Yale University

NIH Research Projects · FY 2025 · 2023-07

PROJECT SUMMARY Abnormalities in sensory perception are prevalent features in individuals with autism spectrum disorders (ASD), accompanying the core social deficits. A central challenge in autism research is to identify alterations in neurobiological mechanisms that underlie processes as distinct as sensory perception and social cognition. As such, our long-term goal is to understand common developmental and circuit mechanisms shared by sensory and social information processing. Considerable evidence indicates that the neuropeptide oxytocin significantly contributes to a wide range of social behaviors, and more recently, it has been linked to synaptic plasticity in sensory cortices during development. These findings raise an exciting but untested possibility that oxytocin signaling is associated with both tactile processing and social function. In our preliminary studies, we found that oxytocin receptors (OXTRs) are expressed abundantly and specifically in the somatostatin-expressing interneurons (SST INs) in the primary somatosensory cortex (S1) during development. Activating OXTRs selectively and strongly depolarizes SST INs, while OXTR deletion in these neurons leads to hyperpolarization of the resting membrane potential and reduced in vivo network activity in the developing S1. In addition, mice with targeted OXTR deletion in SST INs show impaired texture discrimination and sensory sensitivity, as well as deficits in social preference. Based on these preliminary results, we hypothesize that oxytocin is required for establishing proper synaptic connectivity in the developing somatosensory cortex, and that impairment in oxytocin signaling leads to both tactile sensory abnormalities and social deficits. We will leverage our novel longitudinal 2-photon imaging technique, electrophysiological and genetic approaches to identify the cell-type specific role of oxytocin in the development of S1 and during acute social interactions through three aims. We will assess the effects of oxytocin on the growth and survival of SST INs, as well as the maturation of circuit connectivity in the developing S1 (Aim 1). We will dissect the role of oxytocin signaling in general tactile sensory processing, and in encoding social cues during social contacts (Aim 2). We will explore the behavioral outcomes of oxytocin signaling dysfunction and their neural corelates, and test if developmental tactile dysfunction as a result of OXTR deletion exacerbates social deficits (Aim 3). Together, the results are expected to reveal common neural mechanisms underlying sensory and social information processing, providing insights into basic rules for brain circuit development, as well as identifying early diagnostic markers associated with ASD and other mental disorders that can guide novel therapeutics.

NIH Research Projects · FY 2025 · 2023-07

PROJECT SUMMARY The goal of this proposal is to train the next generation of scientists that will advance our understanding of Alzheimer’s Disease and Related Dementias (ADRD) at Yale University, and to fulfil the promise of developing disease-modifying therapeutics for these debilitating conditions. The rationale of this program is to take an integrated approach to understand the diversity and similarities of ADRD conditions as well as their co-morbidity, using cell biology, structural biology, pathology, biostatistics, and clinical medicine. Twenty nine (29) faculty from twelve (12) basic and clinical departments at Yale School of Medicine and Yale College are participants in this multidisciplinary program. The program offers both depth and breadth. The depth derives from the expertise of the faculty investigating ADRDs and the many institutional resources that can be brought to bear including, an Alzheimer’s Disease Research Center (ADRC), a Parkinson’s Foundation Research Center, three Aligning Science Across Parkinson’s (ASAP) teams, a recently instituted Center for Human Brain Discovery brain bank, and a new research building where most mentors will co-locate. The breadth of the program derives from the diversity of approaches being used to tackle these diseases ranging from genetics to drug development. Mentors are Ph.Ds. and M.D.s. with substantial NIH support and NIA/NINDS related research foci. Faculty investigate all major forms of dementia, including Alzheimer’s disease (AD), Frontotemporal Dementia (FTLD), Lewy Body Dementia (LBD), and Vascular contributions to cognitive impairment and dementia (VCID). Methodologies include deep sequencing; transcriptomics; proteomics; cell and induced pluripotent stem cell (iPSC) culture; immunohistochemistry; electron and advanced light microscopy; biochemistry and molecular analyses; structural biology; rodent, monkey behavior; and fMRI and PET imaging in human subjects. Six predoctoral positions are requested. Trainees are selected by the Executive Committee from an outstanding pool of advanced Neuroscience and Biology graduate students (3rd and 4th year), which are amongst the best in the country and come from a variety of backgrounds in the sciences. Trainees are selected based on their potential for excellence, leadership in research as well as their diverse backgrounds. Training includes focused coursework, instruction in experimental design and statistical methods, Clinicopathologic correlation (CPC) conferences, thoughtful mentorship through advisory committees with oral and written feedback, structured seminar programs, career skills development, and numerous opportunities for written and oral presentation of research progress.

NIH Research Projects · FY 2025 · 2023-07

One of the major contributions of developmental psychology is the demonstration that early caregiving experiences within the normative range (i.e., sensitive caregiving) not only contribute to offspring’s mental and physical health disparities, but also that such associations are enduring over the life course. Research by the PIs and others has identified brain mechanisms by which key maternal risk factors—depressive symptoms and attachment insecurity—undermine caregiving behavior. However, given evidence documenting significant change in the maternal brain over the transition to motherhood, there is a critical gap as to whether this transition serves as a sensitive period during which maternal neural responding to infants is particularly impacted by maternal depressive symptoms and insecurity that pose risk for caregiving behavior and infant adjustment. Moreover, the majority of research has focused exclusively on mother-driven effects, limiting understanding of the significance of infant characteristics for the maternal brain. Additionally, research on the maternal brain primarily comprises samples of European-ancestry women, thus, little is known about whether such processes operate similarly in families of color. Therefore, this R01 application seeks to programmatically investigate whether maternal psychological risk undermines maternal sensitivity and, in turn, infant adjustment via negatively impacting change in maternal brain responding to infants over the transition to motherhood. Further, we will test the role of infant characteristics (i.e., negative emotionality) in moderating this pathway. Critically, we include a racially/ethnically diverse sample of 400 women to explore moderation of our findings by maternal race/ethnicity. We further propose to identify person (parenting/emotion beliefs) and community (kinship/social support) factors that may impact their neural adaptation to motherhood. We will examine maternal risk factors (depressive symptoms, attachment insecurity), person and community factors, and brain responding to infant cues prenatally (3rd trimester) and postnatally (4 and 8 months). Postnatal assessments will include caregiving behavior (4, 8, and 12 months), infant negative emotionality (4 and 8 months), and infant adjustment (12 months), including attachment security and behavior problems. Our approach is innovative given its intergenerational, prospective, multi-level, and multi-time point design and the racial and ethnic diversity in the maternal sample enrolled. Our findings will inform models of the changing maternal brain from pregnancy to the postpartum period and how maternal depression and attachment insecurity may pose risk for maternal caregiving and infant adjustment as a function of infant negative emotionality and maternal race/ethnicity. Furthermore, our approach will allow for more targeted intervention strategies for women during their transition to motherhood to optimize mother and child well-being.

NIH Research Projects · FY 2026 · 2023-07

Project Summary/Abstract Mitochondria house the metabolism of all building blocks of life and are central for cellular metabolism, however, how metabolites translocate across the mitochondrial membrane is poorly understood; and the impact on neuronal cellular metabolism is yet to be explored. The mitochondrial carrier SLC25 family represents the largest protein family critical for mitochondrial metabolite transport, in which approximately 20 out of the 53 human SLC25 genes remain of unknown function. Our overarching research program is to characterize mitochondrial metabolite transport by identifying the endogenous metabolite ligands for SLC25 transporters. Recently, my laboratory applied mitochondrial metabolomics to discover the role of a poorly characterized mitochondrial transporter SLC25A39 in glutathione uptake (supported by R00). Here, building upon this recent progress, we propose to expand the strategy to other SLC25 transporters using loss-of-function and gain-of-function study in cells. As a distinct and complementary approach, we will apply sequence and structure analysis towards SLC25 transporter to guide in vitro mitochondrial metabolite uptake screen with a goal to characterize ligand recognition mechanism. To study mitochondrial metabolism in neurons, we will adopt iPSC-derived neurons as an in vitro model to profile the impact of SLC25 transporters loss on mitochondrial and synaptic metabolism. Together, our study of SLC25 transporters would reveal fundamental biology in mitochondrial metabolite transport, an emerging new frontier in cellular metabolism. Our expertise in cellular metabolism, uniquely in applying state-of-art, high- resolution mass spec metabolomics to fundamental biochemistry and cell biology, is perfectly suited for the research direction. The ESI-MIRA program enables launching my research career in cellular metabolism as well as moving into a new research area in neuronal cell biology. The flexibility in the funding mechanism allows this ambitious project to systematically decode mitochondrial metabolite transport.

NIH Research Projects · FY 2025 · 2023-06

Significance: The racial and ethnic distribution of the cancer workforce contrasts starkly with that of the general population. Only 2-3% of oncologists identify as Black or Latinx, compared to 13% and 18% of the U.S. population, respectively. While evidence from the business literature suggests that diversity in teams impacts organizational performance, it is not known whether provider team diversity as well as patient-provider racial and ethnic concordance is associated with quality of cancer-related care and outcomes. If the diversity of teams (physician patient-sharing networks) does indeed improve cancer care, this benefit could improve care for all patients, regardless of the individual patient's race or ethnicity or the race or ethnicity of their provider. Objective: Our over-arching goal is to generate actionable evidence to inform efforts to improve cancer workforce diversity and increase equity in cancer care. Our hypothesis is that the racial and ethnic representation of the oncology workforce varies across regions and patient-sharing networks and that this variation is associated with clinical care. Previously, addressing this knowledge gap has not been possible due to a lack of available data combining physician race and ethnicity with patient clinical data. Specific Aims: We propose a retrospective study using a novel data linkage between the American Medical Association; Association of American Medical Colleges; Surveillance, Epidemiology and End Results population-based cancer registries; and Medicare data to address the following aims: (Aim 1) To ethnic and sharing and regions patient-sharing or assess changes in racial and diversity of the cancer physician and trainee workforce between 2015 and 2020, according to specialty regional healthcare market and ( Aim 1A ) to assess the racial and ethnic diversity of physician patient- networks providing cancer care during the period 2015 – 2020; ( Aim 2 ) To assess variation in racial ethnic representativeness of the oncology workforce across specialty, physician networks, and geographic and (Aim 2A) to identify whether underrepresented in medicine (URM) physicians, as well as physician networks containing a higher proportion of URM physicians, are more likely to care for Black Latinx patients with cancer; ( Aim 3 )To assess geographic and health system contextual factors (e.g. health system factors, area sociodemographics, and structural racism) associated with physician diversity within physician patient-sharing networks; (Aim 4) Among patients diagnosed with invasive lung, prostate, breast, or colorectal cancer during 2015-2019, to networks Receipt assess the association between the racial diversity of their physician , and ( Aim 4A) Early stage at diagnosis for patients with colorectal or breast cancer, ( Aim 4B ) of guideline-concordant cancer treatment, and ( Aim 4C) Quality of end of life care. Through this study, we will create a novel data linkage, and incorporate network science methods to further our understanding of the cancer physician workforce and to identify whether physician team diversity may serve as a previously unidentified mechanism of reducing racial and ethnic disparities in cancer outcomes.

NIH Research Projects · FY 2026 · 2023-06

PROJECT SUMMARY The goal of this study is to investigate the role of the kappa opioid receptor (KOR) in the symptomatology of borderline personality disorder (BPD), a condition associated with alarmingly elevated risk for suicide attempt (SA; up to 75%) and death by suicide (up to 10%). Despite BPD’s relatively low prevalence (1-5%), epidemiological research has shown that up to 33% of suicide deaths in the general population are attributable to BPD. Adding complexity, research suggests that significant sex differences exist in BPD with respect to both symptoms’ presentation and neurobiology; BPD males have higher suicide risk, but less access to effective treatment. Despite this, available treatments are largely not capable of addressing overall BPD symptom severity or rapidly reducing suicide risk. Magnetic resonance imaging (MRI) studies have identified structural and network alterations in BPD and have associated structural differences and dysregulation in a frontolimbic circuit of regions with incidence of BPD and increased symptom severity, and suicidal behavior in BPD. Investigation of molecular mechanisms responsible for BPD symptoms, and suicide risk specifically, is an essential next step to both promote development of novel treatments and facilitate risk prevention in BPD. Emerging evidence implicates KOR in BPD and suicidal behavior. KOR plays critical roles in emotion regulation, social functioning, and impulsivity– all of which are both central to BPD and related to suicide risk. Postmortem studies have shown an association between KOR and death by suicide. Further, a variety of studies in both animals and humans have shown that KOR antagonists can produce antidepressant, anxiolytic, and even anti-suicidal effects, though research also suggests men and women may respond differently to such agents. Importantly, KOR agents’ effect on dopamine is modest relative to drugs of abuse, reducing concerns about abuse potential. Based on support from novel pilot data using the same techniques, we now propose a novel investigation of KOR availability in individuals with BPD relative to healthy adults (HA) using positron emission tomography (PET), a brain imaging technique, and radioligand [11C]EKAP which binds selectively to KOR in the brain (Aim 1a). We will also evaluate the association between KOR availability and SA history in BPD (Aim 1b). Next, we will evaluate the association between impulsivity, emotion dysregulation, and BPD symptom severity – key endophenotypes related to prognosis and suicide risk and resistant to treatment – and KOR availability in BPD (Aim 2). Finally, we will evaluate sex differences in KOR availability in BPD and HA. Results of this study will provide potentially critical insight into the relationship between this novel molecular target, BPD symptom presentation, and suicidal behavior. Based on findings we will pursue funding for a larger PET study to test potential non-addictive KOR targeted medications for both overall BPD symptom reduction, and suicide risk.

NIH Research Projects · FY 2025 · 2023-06

PROJECT SUMMARY The goal of this study is to investigate the role of the kappa opioid receptor (KOR) in the symptomatology of borderline personality disorder (BPD), a condition associated with alarmingly elevated risk for suicide attempt (SA; up to 75%) and death by suicide (up to 10%). Despite BPD’s relatively low prevalence (1-5%), epidemiological research has shown that up to 33% of suicide deaths in the general population are attributable to BPD. Adding complexity, research suggests that significant sex differences exist in BPD with respect to both symptoms’ presentation and neurobiology; BPD males have higher suicide risk, but less access to effective treatment. Despite this, available treatments are largely not capable of addressing overall BPD symptom severity or rapidly reducing suicide risk. Magnetic resonance imaging (MRI) studies have identified structural and network alterations in BPD and have associated structural differences and dysregulation in a frontolimbic circuit of regions with incidence of BPD and increased symptom severity, and suicidal behavior in BPD. Investigation of molecular mechanisms responsible for BPD symptoms, and suicide risk specifically, is an essential next step to both promote development of novel treatments and facilitate risk prevention in BPD. Emerging evidence implicates KOR in BPD and suicidal behavior. KOR plays critical roles in emotion regulation, social functioning, and impulsivity– all of which are both central to BPD and related to suicide risk. Postmortem studies have shown an association between KOR and death by suicide. Further, a variety of studies in both animals and humans have shown that KOR antagonists can produce antidepressant, anxiolytic, and even anti-suicidal effects, though research also suggests men and women may respond differently to such agents. Importantly, KOR agents’ effect on dopamine is modest relative to drugs of abuse, reducing concerns about abuse potential. Based on support from novel pilot data using the same techniques, we now propose a novel investigation of KOR availability in individuals with BPD relative to healthy adults (HA) using positron emission tomography (PET), a brain imaging technique, and radioligand [11C]EKAP which binds selectively to KOR in the brain (Aim 1a). We will also evaluate the association between KOR availability and SA history in BPD (Aim 1b). Next, we will evaluate the association between impulsivity, emotion dysregulation, and BPD symptom severity – key endophenotypes related to prognosis and suicide risk and resistant to treatment – and KOR availability in BPD (Aim 2). Finally, we will evaluate sex differences in KOR availability in BPD and HA. Results of this study will provide potentially critical insight into the relationship between this novel molecular target, BPD symptom presentation, and suicidal behavior. Based on findings we will pursue funding for a larger PET study to test potential non-addictive KOR targeted medications for both overall BPD symptom reduction, and suicide risk.

NIH Research Projects · FY 2026 · 2023-06

This K23 Career Development Award will support Dr. Allison Gaffey’s development into an independent patient-oriented investigator with a focus on women’s risk for hypertension (HTN) and cardiovascular disease (CVD), the contributions of social vulnerability (SV; i.e., the degree that social factors including socioeconomic status, demographics, housing, and access to healthcare, increase susceptibility to adverse cardiovascular health when individuals are exposed to stress) and insufficient sleep (e.g., short sleep duration) to this risk, and the identification of early opportunities to mitigate this risk. By age 35, women begin to show a steeper annual increase in blood pressure (BP) than men and over 1 in 3 premenopausal women exhibit an early stage HTN phenotype (i.e., elevated BP or Stage 1 HTN). SV and short sleep duration - each amenable to behavioral and public health interventions - are especially impactful for women, and may contribute to this observed, yet underappreciated BP increase prior to menopause. The K23 Award will ensure that Dr. Gaffey develops the knowledge and skills to investigate the social and behavioral determinants of early risk for HTN, to improve related behavioral CV prevention for women. In the resource rich environment of the Yale School of Medicine, Dr. Gaffey has assembled a multidisciplinary mentoring and advisory team to facilitate her transition to independence via training in: (1) the pathophysiology of BP, HTN, and CVD, including associations unique to women; (2) physiological and behavioral mechanisms of sleep, state-of-the-art sleep measurement, and sleep health disparities, including those specific to women; (3) social determinants of health in CV epidemiology, including associations unique to women; and (4) statistical modeling of longitudinal and repeated sampling data. Dr. Gaffey’s training will be complemented by a novel plan of research: (AIM 1) With longitudinal data from the Coronary Artery Risk Development in Young Adults Study (CARDIA), test associations of SV and self-reported sleep duration to: a) the onset of early stage HTN phenotypes, and b) the rate of BP change from early- to mid-adulthood. Analyses will be stratified by biological sex. (AIM 2) Limitations of CARDIA will be addressed by conducting a mixed methods, pilot study with a community sample of premenopausal women and same-aged men to, a) test short-term associations of home BP to SV-related stress exposures and ecologically, objectively assessed sleep duration; and b) qualitatively assess personal experiences of SV-related stress, barriers to sleep, and study feasibility/acceptability. Outcomes will include within-person variability in stress, sleep, and BP associations over time, contextual themes to inform future assessment of SV, stress, and sleep, and rates of recruitment, adherence, retention, and satisfaction. This K23 builds logically on Dr. Gaffey’s prior research and clinical background and provides her with the requisite expertise and evidence base to prepare a later R01 application to collect more comprehensive, objective, and ‘real-world’ assessments of SV, sleep, and BP. This knowledge will simultaneously address critical gaps concerning BP progression in younger adults and advance Dr. Gaffey’s planned career objective to identify earlier opportunities for HTN and CVD prevention in women.

NIH Research Projects · FY 2025 · 2023-06

The IEEE Medical Imaging Conference (MIC) is the leading international scientific meeting bringing together a broad community interested in the physics, engineering, and mathematical aspects of medical imaging, with particular emphasis on nuclear medicine and multi-modal systems. The MIC runs in conjunction with the IEEE Nuclear Science Symposium (NSS) and the Workshop on Room Temperature Semiconductor X-ray and Gamma-ray Detectors (RTSD). The purpose of the MIC is to disseminate and foster new research in physics and bio-engineering methods in medical imaging. While the traditional topics of primary interest are related to nuclear medicine techniques such as positron emission tomography (PET) and single photon emission computerized tomography (SPECT), increasing space will also be given to recently evolving imaging modalities such as X-ray, CT, optical, MR, with particular emphasis on their multi-modal combination with nuclear medical imaging. Lately, there has also been additional interest in employing deep learning and AI to enhance the field of medical imaging. The conference provides a well-established forum for scientific exchange and dialogue between researchers in academia, industry, and government, as well as public education. The large spectrum of educational refresher sessions and short courses reflects its special emphasis on young generations. One of the primary objectives of the conference is the education of young investigators. Therefore, this NIH R13 proposal seeks $10,000 in funding for each of the next three years to provide 50 trainee grants of $200 each to partially cover the costs of MIC conference registration, housing, or short course fees for graduate students and postdoctoral fellows. We anticipate that the main impact of this grant program will be to increase the attendance of students and postdocs at the 2023 through 2025 meetings and support their participation in educational activities. It is important to bring young generations into the medical imaging field, where they could become leading players in the coming years. They will attend plenary and oral presentations given by many world leaders in the nuclear medical imaging instrumentation, image processing, and quantitative analysis fields. Moreover, they will be given the unique opportunity to have direct personal interaction through short courses and dedicated poster presentations. Their work will be exposed to the other participants for critical evaluation, constructive suggestions, and dissemination. Furthermore, many of these trainees will likely continue in this field, thereby contributing to advancing technology with high societal relevance as it is increasingly used in the clinical management of disease and therapeutic interventions.

NIH Research Projects · FY 2025 · 2023-06

The goal of this interdisciplinary team science proposal is to extend and inform biochemical and structural biology approaches for studying membrane proteins by understanding how their native environments define structure and function. To date, the majority of mechanistic studies of integral membrane proteins (IMPs) have not captured the properties and functional contributions of the membranes in which the IMPs are embedded. The central goal of our collaborative team is to develop new technologies and approaches that will allow us to: i.) Define lipid components and protein co-receptor components of functional complexes; ii.) Evaluate the role of the local membrane environment in function and regulation of the IMPs; and iii.) Determine the structures of these assemblies. Driven – and made possible – by the recruitment of six key junior faculty to the Departments of Pharmacology and Cell Biology over the past 5 years, we have assembled an interdisciplinary team with shared interest in transmembrane protein structure and function. Our team members bring complementary expertise to the project with skills in cryo electron microscopy (cryoEM), top-down and bottom-up mass spectrometry (MS), multi-omic analysis, optical imaging, biochemistry, and cellular signaling. We are very well placed to make unique advances in understanding membrane proteins involved in regulation of bacterial lipopolysaccharide synthesis, insect olfaction, mammalian ion channels, and mammalian receptors in the G protein-couple receptor (GPCR), Frizzled, and receptor tyrosine kinase families. Our Specific Aims are: 1: Identify native environments of integral membrane proteins To achieve this, we will identify new membrane-active copolymers that efficiently extract IMPs of interest, and use state-of-the-art lipidomics, proteomics, and native mass spectrometry to elucidate the molecular components of the protein’s membrane environment. 2: Understand how the native membrane environment modulates or determines membrane protein function Using a wide variety of assays – tailored to each IMP – we will ask how the specific membrane environment identified in Aim 1 influences IMP activity and oligomerization. We will also use limited proteolysis and H/D exchange mass spectrometry approaches to assess the influence of the membrane composition on conformation and structural dynamics 3: Determine structures of membrane proteins and complexes in native membrane environments We will determine structures of the target IMPs in defined membrane environments using cryoEM, to ask how known specific IMP-associated lipids and other components interact with and modulate IMP structure.

NIH Research Projects · FY 2025 · 2023-06

Project Summary/Abstract Endothelium plays a vital role in hemostasis and thrombosis. It is essential to maintain blood fluidity, but it also expresses and releases numerous “factors” that regulate blood cell activation and coagulation. Among these, von Willebrand factor (vWF) is an essential plasma hemostatic factor released by the endothelium. Deficiency of mature vWF is the most common bleeding disorder in humans. On the other hand, elevated plasma levels of vWF, or abnormal concentrations of its high-molecular weight multimers, is associated with increased risk of cardiovascular morbidity. As such, understanding of the molecular mechanisms that underlie regulated release of vWF have broad implications in hemostasis and thrombosis. One factor that plays a crucial role in normal vWF exocytosis from endothelial cells is unimpaired biogenesis of its storage granules, the Weibel-Palade bodies (WPBs), which is a highly complex process that remains poorly characterized. We have previously shown that deficiency of biogenesis of lysosome-related organelle complex 2 (BLOC-2) results in impaired vWF exocytosis. Since, BLOC-2, and other related trafficking proteins, are essential for biogenesis of lysosomal-related organelles, a group of specialized granules that includes platelet dense granules and melanosomes, it seems plausible that this protein complex is also required for biogenesis of WPB. We hypothesize that BLOC-2-mediated endosomal trafficking is critical for biogenesis of WPB. We further postulate that the exocyst complex plays an essential role in WPB trafficking by 1) interacting with BLOC-2 in its role in endosomal trafficking 2) and regulating soluble NSF adaptor protein receptor (SNARE)-mediated fusion of WPBs at the plasma membrane. In Aim 1, we will characterize cargo trafficking from the endosomes to the maturing WPBs and the dependence of this pathway on BLOC-2. In Aim 2, we will evaluate the role of the exocyst complex in BLOC-2-dependent endosomal trafficking and characterize the core trafficking machinery involved in this pathway. And, finally, in Aim 3, we will evaluate the regulatory function of the exocyst complex in SNARE-mediated fusion of WPBs at the plasma membrane. The applicant, Dr. Anish Sharda, previously completed clinical and research fellowship in hematology and is currently pursuing a post-doctoral fellowship under the mentorship of Drs. Robert Flaumenhaft and Bruce Furie, who will serve as primary mentor and co-mentor, respectively. The Division of Hemostasis and Thrombosis at Beth Israel Deaconess Medical Center has a distinguished track record of scientific innovation and mentorship, and will provide an excellent environment for the applicant in pursuit of his career goals. The advisory committee of exceptional scientists that Dr. Sharda has established will bring diverse intellectual expertise to his training and scientific growth. Dr. Sharda is well-qualified to execute the proposed experiments and has presented a comprehensive five-year plan to meet his goal of becoming an independent researcher.

NIH Research Projects · FY 2025 · 2023-06

PROJECT SUMMARY This proposal outlines a five-year training program for Dr. Mark Lee, M.D., Ph.D., with the goal of preparing him for an independent academic research career as a physician-scientist. Dr. Lee completed doctoral studies in immunology at Harvard Medical School as part of the combined M.D./Ph.D. program, and is currently an Instructor at the Brigham and Women’s Hospital and a board-certified Transfusion Medicine physician. Dr. Lee’s career development plan will build on his background in human immunology, adding didactic training and primary research experiences in computational oncology and cancer research. In this effort, Dr. Lee will be mentored by Dr. Matthew Meyerson, who is an international leader in lung cancer genomics and has a history of mentoring physician-scientists who have transitioned to independent academic research positions, as well as a Scientific Advisory Committee composed of highly regarded physician-scientists (Dr. Eliezer Van Allen, Dr. Marcela Maus, and Dr. David Barbie) who have expertise in computational oncology, cancer immunology, and cancer biology. The outstanding research environment and facilities available to Dr. Lee include laboratory space at both Dana- Farber Cancer Institute and the Broad Institute. In addition, using extensive career development resources within the Harvard-affiliated hospital system, Dr. Lee will further develop critical career skills in scientific leadership, laboratory management, research communication, and grant writing. The long-term goal of the proposed research is to apply novel technologies to identify the targets of tumor-reactive T cells within cancer genomes, in order to fundamentally understand immune responses in cancer patients and to therapeutically augment these responses. Although immunotherapy – and in particular, immune checkpoint blockade – has revolutionized treatment for select patients with non-small cell lung cancer (NSCLC), the majority of patients fail to respond. Thus, increasing the efficacy of immunotherapy for non-responders remains a critical priority of cancer research. T cell-based therapies, including adoptive cellular therapies and T cell receptor (TCR) bispecific proteins, have led to major pathologic responses in cancer patients, including in non-responders to checkpoint blockade. However, the currently limited set of well-defined tumor-reactive TCRs – and the technical difficulty of identifying tumor antigen/TCR pairs – currently restricts the number of NSCLC patients that can be treated with these novel therapies. Dr. Lee recently developed a high-throughput method that allows functional testing of thousands of putative T cell targets, and will apply this method to identify the targets of T cell receptors in NSCLC patient tumor and blood specimens. Successful completion of this project will enable a more complete understanding of the cellular markers that enrich for tumor-reactive T cells (Aim 1) and a more complete understanding of how tumor-reactive T cells in the peripheral blood respond to PD-1 blockade (Aim 2). Together with formal training, the proposed research will allow Dr. Lee to launch an independent career as an academic physician-scientist.

NIH Research Projects · FY 2026 · 2023-06

PROJECT SUMMARY Discoid lupus erythematosus (DLE) is a disfiguring autoimmune skin disease with a predilection for affecting the head and neck that causes permanent scarring, hypopigmentation, and alopecia. DLE disproportionately affects African American women, and it severely impairs quality of life. DLE may occur alone or in the setting of systemic lupus erythematosus (SLE), and treatments for DLE are currently unsatisfactory. The DLE inflammatory infiltrate is predominantly composed of T cells, which appear to promote tissue inflammation and damage, but how they adapt to the skin environment and subsequently promote tissue injury is unknown. We recently identified an inflammatory gene program induced by the transcription factor hypoxia inducible factor (HIF) that is necessary for the survival and effector ability of pathogenic T cells in lupus-prone mice, with a similar program upregulated in human SLE. Yet, how HIF1 promotes damage and what other tissue adaptation and effector pathways are activated in skin-infiltrating T cells in DLE are not known. Based on my preliminary studies, I hypothesize that HIF1 regulates pathogenic T cell survival and effector function in DLE skin, causing inflammation and damage that may be mediated in part by enhanced cytotoxicity. This HIF1-regulated effector program also suggests a paradigm of pathogenic adaptation in tissue-infiltrating T cells with the potential to drive tissue damage. To test my hypothesis, I will determine the mechanism of HIF1 blockade in alleviating skin disease in a murine lupus model. I will also study human DLE skin and blood samples using single cell RNA sequencing to probe the developmental trajectory, phenotypic, and functional profile of T cells in human DLE. Finally, I will use imaging techniques to examine the role of cytotoxicity in tissue damage in human DLE, with parallel studies in mouse tissue. My studies will not only elucidate the role of HIF1 and cytotoxicity in DLE, but will also yield the first detailed characterization of infiltrating and circulating T cells in human DLE, paving the way for future studies to develop and evaluate novel therapeutics for this devastating disease. My proposal will also support a period of career development during which I will receive additional training in basic and translational immunology in the laboratory of Dr. Joseph Craft, a leader in the fields of lupus research and T cell biology. Dr. Craft's laboratory in the Yale Department of Immunobiology provides a highly collaborative and supportive research environment. To further support my training, I have assembled an advisory committee with experts in transcriptomic analyses, translational dermatology, cutaneous T cell biology, and autoimmune skin disease. My research studies and directed additional career development activities focused on computational approaches, human translational research, and biostatistics in clinical investigation will allow me to successfully achieve research independence as a physician scientist and open my own laboratory so that I can use basic and translational immunologic approaches to study cutaneous autoimmune diseases including DLE.

NIH Research Projects · FY 2026 · 2023-06

The pattern of social connections within a population (whether a school, firm, village, or online group) is mentally perceived by those embedded within it. Such “cognitive social networks” (the mental maps people make of the social world around them) are relevant to people’s social, mental, and physical well-being. More formally, a sociocentric social network defines a set of dyadic relationships between individuals in a defined population and can be represented by a 𝑁 × 𝑁 matrix A where each element Aij represents a tie between individuals i and j, e.g., reported by individual i. But individuals not only form mental representations of their own relationships, they also cognize relationships between others. For instance, an individual k may have a perception of the relationship between i and j, say, that i is a friend of j. This yields a three-dimensional network structure with entries 𝑖, 𝑗, 𝑘 ∈ 𝑁 × 𝑁 × 𝑁, where i is the “sender,” j the “receiver,” and k the “perceiver” of the relationship. Humans are innately interested in tracking relationships, despite the cognitive burden. Such knoweldge is often the basis for introductions, strategic information disclosure, and accessing social support. In an ongoing longitudinal cohort involving 24,862 people aged 12-93 in 176 villages in rural Honduras, we have mapped real, face-to-face network ties. Pertinently, we have 4,589 participants older than 50 at baseline (in 2016). Here, in new work involving an ongoing subset of 136 villages, we will assess how people form such cognitive social maps, how these maps vary, and how these perceptions might matter. We have four specific aims. In Aim 1, we ascertain the actual and perceived ties among individuals in the networks of 136 villages. We will ask each resident, in every village, about their perceptions of the connections that might exist among 40 randomly chosen other pairs of people in their village. In Aim 2, we compare the actual ties seen in village- level social networks to the ties perceived by members of the village. Our primary hypotheses are that ties geodesically further away from individuals will be assessed less accurately; that more socially connected individuals will be more accurate; and that older, male, or cognitively impaired individuals will be less accurate. In Aim 3, we assess how the accuracy of perception depends on the characteristics of the perceived tie. Our primary hypotheses are that ties between older individuals or ties involving fewer public displays of connection will be less well perceived by others. In Aim 4, taking advantage of a randomized experiment, we evaluate if being better able to accurately perceive social connections in one’s village is associated with one’s ability to spread novel information, including health information. Our primary hypothesis is that more socially perceptive individuals will have a greater ability to spread exogenously introduced information. Our results have fundamental implications not only for the social neuroscience of aging, but for a practical understanding of social isolation and whether and how social cognition can affect the spread of information and behaviors.

NIH Research Projects · FY 2026 · 2023-05

Our ability to identify genetic sequence variation in humans has thus far outstripped the field’s ability to interpret these mutations. Genome-wide association studies have identified hundreds of thousands of genomic loci associated with disease risk and human phenotypic traits, yet in few instances do we know the identity of the exact causal mutation, nor the molecular mechanism behind its function. Much of this limitation is due to a large portion of this variation residing in cis-regulatory regions (CREs), where our inability to identify a variants’ regulatory impacts or target gene(s) presents a major hurdle. Better understanding of this regulatory grammar - the complex logic of how sequence content in CREs controls transcription – is a crucial next step for genomics, but requires a vast expansion of well characterized regulatory mutations. To achieve this goal, we will employ a multi-pronged approach to build a large-scale, regulatory variant functional catalog. We will focus on CREs harboring genetically fine-mapped, likely causal variants from global populations for a variety of metabolic traits and disease (Aim 1). We will first identify CRE-gene interactions using highly-sensitive and scalable endogenous CRISPR approaches. This large-scale mapping effort will inform our understanding of the CRE-gene targeting logic of regulatory grammar. We will use this data to map the transcriptional architecture of metabolic complex traits. We then propose to interrogate sequence determinants of regulatory grammar for hundreds of trait-associated CREs at their endogenous location in the genome (Aim 2). We will first develop an endogenous saturation mutagenesis system to generate hundreds of thousands of nucleotide changes in these CREs. We will then assay the regulatory architecture of these changes using multiplexed amplicon ChIP-sequencing to identify epigenetic changes, and HCR-FlowFISH to detect transcriptional changes. In addition to identifying causal variants for a variety of metabolic diseases, this proposal will generate a repertoire of 300,000+ functionally characterized regulatory variants. This variant impact catalog will serve as an ideal training set to model regulatory grammar with our powerful machine learning approaches. We will incorporate endogenous saturation mutagenesis data into our variant effect prediction models (VEPs). Importantly, such models will find utility across global populations as they will explain a universal regulatory code of the human genome and thus enable interpretation of population-specific variation. We will then deploy these VEPs to understudied variation and in understudied populations. Overall, this proposal is structured to generate a functional characterization catalog at multiple levels: first providing molecular mechanisms and gene targets for thousands of causal variants, secondly building comprehensive genomic etiological understanding for phenotypically related complex traits, and lastly providing the scale of endogenous data necessary to improve VEPs. Our approach combines our group’s unique expertise spanning functional genomics, CRISPR screens, statistical genetics, and machine learning.

NIH Research Projects · FY 2026 · 2023-05

PROJECT SUMMARY Dilation & curettage (D&C) is one of the most common surgical procedures performed on women throughout the world. Intrauterine adhesions (iUA), or Asherman, develop in about 40% of women who undergo D&C in the postpartum (6 week period after birth), but is very rare after D&C in nonpregnant women (<1%) for reasons that are not well understood. It is a debilitating condition characterized by intrauterine fibrosis and scarring. Patients with iUA suffer from infertility, recurrent pregnancy loss and a broad range of dangerous pregnancy complications (e.g. preterm birth). While endometrial mesenchymal stem/progenitor cells (eMPCs) are crucial for endometrial repair, the role of these cells and underlying molecular mechanisms in this postpartum susceptibility of the endometrium to fibrosis and abnormal repair are unknown. This application is specifically focused on defining the role that eMPCs and their stromal fibroblast progeny play in abnormal uterine repair. The central hypothesis is that eMPCs of the recently postpartum uterus are more senescent and inherently different in their response to uterine injury compared to eMPCs of the nonpregnant uterus, leading to fibrosis and scar formation. The approach is to use our novel postpartum mouse uterine injury model which recapitulates the susceptibility of the human postpartum uterus to injury. Using it, we will define the dynamic changes in eMPCs and their differential response to uterine injury in the postpartum vs. nonpregnant, identify using lineage tracing the eMPC subsets that become the profibrotic fibroblast cells, and conditionally ablate each of these eMPC subsets to define their functional role in endometrial fibrosis (Aim 1). We will obtain fresh human endometrial tissue from women undergoing postpartum D&C and compare it to nonpregnant tissue using innovative single cell technology and functional in vitro studies to gain detailed insights into the cellular and molecular differences that predispose the human endometrium to form iUA (Aim 2). In Aim 3, we will obtain archived endometrial specimens from the time of inciting D&C event from women who developed Asherman vs. non-Asherman. We will use the innovative deterministic barcoding in tissue spatial multi-omics sequencing (DBiT-seq) platform and integrate it with immunofluorescence to gain detailed molecular insights regarding eMPCs and their cell interactions within the tissue, identifying novel therapeutic targets for iUA prevention. The proposed aims are conceptually and technically innovative and together will have a broad impact on the field by filling a substantial gap in our fundamental knowledge of endometrial biology and infertility pathogenesis using Omics approach, which are major research priorities of the Fertility and Infertility Branch of the NICHD. Ultimately, the knowledge gained from this proposal will not only be invaluable to our understanding of many more subtle conditions of abnormal endometrial repair, but provide unique insights into the body’s physiological anti-fibrotic wound healing mechanisms leading to a deeper understanding of the pathogenesis of fatal idiopathic fibrotic diseases in other organs.

NIH Research Projects · FY 2026 · 2023-05

PROJECT SUMMARY Despite effective antiretroviral therapy (ART), HIV-1 persists in the latent reservoir lifelong. Although most HIV- 1-infected cells die of viral cytopathic effects or immune clearance, HIV-1-infected cells, even those having active HIV-1 expression, can survive, persist, and proliferate. We want to examine how HIV-1 establishes infection during viremia and persists under viral suppression in people living with HIV-1. Understanding the immune cell subsets, immune programs, and cell markers of HIV-1-infected cells will identify therapeutic targets. The challenge is the heterogeneity and rarity of HIV-1-infected cells: in ART-treated, virally suppressed individuals, only 1–100/106 (<0.01%) CD4+ T cells harbor inducible HIV-1. To this end, we profiled CD4+ T cells from the Sabes cohort during viremia and after viral suppression using single-cell ECCITEseq, which captures single-cell transcriptome, protein expression, HIV-1 RNA, and T cell receptor sequence (TCR) within the same single cell. We have established advanced single-cell bioinformatic analysis pipelines and machine learning tools. This approach enables multi-dimensional, high-resolution, single-cell profiling of immune cell subsets, immune programs, cell markers, T cell clonal expansion, and HIV-1 RNA+ cells at the same time. Our single-cell ECCITEseq found that HIV-1 RNA+ cells upregulated cytotoxic CD4+ T cell genes. Using flow cytometric measurement of HIV-1 p24 protein and granzyme B expression, our RNA-seq based results were validated by a protein-based orthogonal approach, revealing that HIV-1 persists by hiding in granzyme B+ cytotoxic effector memory CD4+ T cells. Based on our results from viremic samples, we can examine the rare HIV-1 RNA+ cells under suppressive ART over time. Using single-cell ECCITEseq, we found that despite suppressive ART, tumor necrosis factor (TNF) responses persist. Furthermore, antigen and TNF responses drive the proliferation of T cell clones. In addition, different antigen responses drive distinct T cell polarization and proliferation. Altogether, we hypothesize that antigen stimulation and TNF responses can shape T cell polarization, cellular susceptibility to HIV-1 infection, cellular survival, and proliferation of the infected cells, particularly granzyme B cytotoxic CD4+ T cells. Our goal is to understand why HIV-1-infected cytotoxic CD4+ T cells can preferentially survive, proliferate, and persist, as opposed to other T cell subsets. Achieving this goal will identify immune programs that drive HIV-1 persistence and identify cell markers for HIV-1-infected cells for more specific therapeutic targeting. Our approach is to combine cutting-edge single-cell ECCITEseq and orthogonal validations to examine how HIV-1 RNA+ granzyme B+ CTLs survive and persist under viral suppression by profiling cell subsets, immune program, markers, and proliferation dynamics for the rare HIV-1 RNA+ cells over time during viral suppression in vivo and in vitro. Overall, we will understand why HIV-1 preferentially persists in cytotoxic CD4+ T cells, identify upstream immune drivers promoting the survival and proliferation of the HIV-1-infected cytotoxic CD4+ T cells, and guide the development of therapeutic strategies specific for HIV-1-infected cells.

NIH Research Projects · FY 2026 · 2023-05

Project Summary: Acute kidney injury (AKI) is defined as an abrupt loss of kidney function and is very common in children with chronic kidney disease (CKD). AKI is associated with high mortality rates in children and is thought to be a risk factor for a permanent loss of kidney function and development of end stage kidney disease. These elevated risks require urgent focus on AKI in children with CKD to better characterize the modifiable risk factors of AKI as well as understand the relationship between AKI and kidney health. Improving the understanding of the risk factors and pathogenesis of AKI will provide a basis for interventional studies to prevent AKI, limit progression of CKD, and improve long-term outcomes. To study AKI in children with CKD and address a substantial gap in pediatric research, we have developed research studies with the 1100 participants of the CKD in Children (CKiD) cohort, the largest cohort of children with CKD. The yearly study visits with kidney function, blood pressure, and albuminuria measurements for all CKiD participants minimizes the bias and confounding of previous research which retrospectively examined kidney function assessments performed only when clinically indicated. As the kidney tubules are critical to life and essential to supporting multiple critical functions in a growing child, we will conduct a global assessment of kidney health using biomarkers of both glomerular and tubular health. To characterize tubular health including tubular regeneration, injury, dysfunction, and inflammation before and after AKI, we will measure 4 urine biomarkers (epidermal growth factor, kidney injury molecule-1, monocyte chemoattractant protein-1, α-1 microglobulin). They will add substantially to the examination of key pathways that may contribute to CKD progression after AKI. In preliminary data, we observed that after multivariable adjustment, each of these tubular biomarkers is associated with a subsequent decline in kidney function. We also observed at two CKiD sites, that 25 of 83 children (30%) developed at least one episode of AKI and that those with AKI were more than twice as likely to develop CKD progression. The specific aims are: 1) Determine the relationship between characteristics of glomerular and tubular health with the risk of AKI; 2) Determine the association between AKI with the subsequent change of GFR, blood pressure, albuminuria, growth, and tubular health biomarkers; 3) Develop and validate a risk prediction model for future progression of CKD in children combining CKD risk factors, prior AKI characteristics, and biomarkers of tubule health. Our research will represent a foundational epidemiologic study of AKI and may better explain the highly variable long-term outcomes in children with CKD. Completion of our research will provide new insights to identify therapeutic targets and support future interventional studies of AKI in CKD. Furthermore, a validated risk prediction model and understanding of the relationship between AKI and long-term outcomes may provide for the early detection and prompt treatment of GFR decline after AKI.

NIH Research Projects · FY 2026 · 2023-05

Abstract High image noise degrades the diagnostic efficacy and quantitative accuracy of PET, as noise could easily results in overestimation of SUV and cause false positive lesion detections in diagnosis. High image noise also decreases the confidence of clinical decision making, leading to additional unnecessary follow-ups through other imaging modalities and invasive procedure. Deep learning-based noise reduction has shown promises for PET imaging. However, existing approaches only focus on converting low-count image (e.g. acquired through low- dose injection or shorter scan time) to standard-count image in typical clinical scans. However, for both low- count and the vast majority of routinely acquired clinical PET images with normal dose and scan time, there is no approach to convert such clinical images to high-count images to further reduce the image noise, mainly due to the challenge of obtaining high-count PET images as training labels. Another challenge in the real-world application is to match the training data with the testing data, in terms of noise level, noise structure, reconstruction parameters, scanner model, etc. Such matching is particularly challenging in a multi-center multi- scanner setting. In this Academic-Industrial Partnership R01 project, we formed an ideal partnership between Visage Imaging, a leading PACS company, and three leading academic centers (Yale, MGH, UC Davis) to develop, evaluate, deploy, and translate robust deep learning methods to generate virtual-high-count PET images in a highly personalized manner by taking into account the noise level of each organ in each patient, as well as associated non-imaging patient information. The academic sites have access to a large number of high- count data that are acquired either through long dynamic scans (at least 90 minutes) or by the ultra-sensitive long axial field-of-view (FOV) Explorer scanner. The developed product would be deep learning networks that can convert any clinical PET images data from all major vendors (Siemens, GE, United Imaging Healthcare (UIH)) into virtual-high-count ultra-low noise images. Since Yale, MGH, and UC Davis are all serviced by Visage Imaging, the developed deep learning technique can be seamlessly translated into Visage PACS research/clinical servers for validation and evaluation, beta testing and user feedback, and ultimate translation and regulatory filings. In Aim 1, we will develop deep learning models for virtual-high-count PET generation. In Aim 2, we will evaluate and deploy the models into Visage research PACS server and evaluate virtual-high-count PET in clinical environments. In Aim 3, we will integrate the developed virtual-high-count PET deep learning models into the clinical production PACS server and generate regulatory documents and supporting data for FDA 510(k).

NIH Research Projects · FY 2026 · 2023-05

PROJECT SUMMARY/ABSTRACT Particle-based fetal therapy is a promising approach to address organ damage caused by structural diseases in utero. By prenatal imaging, structural diseases can be diagnosed and imaging features can predict the severity of outcome. Fetal surgery has demonstrated improved outcomes (but not cures) for structural diseases such as congenital diaphragmatic hernia (CDH), where lung growth is impaired and spina bifida (MMC) where the unprotected spinal cord is damaged. The challenges with fetal surgery are the complexity and invasive nature of these procedures and the limit to how early in pregnancy these techniques can be applied. In most cases, earlier treatment results in shortened duration of organ damage and longer duration of normal organ growth and development. We have generated data that nanoparticles (NPs) carrying epigenetic therapy in the form of specific microRNAs changes various downstream targets and improves the growth of lung in a rat of CDH. This approach can be delivered safely through a needle very early in pregnancy by clinical techniques that carry a very low rate of fetal demise (amniocentesis and fetal blood transfusion). To improve on our success in these animal models, we will engineer particles for two modes of delivery: 1) systemic/intravenous (IV) to reach internal organs (lung) and 2) intra-amniotic (IA) to reach tissues sites that are in contact with the amniotic fluid (such as the lung epithelial surface). In aim 1, we will test and improve particle behavior (stability and controlled protein binding) in human fetal blood to improve IV delivery. We will then use optimized particles to deliver epigenetic therapy to improve lung morphology in the rat model of CDH. In aim 2, we will test and improve particle behavior and stability in rat, lamb and human amniotic fluid to improve IA delivery. We will use particles carrying epigenetic therapy to treat a rat model CDH. Finally, with an eye on translation, in aim 3, we will test the distribution of particles in lamb after IV or IA administration to lung and other tissues. This project takes advantage of the synergistic expertise (biomedical engineering and fetal therapy) of the two principal investigators who have already worked together for several years. Successful completion of our aims will establish principles with broad implications for fetal therapy, would inform strategies to improve outcomes for children afflicted with congenital diseases. Our strategies—which aim for clinical translation—could lead to a paradigm-changing “off-the-shelf” therapy for structural diseases that, due to their simplicity, could be offered at many hospitals.

NIH Research Projects · FY 2025 · 2023-05

PROJECT SUMMARY There is a critical need to develop high-throughput scalable assays to identify biological mechanisms underlying risk genes in neurodevelopmental and neuropsychiatric disorders (NPD). In this proposal, we aim to leverage the unique advantages of two scalable systems – human induced pluripotent stem cells (hiPSCs) and zebrafish – to perform parallel functional assays of NPD genes in vitro and in vivo, and to pilot the development of innovative spatial multi-omics technologies applicable across systems. We propose to establish an Assay and Data Generation Center (ADGC) as part of the SSPsyGene Consortium that capitalizes on the unique and complementary expertise of our labs in large-scale hiPSC CRISPR screens (Brennand), high-throughput zebrafish screens (Hoffman), and cutting-edge multi-omics tool development (Fan). Our goal is to gain novel insights into the convergent and divergent mechanisms by which diverse NPD gene loss of function affects neurodevelopment at the molecular, cellular, structural, circuit, and behavioral levels. We propose to screen 250 NPD genes using a tiered strategy in hiPSCs and zebrafish by conducting pooled and arrayed transcriptomic and phenotypic screens in hiPSCs-derived neurons and glia (Aim 1), CRISPR screens in zebrafish to assess the effects of gene loss of function on whole-brain structure, activity, and basic behaviors (Aim 2), and spatial transcriptomic and multi-omic CRISPR screens to investigate the transcriptional effects of NPD gene disruption in both systems (Aim 3). We will advance the field by identifying biologically relevant phenotypes resulting from NPD gene loss of function across multiple scales, informing gene prioritization schema, and establishing new spatial multi-omics platforms for the functional analysis of NPD genes. These studies will generate an unprecedented resource of matched molecular, cellular, structural, circuit, and behavioral data in hiPSCs and zebrafish, which will be provided for open distribution to the broader community to yield new insights into NPD.

NIH Research Projects · FY 2026 · 2023-05

PROJECT ABSTRACT Intensive care unit (ICU) teams (i.e., nurses, physicians, and respiratory therapists) have some of the highest rates of burnout in healthcare. Burnout is an occupational phenomenon resulting from chronic workplace stress and is characterized by exhaustion, depersonalization, and reduced professional efficacy. Burnout has been associated with poorer safety ratings, quality of care, and patient outcomes. Interventions to reduce burnout have focused on individual clinicians, but this approach neglects the organizational factors contributing to burnout, and consequently, has been only marginally effective. Organizational resilience is a promising approach for addressing burnout in ICU teams and improving outcomes in patients with acute respiratory failure. Organizational resilience is the capacity of a complex adaptive system to anticipate stressors, perform under stressful conditions, and adapt moving forward. While the relationships among organizational resilience and employee health and performance outcomes have been described in other settings, organizational resilience has not been measured in healthcare settings. Our scientific premise is that the key to improving ICU clinician burnout and preventing adverse outcomes in patients with acute respiratory failure is to investigate the role of organizational factors in ICU resilience. When ICUs are more organizationally resilient, clinicians feel better equipped to manage workplace stressors, and thus are more likely to provide high-quality care for patients with acute respiratory failure. Capitalizing on our team’s expertise in ICU organization and survey research, our partnership with CommonSpirit Health, the 4th largest U.S. healthcare system with hospitals in 21 states, and our preliminary data, we propose a novel mixed-methods sequential explanatory design study that examines resilience as an organizational phenomenon. We will administer a survey about resilience (Connor-Davidson resilience scale and Lee et al’s measure of organizational resilience), burnout (two single-item Maslach Burnout Inventory measures), and wellbeing (WHO-5) to 6000 clinicians working in 60 ICUs at two timepoints to examine the dynamics of individual and organizational resilience over time (Aim 1). We will then test the interdependent contributions of individual and organizational resilience to patient outcomes (mortality and ventilator-free days) and clinician outcomes (burnout and wellbeing) (Aim 2). Lastly, we will qualitatively describe the relationships between work environment, ICU organizational resilience, and interprofessional care and characterize perceived barriers and facilitators of organizational resilience (Aim 3). Our long-term goal is to develop a multi-pronged intervention that will enhance ICU resilience. Our objective in this proposal is to empirically test the relationship between resilience and patient and clinician outcomes so that administrators, policymakers, and researchers can more appropriately target efforts to support ICU clinicians. This project addresses a major gap in understanding how to best support a valuable healthcare resource: the clinicians that care for mechanically ventilated adults.

NIH Research Projects · FY 2026 · 2023-05

Project Summary The overarching goal of this project is to develop innovative, robust and plausible analytical methods to uncover individualized biomarker trajectories that interrelate with Alzheimer's onset during asymptomatic stage, dissect their associated genetic bases, and dynamically predict the overall disease risk composited with quality of life through massive and time-varying health and biomedical profiles. Alzheimer's disease (AD) is incurable, and its soaring prevalence has induced a global crisis on health and finances. Recent research reveals that AD is a continuum with pathological changes launched years before the emergence of clinical symptoms. The ongoing biomarker research plays a dominate role in tracking disease evolution and predicting AD-related outcomes, and the more accessible electronic health records (EHRs) nowadays further provide an untapped resource for a prompt management of disease progression. However, existing disease dynamics and predictive studies suffer with 1) ignoring the interplay between biomarker dynamics and disease hallmarks, 2) inadequate power under sparse and irregular measurements, 3) failure to handle time-dependent EHRs with subject-specific landmarks, and 4) oversight on predicting risk profiles accounting for patients’ quality of life. To address these barriers, the current project proposes the following aims: Aim 1) to construct AD biomarker trajectories interrelated with disease onset during asymptomatic stage and dissect associated genetic risk profiles; Aim 2) to build dynamic risk prediction and quality of life assessment tools for AD-related events integrating electronic health records, brain imaging traits and neuropsychological metrics; Aim 3) to perform systematic evaluation for the proposed methods through extensive simulations and real data analyses, and develop user-friendly analytical pipelines for the proposed methods. This project is innovative in multiple aspects for and beyond AD medical and biomedical research including but not limited to a) establish multi-domain biomarker trajectories interacted with disease onset, b) consider age and time-to-event indices for marker dynamics as well as flexible and knowledge- driven shapes, c) uncover relevant genetic underpinnings d) account for sampling bias due to delayed entry, e) develop dynamic prediction with subject-specific landmarks, f) predict risk profiles accounting for the life quality, g) develop efficient and user-friendly pipelines for our products. We will implement the proposed paradigms on three large-scale AD cohort studies containing multi-domain repeatedly measured biomedical and clinical data, with one of them linked with a massive EHR dataset of over 2.5 million patients. A successful completion of this project will pave unique ways to achieve early detection, intervention and management for AD. By contributing on laying the groundwork for proactive disease modeling based on multi-domain data sources, we anticipate the proposed research will simultaneously provide valuable insights for more general neurological and psychiatric research for public health outcomes.

NIH Research Projects · FY 2025 · 2023-05

Abstract Oral potentially malignant disorders (OPMD) are a group of mucosal diseases in the oral cavity with a risk of progressing to oral squamous cell carcinoma. Risk assessment is traditionally done through a combination of clinical and histologic evaluation. Leukoplakia is a common type of OPMD that is given a histologic grading score that is supposed to be related to its risk of progression. However, there is tremendous intra- and inter- observer heterogeneity in dysplasia grading, leading to variability and uncertainty in risk assessment and treatment planning. This also hinders the ability to study the biology of these lesions. We propose to use whole slide imaging on routine hematoxylin and eosin (H&E) stained sections in combination with deep learning methods to build a consistent risk scoring system for OPMD. Our methods will identify cell, nucleus, and tissue architectural features relevant to risk of progression in OPMD. These features will be tested in a large retrospective case-control study and then validated prospectively. We will also explore combining them with genomic and immune biomarkers in order to improve the prognostic power and explore the biolo gy of progression in OPMD. We hope that these efforts will improve and standardize risk assessment for OPMD. This could lead to improved treatment and prevention options by enabling risk stratification and allowing future clinical trials be conducted in a more uniform patient cohort. Similarly, it could improve our understanding for the biology of OPMD and the process of progression to cancer.

NIH Research Projects · FY 2026 · 2023-05

Project Summary/Abstract Episodic memory and memory-guided decision making are quintessential cognitive functions ensuring our identity, successful everyday life, and survival. Memories have a strong spatial and temporal sequential component. The field of memory research has long used rodent spatial navigation on linear environments as a framework for studying memory encoding and consolidation. Large-scale electrophysiological recordings from the adult rodent brain performed during animal navigation in novel environments have established that neuronal ensemble computations within and between the hippocampus and medial entorhinal cortex (MEC) are critical for the encoding and consolidation of spatial memories. During memory-guided decision- making tasks, the hippocampus and mPFC neurons re-engage in coordinated computations and communication, particularly during the successful trials. Optimal investigation of memory and decision-making processes require simultaneous interrogation of large ensembles of neurons from interconnected brain areas such as MEC and the hippocampus, and hippocampus and mPFC, respectively. Without exception, these experiments have been performed exclusively in adult animals where large neuronal samples could be obtained in freely-behaving rodents. Yet these findings in the adult brain raise new critical, still unanswered questions: When and how do coordinated activities between hippocampal neuronal ensembles and their upstream/downstream MEC emerge during postnatal life to support encoding and consolidation of long-term memories? When and how do mPFC neuronal ensemble patterns critical for decision making mature and how does their coordination with the hippocampus develop during postnatal life? In this proposal, I will investigate the age- and experience-dependent early- postnatal development of neuronal ensemble patterns known to be significant for spatial memory and navigation and decision making in the adult rat. The chronic, large-scale electrophysiological recordings will be performed over several days in freely-behaving and sleeping developing and adult rats simultaneously from interconnected brain areas, MEC and the hippocampus and the hippocampus and mPFC, respectively. These experiments will define the principles and stages of coordinated development across connected brain areas, their age and experience-dependence and the developmental critical periods specific to each brain area investigated.