3) tailored age at screening cessation, (4) tailored strategies for Black men, as these men are at higher risk of aggressive and fatal PCa, yet remarkably under-represented in the screening literature, and (5) prostate-specific kallikreins used for screening, as kallikreins beyond total PSA have also been found to predict PCa risk and mortality and thus might help to optimize PSA-based risk-stratified screening. Therefore, to address each of these gaps, we propose to leverage data and serum specimens collected in the large racially-diverse Kaiser Permanente Northern California integrated health system, along with its long- running (over 5 decades), embedded Multiphasic Health Checkups cohort and nested case-cohort to: (1) evaluate the utility of initiating baseline PSA screening before age 50, (2) determine the optimal re-screening interval after a baseline PSA test, (3) identify populations of men at age 60 who might consider stopping screening, (4) explore whether Black men should initiate screening earlier and be screened more frequently than White men, and (5) evaluate whether adding other prostate-specific kallikreins to total PSA enhances prediction of clinically-relevant PCa. Our overall goal is to provide evidence for “smarter” or more nuanced PSA screening strategies to preserve or enhance the mortality benefits of PSA screening, while greatly minimizing its harms and costs.

NIH Research Projects · FY 2024 · 2023-08

Project Summary/Abstract Glaucoma is a group of neurodegenerative diseases marked by the loss of retinal ganglion cells (RGCs) and their axons. It is characterized as the second leading cause of blindness in the United States with at least 3 million people affected. This number is likely to rise to 4.2 million by 2030 if no new therapeutics can be developed. Astrocytes are recently gaining attention as therapeutic targets for neurodegeneration diseases. They become reactive and play critical roles in glaucoma pathogenesis. Unfortunately, the underlying mechanisms of reactive astrogliosis and its impact on RGC axons in optic neuropathies remain unclear. Primary cilia are microtubule-based organelles on the cell surface that are known for detecting and transducing extracellular cues to regulate cellular processes through a variety of signaling pathways such as hedgehog signaling. Defective primary cilia are associated with numerous neurodegenerative diseases. In this project, the candidate proposes to study cilia signaling in optic nerve astrocytes. A deeper understanding of astrocytes' role could have significant implications for developing astrocyte-targeting therapeutics for glaucoma. The proposed study will pursue the following aims: 1) whether primary cilia in astrocytes protect against RGC death in experimental glaucoma mouse models; 2) the role of sonic hedgehog signaling in optic nerve astrocytes in RGC death. Overall, insights from the study of cilia-associated sonic hedgehog signaling in astrocyte reactivity will be applied to develop potential astrocyte-targeting treatments for glaucoma. The candidate’s overall career goal is to understand the process of astrocytes that contribute to glaucoma and to characterize novel cilia-based targets for neuroprotective treatments. The candidate has a deep background in primary cilia and retinal diseases and proposes to obtain training in glaucoma because astrocytic cilia is rarely studied in the vision field. During the K99 phase, the candidate will obtain training to increase her understanding of neuroscience research and single- cell RNA sequencing technique. The PI will work with mentors Drs. Yang Sun and Yang Hu, together with members of a Stanford advisory committee team. This proposal will dissect the molecular pathways underlying reactive astrogliosis in glaucomatous optic neuropathies and develop astrocyte-targeting therapeutics for neurodegenerative diseases.

NIH Research Projects · FY 2024 · 2023-08

Project Summary Cardiotoxicity of cancer treatments can lead to severe heart failure in cancer survivors or discontinuation of cancer treatments. Currently, it is challenging to evaluate who is at the risk of developing cardiotoxicity prior to cancer treatments and prevent the adverse side effects. Genome-wide association studies (GWASs) have shown that genetic predispositions are one of the key determinants of risk susceptibility to chemotherapy- induced cardiotoxicity. Consistently, the susceptibility to anti-cancer agents can be recapitulated by patient- specific induced pluripotent stem cell (iPSC)-derived cardiomyocytes (iPSC-CMs), which reflect the donor patients’ genetic makeup. The goal of this project is to identify genes and genetic variants that affect the susceptibility to anti-cancer agents for developing cardio-protective therapies and risk assessment systems. Although this proposal focuses on doxorubicin, which is one of the most commonly-used anti-cancer agents, the approach described here is expandable to any other cancer treatment-induced cardiotoxicities such as those by tyrosine kinase inhibitors and radiation therapy. First, I plan to identify genes whose inhibition or activation can protect iPSC-CMs from doxorubicin using our iPSC-based CRISPR screening platform. The screened genes will be causative in doxorubicin-induced cardiotoxicity (DIC) and thus promising therapeutic targets. Second, I plan to utilize bioengineering technologies and in vivo mouse models to assess the effects of candidate therapies more accurately than simple monolayer culture systems. Since repurposing of approved drugs can accelerate the clinical application of the findings, I plan to test existing drugs that target the validated genes in these models. Finally, to develop a system to evaluate the genetic susceptibility to DIC, I plan to perform parallel characterization of many genetic variants using iPSC-based base/prime-editing screens in DIC and generate “susceptibility scores” of individual variants that are clinically implicated in DIC. The result will help with risk stratification of patients who receive chemotherapies.

NIH Research Projects · FY 2025 · 2023-08

PROJECT SUMMARY/ABSTRACT Coronary artery disease (CAD) is the leading cause of death worldwide and there remains a crucial need to discover mechanisms of disease and develop new therapies. Leveraging the power of human genetics and mechanistic discovery, we are poised to understand causal mechanisms of disease and design critical therapies. Although there are more than 160 genetic loci discovered which are associated with CAD, outside of lipid lowering therapies, the promise of these genome wide association studies (GWAS) to identify causal genes and result in novel mechanisms for treatment has not been fulfilled. Recent discoveries have revealed that RNA editing is a fundamental mechanism of inflammation and disease, a process mediated by ADAR enzymes. In a groundbreaking discovery now accepted in Nature, the lab of the applicant’s co-mentor, Dr. Jin Billy Li, has discovered that common genetic variation which decreases RNA editing powerfully increases CAD risk. Preliminary data implicates RNA editing in vascular smooth muscle cells (SMCs) to have a causal role in CAD. In this proposal, the applicant aims to elucidate the fundamental mechanisms of ADAR mediated RNA editing, and the potential for targeting the pivotal downstream double stranded RNA (dsRNA) sensor, MDA5 (encoded by IFIH1), as treatment in CAD. Vascular inflammation has long been implicated in the onset and progression of atherosclerosis, but the specific disease modifying targets remain elusive. Pivotal studies have discovered that endogenous dsRNA is formed in normal RNA transcription and undergoes RNA editing by ADAR1. If insufficiently edited, dsRNA will activate a powerful interferon stimulated gene (ISG) response through MDA5 (IFIH1). Common genetic variation can modify RNA editing frequency — ‘editing-QTLs’ (edQTL) — where edQTLs are not only predictive of CAD risk, but also other autoinflammatory disorders including lupus and inflammatory bowel disorders. In this proposal, the applicant hypothesizes that the ADAR-MDA5 axis plays an important role in the onset of CAD and that MDA5 is an ideal therapeutic target. However, there is a critical gap in knowledge, and it is unknown if deficient RNA editing in SMCs accelerates the development of atherosclerosis, and it is imperative that the ADAR-MDA5 axis is investigated to reveal its potential for therapeutic innovation. To address this, the applicant has bred a novel SMC lineage traced atherosclerosis mouse model with conditional SMC deletion of Adar with and without Ifih1 deletion. Through a one-of-a-kind biobank of primary HCASMCs, the applicant will further characterize the effect of MDA5 activation from decreased RNA editing. Further, the applicant will discover the key genes downstream of MDA5 activation through a cutting-edge genomics approach using epigenetic editing and single cell RNA sequencing (perturb-seq). This work will advance the applicant’s training and enable the applicant to gain skill sets in bioinformatics, genetics, and molecular biology — launching the applicant’s career as an independent physician-scientist.

NIH Research Projects · FY 2025 · 2023-08

This proposal describes a 5-year training program to develop an academic career focused on investigating the role of mechanosensitive ion channels in glaucoma. My long-term goal is to discover new strategies for treating glaucoma by understanding the mechanisms of mechanosensation in the eye. Although intraocular pressure (IOP) is the most significant risk factor for glaucoma, the identify and function of mechanosensitive proteins in the eye remain largely unknown. I will use human genetic analyses, in vitro molecular and electrophysiological approaches, and in vivo mouse models of glaucoma to study the role of mechanosensitive ion channels in mediating retinal ganglion cell (RGC) death in glaucoma. Preliminary results have identified human variants in mechanosensitive ion channel genes associated with glaucoma risk. I hypothesize that mechanosensitive ion channels in retinal cells sense IOP and mediate RGC death in glaucoma, and that human variants confer differential risk in these functions. Aim 1 determines the contribution of mechanosensitive ion channels to pressure-activated currents in retinal cells in vitro upon mechanical stimulation. Aim 2 investigates how human variants of mechanosensitive ion channel genes alter channel function in a heterologous system. Aim 3 tests the role of mechanosensitive channels in a mouse model of glaucoma. The proposed studies have the potential to provide insight into how IOP leads to RGC death and identify novel therapeutic targets for glaucoma. With my graduate training in sensory neuroscience and electrophysiology, I am well equipped to conduct this research. My career development plan will allow me to 1) learn retinal physiology, 2) develop knowledge and technical expertise in the field of mechanosensation, 3) acquire experience with mouse models of glaucoma and 4) develop grantsmanship, leadership and managerial skills to lead an independent research team. I am supported by a committed team of mentors who are dedicated to advancing my career as an independent clinician scientist. I will work with retinal physiology expert Dr. Stephen Baccus, leaders in translational glaucoma research Dr. Jeffrey Goldberg, Dr. Yang Hu and Dr. Yang Sun, mechanosensation and ion channel experts Dr. Ardem Patapoutian, Dr. Miriam Goodman and Dr. Merritt Maduke, and human glaucoma genetics expert Dr. Janey Wiggs. This training will take place within the collaborative vision and neuroscience community at Stanford, with access to its extensive resources for research and career development. This research addresses a critical need to understand the mechanisms of mechanosensation in glaucoma and prepares me for a career as an independent NIH-funded investigator, with the ultimate goal of advancing these discoveries to the bedside to develop better treatments for this common blinding disease.

NIH Research Projects · FY 2026 · 2023-08

PROJECT SUMMARY Death or chronic lung dysfunction from acute respiratory distress syndrome (ARDS) is a dreaded consequence of acute injury to the alveolar gas exchange region of lung. Other than antibiotics for bacterial pneumonia and in some cases anti-inflammatory medications like corticosteroids, there are no specific therapies beyond supplementary oxygen and ventilatory support. Thus, there is an urgent need to better understand how acute alveolar injury is repaired and in cases when this is insufficient, what are the reasons for the failure to recover gas exchange function. Once the precise cellular and molecular regenerative and maladaptive alveolar responses are identified, we can move on to rationally engineer novel and specific treatments to promote repair. We have recently mapped at high resolution the alveolar regenerative response to alveolar epithelial type I (AT1) cell ablation, which revealed several unexpected mechanisms. In addition to conventional AT2 stem cell proliferation, we identified two other regenerative mechanisms. The first was immediate transdifferentiation of AT2 cells without prior proliferation, followed by mitosis of resident binucleated AT2 progenitors found in healthy lungs. We also identified pathological responses from repeated AT1 cell ablation consisting of excessive AT2 stem cell proliferation with loss of surfactant function and impaired AT1 cell differentiation. Here, we plan to flesh out the molecular and cellular regulation of these regenerative programs and to determine their physiological impact on maintaining proper gas exchange by preventing capillary leak and pulmonary edema. In summary, we will apply precise cell type ablation and injury with state-of-the-art experimental approaches to clarify at high temporal resolution the cellular and molecular basis of alveolar epithelial repair.

NIH Research Projects · FY 2024 · 2023-08

PROJECT SUMMARY The prevalence of ulcerative colitis (UC) in children continues to increase yearly. Recent evidence in pediatric UC patients showed significant mitochondrial impairment in the colon tissues. This is important as optimal mitochondrial activity is required for the solemn function of colonic stem cells that replenish the physical barrier of the colon epithelium. Since patients are constantly exposed to environmental factors such as diet, it is critical to reveal the dietary factors that influence mitochondrial function in the colon epithelium as they would be vital in the management of UC in children. Sulfites are endogenous products of several sulfur-containing compounds, and they are also ubiquitous in our diets as preservatives. My preliminary data in colon organoids derived from pediatric patients showed a detrimental role of sulfite on mitochondrial metabolism and differentiation, with worse metabolic outcomes in samples from pediatric UC patients. My analysis of transcriptomic data from 206 children with UC showed that the Mocs1 gene required for downstream clearance of sulfites in the mitochondria is downregulated in the colon of UC patients, suggesting a potential for inefficient sulfite detoxification in the colon. In this study, I will use patient-derived colon organoids to define how sulfites regulate mitochondrial metabolism and differentiation in health and in UC (Aim 1), reveal the sulfite-induced and sulfite susceptibility chromatin sites in the pediatric colon that explains these metabolic and differentiation anomalies (Aim 2), and how sulfites and the loss of epithelial Mocs1 shape colon biology in the complex gut environment in vivo using physiological relevant models (Aim 3). This award will advance my training in disease models of IBD, epithelial biology, and epigenomics as I work toward establishing an innovative career in regenerative nutrition with a focus on pediatric digestive diseases and continue efforts to enhance diverse representation in the biomedical sciences.

NIH Research Projects · FY 2025 · 2023-08

Abstract No model organism has contributed more than the laboratory mouse to improving human health. Many genetic factors and therapies for human diseases were initially discovered or characterized in mice, before they were transitioned to human use. Large-scale efforts are underway to integrate recent advances in artificial intelligence (AI) into human healthcare, but very few AI advances have been used for analysis of the data produced using the model organism that has formed the foundation for many healthcare innovations. We recently developed an AI-based computational pipeline that could identify causative genetic factors for murine genetic models of human biomedical traits and diseases. After assessing the strength of allelic associations with the phenotypic response pattern exhibited by the inbred strains; this AI pipeline uses a machine-learning trained method to analyze 29M published papers and assess candidate gene-phenotype relationships; and the information obtained from assessment of their protein-protein interaction network and protein sequence features of the candidate genes are also incorporated into the graph neural network-based analysis. This project will produce a markedly enhanced AI pipeline (AIv2) that will greatly accelerate the pace of genetic discovery using murine genetic models. First, long read genomic sequencing (LRS) and computational tools are used to produce a more complete map of the pattern of genetic variation among the inbred strains, which also includes alleles for two major types of genetic variation (structural variants, tandem repeats), which are poorly characterized using conventional sequencing methods. Second, we develop two additional computational tools for the AI, which facilitate candidate gene prioritization through the evaluation of: (i) the phenotypes exhibited by 8200 mouse lines with individual gene knockouts (KOs); and (ii) the results of 5700 human GWAS covering many biomedical phenotypes to determine if alleles within the human homologues of candidate murine genes affect an analyzed trait. The ability of AIv2 to accelerate genetic discovery will be demonstrated by using it to identify new genetic factors through analysis of a public database with >10,307 datasets, which measure biomedical or disease-related responses in panels of inbred strains. Since it is critical to experimentally confirm some of the computational findings, genetic factors for two murine models of human diseases that are major public health problems (cancer, diabetes/obesity), which were identified by the AI pipeline, will be experimentally validated. CRISPR engineering is used to revert the causative mutation(s) to wildtype on the genetic background of the strain exhibiting the disease phenotype, and the genome engineered mice are analyzed to assess the contribution of the genetic factor to the disease phenotype.

NIH Research Projects · FY 2024 · 2023-08

Project Summary/Abstract Alzheimer’s Disease (AD) is a devastating disease with enormous unmet medical need. It is likely necessary to understand, detect, and treat Alzheimer’s Disease earlier in disease development. Patients often exhibit aberrant neural activity even before pathology or cognitive decline. Amyloid-beta (Ab) and tau can perturb neural activity, and activity can affect their levels, thus aberrant neural activity may be both a symptom and cause of Ab and tau, forming a vicious cycle. This project will investigate the hypothesis that aberrant neural activity is a primary driver of and tractable therapeutic target for Alzheimer’s Disease, and that targeting it can rescue cognitive deficits. There is a lack of direct evidence on the causative role of aberrant neural activity in Alzheimer’s Disease, let alone the mechanisms, a significant gap in our understanding. Human imaging methods have low resolution, and human studies cannot use precise perturbations to test direct cause and effect. Yet, stimulation therapies are used on patients, using limited data to inform protocols, resulting in promising but inconclusive results. This project will use cutting-edge systems neuroscience techniques to conduct single-cell resolution examination and perturbation of the brain to determine the mechanistic role of aberrant neural activity in cognitive decline in Alzheimer’s Disease mice, and to reverse it. To identify aberrant single-neuron and network dynamics, 2-photon Ca2+ imaging will be used in Alzheimer’s Disease mice during cognitive tasks over disease progression. This will be the first longitudinal study of single-neuron activity in Alzheimer’s Disease mice during cognitive tasks, and the first lifelong study of neural activity. To discover activity-based anatomical connectivity changes, activity- dependent neuron projection labeling will be used to label neurons activated during learning and recall. Tissue- clearing will enable imaging of projections across the entire brain in 3D, along with Ab and tau, over disease progression. This will discover specific brain regions, circuits, and cells that change in parallel to Ab and tau and correlate with cognition. These will be the first brain-wide, activity-dependent projection tracing experiments, and the first longitudinal study of anatomical connectivity changes in Alzheimer’s Disease. To test the functional role of aberrant activity and to restore cognition, single-cell optogenetics will be used to recapitulate or reverse the activity patterns changed in Alzheimer’s Disease, and circuits will be modulated to correct connectivity. Optogenetics will be used in AD mice to determine if AD therapies improve cognition through effects on neural activity. The investigator will receive technical, conceptual, and career development training from a mentoring team of leading experts in world-class labs at Stanford University in preparation for transition to a faculty position. This work will discover fundamental mechanisms of Alzheimer’s Disease. It will result in unprecedented, high- resolution, comprehensive data on changes in neural activity and connectivity during Alzheimer’s Disease that will identify the specific circuits, cells, and activity dynamics that drive cognitive decline, which will help inform intelligent design of new, precise, and earlier biomarkers, diagnostic strategies, and therapeutic treatments.

NIH Research Projects · FY 2026 · 2023-07

Safety net newborn intensive care units (snNICUs) are challenged in their care and outcomes delivered very low birth weight (VLBW; <1500g) infants. In our population-based California cohort of NICUs, we find large variation in performance across snNICUs. For example, in a key national quality metric, any breast milk feeding at discharge, which exhibits the largest variation, California snNICUs as a group perform worse that non-safety net NICUs. However, some snNICUs are among the state’s best performers, even after adjustment for clinical risk. There is a dearth of knowledge regarding the malleable organizational features differentiating quality of care across snNICUs. We propose to bridge this gap by gaining a deep understanding of network characteristics and their links to clinical care and outcomes. We will accomplish this by leveraging the unique population-based data resources and applied quality improvement expertise of the California Perinatal Quality Care Collaborative (CPQCC) to conduct a novel improvement collaborative among snNICUs to address performance in breast milk feeding rates at discharge for VLBW infants. This collaborative will serve to create an unprecedented peer learning network of snNICUs and serve as a vehicle for our team for a multimodal inquest to study the organizational features that either support or hinder quality of care. We propose a large, population-scale study of snNICUs, with a large estimated sample of approximately 5,300 VLBW infants receiving care in 30 NICUs between 2024 to 2026. Specific aims: 1. Conduct a quality improvement collaborative of safety net NICUs, 2. Identify organizational features that may be associated with quality of care delivery, and 3. Associate safety net NICU organizational features with clinical outcomes. Our analyses will be guided by quality and implementation frameworks. Methods will include an Institute of Healthcare Improvement style quality improvement collaborative, quantitative validated surveys of safety culture and healthcare worker well-being, key informant interviews, and guided site visits. We will link organizational features with clinical quality of care and outcome metrics using epidemiological causal and observational modeling approaches. We have a long track record of impactful research funded by NIH using CPQCC data. We expect our research to have an immediate positive impact; internally, it is designed to build quality and safety capacity in snNICUs that can readily be extended to other aspects of care; externally, it will result in actionable information for policy makers, administrators and clinicians to improve perinatal care delivery. The topic is timely, the sample (~90% of all CA snNICUs) is unique, the research team is accomplished, and the focus on an outcome of high importance to snNICUs, and to public health are significant strengths of this study.

NIH Research Projects · FY 2026 · 2023-07

ABSTRACT A collaborative network of research teams from Stanford, Harvard, The Ohio State University, and Impactivo, LLC propose practice-relevant research focused on diabetes care in federally qualified health centers (FQHCs). Some 37.3 million Americans have type 2 diabetes and FQHCs shoulder a high prevalence of diabetes (21% FQHC, 11% U.S.), offering a promising venue for innovating in diabetes care. The iPATH project will refine and implement an approach to practice transformation originally conceived to support FQHCs’ pursuit of National Committee for Quality Assurance recognition as patient-centered medical homes. A pilot demonstrated significant decreases (average 31% reduction) in poorly controlled diabetes (A1c>9%) among patients at 7 clinics affiliated with one FQHC in 2017-20. Improvements in patients’ diabetes control were sustained. Aim 1. Refine the iPATH implementation approach by identifying organizational conditions and processes at FQHCs that promoted or impeded the effectiveness of type 2 diabetes care. Research teams will simultaneously conduct 12 in-depth regional case studies, enabling contrast between FQHCs considered high-performing and low-performing for diabetes control. Teams will identify actionable, how-to implementation factors for ensuring chronic, preventive, and acute care for patients with diabetes. Employing an innovative Rapid Data Collection and Reporting methodology, teams will rapidly collect, analyze, and share data to accelerate dissemination of customized feedback to FQHC leaders and to inform adaptation and implementation of the iPATH practice transformation approach. Aim 2. Implement a multi-level, multi-component, technology-enabled practice transformation strategy to improve type 2 diabetes for patients at 8 multi-clinic FQHCs. Teams will adapt, tailor, implement, test, and spread a practice transformation strategy across FQHCs located in California, Massachusetts, Ohio, and Puerto Rico. The iPATH implementation approach will be modularized and customizable to accommodate organizational readiness, patient needs, social and environmental factors affecting patients’ health (such as transportation, employment, and nutrition), tailoring practice transformation efforts to each unique FQHC. Aim 3. Comprehensively evaluate the iPATH implementation approach with a hybrid type 2 study, including a stepped wedge cluster randomized trial. Including formative, process, and summative evaluation elements guided by the Exploration-Preparation-Implementation-Sustainment model, the study will evaluate impact of practice transformation and identify process elements affecting implementation effectiveness. Analyses will leverage the unique advantage of FQHC data.

NIH Research Projects · FY 2024 · 2023-07

PROJECT SUMMARY Pulmonary fibrosis (PF) represents a global clinical burden that affects over 5,000,000 people and can occur as a result of chemical injury, chronic conditions such as systemic sclerosis, or respiratory infections such as influenza and COVID-19. Commonly, PF has no clinically determinable cause and is diagnosed as idiopathic PF, which presents a median survival time of only 2-4 years after diagnosis. Given the often unclear pathogenesis of PF, there exists a strong clinical need to elucidate the biological mechanisms that contribute to its onset and progression. Nevertheless, the factors that drive spatial heterogeneity and temporal progression in fibrotic architecture are not well understood. Furthermore, the post-fibrotic resolution of aberrant PF matrix remains an elusive goal, for which no single-cell characterizations have been performed to date. Thus, this project aims to establish a spatiotemporal atlas of PF progression that links multi-omics with spatially defined tissue neighborhoods and temporally defined architectural states of fibrosis and post-fibrotic resolution. Mesenchymal cell populations play a critical role in the fibrosis of all major organs, with a number of macrophage and fibroblast subtypes often implicated as mediators of fibrotic ECM deposition. Based on prior studies, I hypothesize that transcriptionally defined macrophage and fibroblast subtypes act as both spatial and temporal nodes of fibrosis and post-fibrotic resolution. To investigate this hypothesis, this project will establish a novel computational atlas of transcriptional/epigenetic cell subtypes, interaction networks, and ultrastructural states that mediate the pathological progression of PF and post-fibrotic repair in mice. Specific Aim 1 will investigate the roles of transcriptionally defined cell subpopulations in the temporal progression and resolution of fibrotic pulmonary architecture, using high-throughput multi-omics (transcriptomic, epigenomic, and ultrastructural) and computational modeling of biological variations over time. Specific Aim 2 will define the spatial tissue neighborhoods of cell- and matrix- mediated interactions in pulmonary fibrosis, by integrating Visium spatial transcriptomics, imputed spatial epigenomics in BABEL, and ultrastructural quantification on consecutive histological slices. Specific Aim 3 will develop a machine learning algorithm for prognosis of clinical outcomes in human pulmonary fibrosis, by unifying histopathological architecture, protein and cell spatial networks, and clinical metadata. Ultimately, this project will establish a multi-omic, cross-species, and computationally rigorous atlas of PF progression and repair that identifies biologically conserved mechanistic pathways and clinically relevant targets for prognosis and therapeutic development.

NIH Research Projects · FY 2025 · 2023-07

Adolescents’ eating behaviors are influenced by their media environments. However, very little is known about the food and beverage-related environment that adolescents experience on their smartphones. Adolescents increasingly interact with the world through smartphone screens that are almost always with them. Thus, any attempt to study or change policy, systems and environmental influences on adolescents’ food and beverage preferences, purchases and consumption must consider the nutrition- related environment and behavior on their smartphone screens. Until now, a comprehensive view of life experienced on smartphones has been invisible to researchers. We have developed a novel method for capturing everything that appears on teens’ smartphone screens – a fully encrypted record of digital life – by taking snapshots of the screen every 5 seconds the devices are on. The resulting sequence of screenshots, including all words and images on the screen, constitute an individual’s screenome. We will collect six months of continuous smartphone screenshots and three 24-hour dietary recall interviews at baseline and after 2, 4, and 6 months, from a national sample of 300 adolescents age 13- 17 years, balanced between female and male, and at least 30% identified as racial/ethnic minority. Aim 1. Describe the food and beverage environment adolescents experience on their smartphone screens Using the text and images from smartphone screenomes, we will create the first comprehensive description of the food and beverage environments being experienced by adolescents on their smartphones. Aim 2. Elucidate the between-person relationships between smartphone food and beverage screenomes and dietary intake. we will examine how differences in digital exposures to food and beverage screenome features are associated with differences in dietary consumption. Aim 3. Elucidate the within-person relationships between changes in smartphone food and beverage screenomes and changes in dietary intakes. Leveraging natural experiments embedded in the screenome data. This study will provide the first comprehensive description of the food and beverage environment that adolescents experience on their smartphones and represents a true paradigm shift in studying media impacts on adolescents’ eating behaviors. The results of this study will identify novel intervention targets and opportunities for smartphone-based precision nutrition interventions and evidence-based policies to improve adolescents’ health.