Duke University

NIH Research Projects · FY 2026 · 2024-07

Specialized cellular identity requires unique protein expression control. Such expression control in gametes and reproductive neurons ensures fertility. By studying cell- and tissue-level genetic code regulation, we discovered multiple links to reproductive biology. Specifically, we found that in both flies (Drosophila) and humans, the germ cells of the testis but not the ovary upregulate numerous mRNAs that are enriched in rarely used codons. We then revealed that rare codons restrict the ribosomal protein RpL10Aa to the fly testis to ensure fertility. Few other fly cell types express a rare codon reporter outside of the testis, with an additional example being most types of neurons of the brain. From genetic screening, we identified the conserved mRNA binding proteins Not3 and Orb2 as critical regulators of rare codon-dependent expression in both germ cells of the testis and in neurons throughout the brain. Notably, Orb2 has two main functions- ensuring spermatogenesis and control of mating behavior in reproductive neurons of the brain. Thus, our data are revealing important rare codon regulation of reproduction in both male gametes and neurons (including those neurons that control reproduction). In this proposal, we capitalize on our model and robust preliminary data to find new rare codon-dependent regulation in the testis and brain, and to define its function in fertility and reproductive behavior. The significance of our proposed work lies in the conservation of our findings in human testis biology and the impact on reproductive biology. Further significance is in the conservation of the new regulators of rare codon expression to be studied (Not 3 and Orb2). Our studies are innovative because we will study testis/neuron biology and reproduction in a new way, from the perspective of tissue-specific interpretation of the redundant code. In Aim1, we will identify the role of testis- and neuron-specific tRNA levels and mRNA stability on rare codon expression. To answer this question, we will determine the impact of rare codon tRNA levels, rates of mRNA decay, and the CCR4-Not de- adenylation complex on rare codon expression. We will compare each of these mRNA translation inputs in the testis vs. ovary and neurons vs. neural progenitors. In Aim 2, we will define the mechanism of Orb2 rare codon regulation in the testis and neurons. To do so, in the testis and neurons we will identify critical Orb2 domains required for rare codon expression, determine the role of rare codons in mRNA/Orb2 interactions, and identify rare codon-enriched Orb2 targets involved in fertility and reproductive behavior. In Aim 3, we will define the function of specific rare codon-derived proteins in the testis and neurons. To do so, we will further our mechanistic study of the testis-specific RpL10Aa in gametogenesis and fertility and use candidate genetics and ribosome profiling to find new examples where rare codons direct expression and/or function, focusing on testis-specific expression in gametogenesis/fertility, and male neuron-specific expression in reproductive behavior (courtship). Together, our proposed work will reveal new insight into how an ancient feature of life, the redundancy of the genetic code, regulates testes and neuron protein expression in the context of reproduction.

NIH Research Projects · FY 2025 · 2024-07

Latino immigrants experience erosions in health that are heightened over time and across generations. In fact, the syndemic (conditions that cluster among marginalized groups) comprised of substance use, intimate partner violence (IPV), risk for HIV, and mental health conditions has been found to increase among Latino immigrants over time and higher levels of US acculturation. Acculturative stress, the stress associated with being a Latino immigrant and acculturating to the US, is the most robust predictor of this syndemic and the impact these stressors have on family level dynamics (e.g., marital stress, acculturation gaps) are particularly harmful. Latino immigrant families have multiple sources of resilience that allow them to resist, recover, and rebound from this stress. These include individual active coping, optimism in the American Dream, and a positive ethnic identity; family support, parental monitoring and positive parent-child communications; and community social support and access to social and health resources. This application aims to prevent syndemic health conditions by decreasing acculturative stress and promoting resilience via SER Familia (Salud, Estrés y Resilencia en Familias/ Health, Stress, and Resilience in Families), a family-based intervention informed by our observational (SER Hispano; R01MD012249) and pilot studies. SER Familia is a six-session intervention co-developed and delivered by community health workers (CHWs) that uses strategies to reduce acculturative stress, promote resilience, improve parent-child and family level health, while simultaneously helping families maintain strong social networks and better navigate community resources to promote their health. More specifically we aim to: 1) Examine the efficacy of SER Familia to prevent or reduce the syndemic comprised of substance abuse, IPV, HIV risk, depression, and anxiety among Parents and Youth; and 2) Identify how individual, family, and community mechanisms of change related to acculturative stress and resilience mediates the effect of SER Familia. We will carry out a community-engaged, mixed-methods, randomized controlled trial with 380 Latino immigrant families to determine the impact of SER Familia compared to a delayed intervention condition. Data from surveys using culturally specific measures of acculturative stress, resilience, and syndemic outcomes collected at baseline, immediately after the intervention, and 6 and 12 month follow-up periods from Parent and Youth dyads will be integrated with interviews with a sub-set of dyads randomized to the SER Familia (n=20) to generate a comprehensive understanding of the impact and mechanisms of the intervention. Our long-term goal is to develop scalable interventions that prevent syndemics and employ multi-level approaches to address acculturative stress and resilience among Latino immigrants in the US. The findings from this study will help identify strategies to promote health for Latino families, the largest racial/ethnic group in the US.

NIH Research Projects · FY 2025 · 2024-07

Abstract: Insufficient research exists on the reproductive health of women with rheumatic disease, leaving young women without reliable guidance regarding contraception and pregnancy. This knowledge gap has resulted in alarming statistics: 15% of pregnancies in women with rheumatic disease occur while taking teratogens, increasing the risk of pregnancy loss to 40% and birth defects to 25%. Moreover, women with SLE experience preterm birth and preeclampsia rates that are 3-6 times higher than healthy women and have remained stagnant for two decades. The scarcity of trained researchers and mentors poses a significant obstacle to progress in this field. To address these challenges, this proposal aims to enhance the scientific rigor of research and expand the workforce of clinician-scientists in reproductive rheumatology through mentoring and hands-on research. Dr. Clowse, a leading reproductive rheumatologist, is exceptionally qualified to bridge these gaps. She has multiple federally-funded grants, delivers lectures worldwide, publishes extensively, and mentors numerous trainees. Dr. Clowse will leverage her unique research platforms to provide mentees with practical research experience through two approaches: 1.) Identifying risk factors for adverse pregnancy outcomes and 2.) Developing and testing clinical tools to enhance reproductive rheumatology care. These projects will expose trainees to outcomes and biomarker analysis, qualitative studies, and implementation science, thereby equipping them with the diverse skill set necessary for addressing the broad range of clinical questions in this field. Additionally, mentees will gain firsthand experience in patient-centered research through regular meetings with a patient collaborator group. They will develop skills in disseminating research findings through manuscripts, oral presentations, and content creation for widely-used websites. To foster the nascent reproductive rheumatology community and extend mentoring beyond Duke University, Dr. Clowse will host a new Reproductive Rheumatology National Lab Meeting as a monthly teleconference with the goal of increasing the rigor of research and facilitate collaboration within the community. New research in this proposal will target active lupus nephritis during pregnancy, as it poses a serious threat to the lives and long-term health of mother and child. With new treatments for nephritis, there is an opportunity to improve outcomes, provided that pregnant women receive optimal treatment. Dr. Clowse will develop a patient-centered, data-driven decision tool to guide the treatment of active lupus nephritis during pregnancy with the goal of transforming care in these high-risk pregnancies. Over the next five years, Dr. Clowse will train clinician-scientists in reproductive rheumatology, publish novel findings, develop decision tools, and establish a collaborative mentoring program. By expanding her mentoring skills, she will effectively guide junior investigators towards independence while cultivating a skilled and resilient workforce in reproductive rheumatology. This next generation of experts will be well-prepared to address critical clinical questions, ultimately improving the health of women and their children.

NIH Research Projects · FY 2026 · 2024-07

Targeting and quantifying metabolic changes non-invasively is a powerful approach to facilitate diagnosis and evaluate therapeutic response. Cellular metabolism involves a vital network of pathways for homeostasis, growth, and survival and can shift from one nutrient pathway to another based on the extent of perfusion available to the cells. Interest in cellular metabolism and tissue vasculature continues to expand across a broad range of disciplines including neuroscience, cardiovascular biology, and the field of cancer research. Though there are many bench-top microscopes and metabolic tools available to provide exquisite resolution and contrast for metabolic or vascular imaging, these systems require extensive training and often have fields of view (FOV), resolution, and wavelengths that fit only the most common use cases. Further, they require researchers to transport animals to specialized facilities, and this limits access to longitudinal imaging. Additionally, there are surprisingly few biomedical imaging technologies available to image both the global landscape and local spatial variations of metabolic and vascular hallmarks in vivo. We propose to develop an optical imaging platform the Capillary-Cell or CapCell to permit studies of metabolic reprogramming and heterogeneity across the laboratory to clinical continuum. This technology will report on the major axes of metabolism, blood vessel architecture and morphology of different biological systems including organoids and xenograft mouse models. Our work will lead to the establishment of predictive biomarkers to support drug development, inform on drug choices and evaluate the efficacy of drugs in bench research and in patients. The technology will be portable and turnkey and therefore can be placed in individual labs instead of a central dedicated facility. This is essential to putting new biomarker capabilities directly into the hands of laboratory scientists. The clinical translatability of the CapCell will focus on breast cancer therapies. The CapCell will inform the selection of compounds for personalized management of cancer patients in adaptive clinical trials and ultimately those in a standard clinical setting. Further, it will enable the identification of successful drugs early in their development, thereby accelerating market approval for candidate therapies. Lastly, this technology will be instrumental in understanding metabolic heterogeneity during primary cancer formation and invasion and its modulation by oncogenic driver mutations and their inhibition. The biological models will include human organoids and mouse models developed at UCSF. Patient-derived organoids (PDO) will serve as a bridge between patients and mouse models – they can be created from patient samples, and they can then be engrafted into mice, and Patient-derived xenografts (PDX) models can be used to identify dynamic biomarkers associated with the risk of recurrence.

NIH Research Projects · FY 2025 · 2024-07

ABSTRACT Retrotransposons are highly enriched in animal genome. Their activation can rewrite the host genetic information and fundamentally impact host biology. While developmental activation of retrotransposons can bring hosts benefits, such as against virus infection, uncontrolled activation promotes diseases or potentially drives aging. Despite their abundance and fundamental impacts on host physiology and pathology, the study of retrotransposons remains an underexplored area of biomedical research. Using new tools and biological systems developed by my team, in the long-term, we aim to characterize the retrotransposon replication cycle and explore the impact of their activation to the hosts under physiological and pathological conditions. Upon activation, retrotransposons use their mRNA as templates to synthesize double-stranded DNA for making new insertions in the host genome. While the reverse transcriptase encoded by them can synthesize the 1st- strand DNA, how the 2nd-strand DNA is generated remains largely unknown. Our recent studies on both Drosophila and mouse retrotransposons indicated that they hijack the alternative end-joining (alt-EJ) DNA repair process from the hosts for a circularization step to synthesize their 2nd-strand DNA. Strikingly, we found that only 10% of replicated retrotransposon DNA achieve new insertions, while 90% exist as extrachromosomal circular DNA (eccDNA). These results lead us to propose that alt-EJ plays a conserved function for retrotransposon DNA replication by driving a circularization step, and that this step dominantly manufactures retrotransposon eccDNA to impact on host biology. To test these hypotheses, we aim to characterize how alt-EJ mediates the circularization step for retrotransposon DNA replication (Aim 1), to investigate how retrotransposon eccDNA can generate genomic variation by integrating into the host genome (Aim 2), and to explore whether human retrotransposons also hijack alt-EJ pathway for eccDNA biogenesis (Aim 3). Collectively, our proposed research will broadly impact the field by identifying new mechanisms to understand the replication process of the most abundant genomic elements. Meanwhile, our work will elucidate how retrotransposon eccDNA could impact host genome by creating genomic variations. As such, our work will provide a new perspective to understand the process and consequence of retrotransposon life cycle.

NSF Awards · FY 2024 · 2024-07

This project focuses on elucidating the molecular workings of the master growth regulators DELLA proteins (DELLAs) in plants. DELLAs are also known as ‘Green Revolution’ proteins because of their pivotal role in modulating stature of the high-yielding wheat varieties, which were crucial for the success of the ‘Green Revolution’ in the 1960s. Recent studies indicate that DELLAs coordinate multiple cellular pathways in response to environmental cues (such as light conditions, pathogens, cold and drought stresses). Although DELLAs play such a central role in regulating diverse plant growth processes, very little is known about how DELLAs control gene expression globally and how DELLA activity is dynamically regulated. This project aims to investigate these two important aspects and elucidate the molecular mechanisms involved. This research will facilitate more effective strategies to manipulate plant growth and stress responses for agricultural improvements since DELLAs are highly conserved in plants. This research project will also have a broad impact in training young scientists, including a postdoctoral fellow, a graduate student and two undergraduate students per year. DELLAs function as transcription regulators, which contain an N-terminal DELLA domain and a C-terminal GRAS domain. DELLAs mediate transcription reprogramming by interaction of their GRAS domain with hundreds of transcription factors (TFs). In addition, DELLAs are associated with both DELLA-repressed and DELLA-activated promoters, and the formation of the TF-DELLA-histone H2A complexes at target chromatin is essential for DELLA activity. DELLA-repressed transcription is mediated by recruiting the Polycomb-repressive complex and histone deacetylases. Moreover, the DELLA domain exhibits transactivation function, which enhances growth repression activity of DELLA proteins in planta. However, the molecular mechanism of DELLA-mediated transactivation remains unclear. Recent studies in this lab also showed that phosphorylation of REPRESSOR OF ga1-3 (RGA, an AtDELLA) in its Poly-S/T region promotes RGA-H2A interaction at target chromatin, but does not affect RGA-TF interactions. However, the specific protein kinase(s) that phosphorylate Arabidopsis DELLA proteins remain elusive. By TurboID-mediated proximity labeling, this lab recently identified new classes of proteins that are present in the vicinity of RGA in planta, including a protein kinase and multiple transcription co-activators and corepressors. Specific Aim 1 will elucidate the precise role of this protein kinase in regulating RGA function by multiple approaches, including genetic, biochemical and mass spectrometry analyses. Specific Aim 2 will elucidate the mechanism of DELLA domain-mediated transcription activation by studying the function of three selected RGA-interacting co-activators using biochemical and mutant analyses. This research will shed new light on the molecular mechanism of how DELLAs regulate gene expression, and elucidate the role of phosphorylation in fine-tuning DELLA activity. This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.

NIH Research Projects · FY 2026 · 2024-07

Abstract The intestinal epithelium serves essential functions of dietary nutrient absorption and defense against microbial infections through the coordinated regulation of gene expression. Intestinal microbiota significantly influence gene transcription in intestinal epithelial cells (IECs), including both induction and suppression of distinct gene sets. We have shown that many microbially-suppressed genes are under control of the host transcription factor (TF) HNF4A and are involved in differentiation and metabolism of absorptive enterocytes. Microbially-induced genes are predicted to be downstream of TF pathways including IRF and NFκB and include genes involved in proliferation, inflammation, and immune defense. What remains unknown is if these distinct microbiota-induced and microbiota-suppressed TF pathways communicate with each other and how they are balanced within IECs to maintain intestinal homeostasis. Our preliminary studies have revealed that these two opposing TF pathways directly communicate within IECs to promote homeostasis by regulating responses to microbes. We find that HNF4A activity in mouse IECs is suppressed by microbiota and protects against microbiota-driven intestinal inflammation. Using single cell RNA sequencing in wild-type gnotobiotic mice, we have uncovered significant heterogeneity in gene expression profiles among enterocytes. For example, immune genes are induced in enterocytes by microbiota and are negatively correlated with HNF4A-dependent genes, implying divergent transcriptional programs. We also find that IEC-specific deletion of Hnf4a leads to induction of immune genes and enhanced protection from enterovirus infection, further confirming a negative relationship between HNF4A and immune programs. In accord, proteomic studies in gnotobiotic mouse IECs and pathway manipulations in human cells revealed significant interactions between HNF4A and immune signaling pathway components. These data support our central hypothesis that HNF4A and immune pathways represent distinct microbiota-regulated enterocyte programs, and that HNF4A suppresses the immune program and thereby increases vulnerability to enterovirus infection. To test this, we will define the roles of HNF4A in mediating the impacts of microbiota on IEC gene regulatory programs and enterovirus infection. We will also identify the molecular mechanisms by which HNF4A and immune pathways interact to regulate gene expression. The expected outcomes will vertically advance the field in several ways. First, they will provide an in-depth understanding of how interactions between the microbiota and HNF4A determine IEC differentiation, gene expression, chromatin organization, and enterovirus infection. Second, they will yield unprecedented insights into the molecular mechanisms by which HNF4A and immune pathways communicate within the same cell. These results are expected to have a positive impact because they would provide important fundamental knowledge about intestinal epithelial biology which could lead to the development of new diagnostic, prognostic, and therapeutic approaches for human diseases such as enteric virus infections.

NIH Research Projects · FY 2025 · 2024-07

SUMMARY Cocaine addiction is driven by drug-induced adaptations in the function of mesolimbocortical brain reward circuits. A major unanswered question in the field of addiction biology is why behaviors such as drug seeking remain persistent even after cocaine use has ceased. A leading mechanistic hypothesis proposes that drug memory is encoded in the epigenome, and that consequent changes in gene expression within specific cell populations play a key role in the persistent circuit plasticities that drive addiction-associated behaviors. However, establishing experimental causality between the epigenome and drug seeking behaviors is challenging. In particular, the cellular heterogeneity of the brain presents a barrier to biochemical sequencing- based methods for chromatin studies, and the descriptive nature of epigenome data on its own is insufficient to demonstrate causality. We have been working to overcome these barriers via the application of innovative molecular genetic methods that allow us to both discover and disrupt chromatin regulation in specific populations of neurons in vivo. This study focuses on dopamine (DA) neurons of the ventral tegmental area (VTA), which play an essential role in the maintenance of drug seeking behaviors after cocaine exposure and forced abstinence. Transcription of the gene encoding Brain-Derived Neurotrophic Factor (Bdnf) is persistently induced in neurons of the VTA following forced abstinence after chronic cocaine, and the experimental elevation of VTA BDNF was shown to be sufficient to promote drug seeking in a rodent model of cocaine craving. Based on these data, we hypothesize that forced abstinence from cocaine induces functional changes in chromatin of VTA DA neurons that mediate the enhanced expression of plasticity genes including Bdnf. We further hypothesize that the enhanced transcription of Bdnf in the VTA is required for the induction of drug seeking. To test these hypotheses we will use an innovative low-input protocol to define the chromatin architecture of DA neurons from the VTA and to discover the changes in 3D chromatin architecture genome-wide that accompany persistent alterations in gene expression upon forced abstinence from chronic cocaine. Then we will use dCas9/CRISPR- mediated functional genome engineering to test the requirement for VTA Bdnf transcription in the maintenance of cocaine seeking behavior in a mouse model of the incubation of cocaine craving after forced abstinence. Taken together, these studies will use leading edge molecular genetic methods to advance circuit-level understanding of the cellular plasticities that contribute to increased drug seeking behaviors.

NSF Awards · FY 2024 · 2024-07

In many real-world decision-making scenarios, be it college admissions or law enforcement or personalized medicine, the underlying decisions are made by algorithms based on data. There has been a growing concern about the quality of these decisions, as often, the data used by the algorithms is neither perfect nor complete, and may even encode biases, leading to inefficiency or unfairness. This project focuses on ameliorating these issues via a framework of "responsive optimization." Specifically, a responsive decision-making system (or optimizer) should consider uncertainty in inputs and allow flexible objectives based on this uncertainty. It should be able to audit a solution for its robustness against uncertain inputs, and, when appropriate, compute an ensemble of solutions as alternatives to a single solution. It should ensure its optimization choices are explainable to human decision makers, and finally, interoperate with other optimizers or existing system components to achieve its objective. This project explores responsive optimization in two application domains: database query optimization and societal decision making. It aims to develop practical algorithms for these domains and advance general methods to pave the way for the next generation of responsive algorithmic decision systems. The key intellectual merit of this project lies in developing a principled and systematic approach to responsive optimization. To help assess solution robustness to uncertainty, the project seeks to approximate the landscape of possible solutions in a computationally efficient fashion. It then explores various ways of auditing solution robustness and tackles both the problem of finding the most robust solution and that of finding an ensemble of robust solutions. Explainability is ensured by imposing simple, low-dimensional constraints on solutions and, similarly, on counterfactuals to illustrate solution robustness (or lack thereof). For interoperability, the project devises techniques to probe existing optimizers, leveraging knowledge of their inner workings but respecting their interfaces. Additionally, the project models interoperability among multiple decentralized optimizers as an economic game and designs mechanisms to ensure that local decisions collectively achieve the global goal. The methods developed by this project are thus relevant to a wide range of domains where increasingly complex algorithms are making decisions, from urban route planning, energy grid management, personalized medicine, to resource allocation in law enforcement and fraud investigation. Building on the team's past success, the project plans to transfer its research to its two target application domains and integrate its research activities with teaching and mentoring. A novel tool for debugging and robustifying the performance of database query plans will be deployed in an educational context and made publicly accessible. The project will work to attract and cultivate a diverse group of young talents, equipping them to tackle the timely challenges in building a more trustworthy generation of algorithmic decision systems. This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.

NIH Research Projects · FY 2025 · 2024-07

ABSTRACT: Although schizophrenia (SCZ) is highly heritable, the genetic underpinnings of SCZ are largely unknown. Over the last decade, genome wide association (GWA) studies have made huge strides in identifying non-coding loci associated with increased risk of SCZ. However, our ability to interpret this data and identify causal variants has significantly lagged behind our ability to identify associations with this disorder. Work in our lab utilizes CRISPR-Cas9 technologies to dissect disease-associated variants and loci at large scale to determine if they function in gene regulation. Our current goal is to utilize high-throughput CRISPR screens to characterize SCZ-associated variants that map within regulatory elements and link them to their target genes. This proposal outlines the use of epigenetic CRISPR screens to dissect SCZ-associated loci that have been detected by both common variant GWA and rare variant whole exome sequencing (WES) studies, as well as loci that contain a single gene. Successful completion of this work will provide a mechanistic understanding of SCZ GWA regions and will provide an optimized strategy for tackling complex disease genetics.

NIH Research Projects · FY 2025 · 2024-07

ABSTRACT: Urine and stool output tracking is essential for hospital treatment of diseases related to the heart, lungs, and blood. For patients who can walk, output monitoring currently involves patients using plastic waste collection hats. The manual nature of patient and nurse handling of collection hats leads to substantial error in patient fluid balances and delays in reporting urine output data to providers. Challenges with urine output tracking are acute when managing cardiovascular or pulmonary complications in which accurate monitoring of patient waste is needed to manage volume overload and fine-tune diuretic dosing. Manual urine tracking also exposes staff to hazardous chemicals and pathogens such as SARS-CoV-2. Our goal here is to develop a platform that will allow the accurate collection urine output data in the setting of clinical management of heart failure patients. Using a toilet-based sensor platform, we will automate the measurement of patient urination so that we are able to mitigate the measurement inaccuracy and treatment delays that are currently caused by manual waste monitoring. Our current device builds on multiple generations of prototype design that have involved extensive simulations and hundreds of tests by human volunteers. Preliminary results from these tests suggest our current prototype can detect urination with high sensitivity and measure urine mass with low error. To complete development of a device suitable for cardiology patient use in hospitals, we will first validate the accuracy and timeliness of our device in heart failure patients. We will measure the accuracy with which the device measures urine volume, comparing device estimates of waste output to gold-standard data obtained from conventional urine collection vessels. Second, we will quantify the decrease in lag time from urination to urine output data reporting to physicians. Third, we will evaluate the feasibility of technology adoption. We will survey patients and nurses to assess the potential increases in nurse and patient satisfaction associated with device usage. Since we expect our automated device to reduce nurse workload, we will also track impacts on nursing effort on waste tracking. In completing this Aim, we expect to develop the first automated platform for tracking urine output among cardiology patients. More broadly, by developing our device in a challenging clinical unit involving frail patients who can excrete large fluid volumes, we set the stage for transforming patient care in other hospital settings relevant to NHBLI such as management of bone marrow transplant patients.

NIH Research Projects · FY 2025 · 2024-07

Patients with life-threatening hematologic cancer experience insomnia and fatigue, distress, and pain symptoms that worsen insomnia during and following hospitalization for high-dose chemotherapy. Despite an urgent need, there are limited symptom management protocols that comprehensively target the challenging treatment (i.e., inpatient, outpatient) and symptom demands faced by hematologic cancer patients. We developed and tested a 6-session, therapist-led, telehealth intervention for hematologic cancer patients following discharge from inpatient treatment (Nite2Day). Nite2Day teaches mindfulness meditations and behavioral strategies to improve insomnia and related fatigue, distress, and pain symptoms. Nite2Day demonstrated strong feasibility, acceptability, and significant improvements to primary (insomnia; d=1.20) and secondary outcomes (fatigue, distress, mindfulness; ds=.38-.89). Nite2Day does not address the inpatient setting where patients describe sleep quality as especially poor. This pilot randomized controlled trial will extend Nite2Day to the inpatient setting (Nite2Day+) and assess its feasibility, acceptability, engagement, and outcome patterns. Hematologic cancer patients (N=60) reporting insomnia symptoms during hospitalization will be randomized (1:1) to Nite2Day+ or Usual Care. Nite2Day+ will be delivered via a self-paced mobile app in the hospital and include: 1) mindfulness meditations promoting acceptance of the challenging inpatient setting; 2) brief videos on sleep education (e.g., sleep drive, circadian rhythm) and behavioral strategies to improve inpatient sleep quality (e.g., stimulus control, daytime activity); and 3) tools to manage inpatient sleep disruptions (e.g., sleep mask, ear plugs). Once discharged home, patients will transition to the previously tested, 6-session protocol. We hypothesize that: 1) Nite2Day+ will be feasible (accrual N=60/24 months; <25% attrition; >75% adherence to assessments and intervention), acceptable (M>3/5 satisfaction with procedures; M>3/4 satisfaction with Nite2Day+), and engaging (Nite2Day+ app log-in, video/skills practice >2x/week); and 2) Nite2Day+ will improve insomnia symptom severity (primary outcome) and secondary outcomes (fatigue, distress, pain, pre-sleep arousal, mindfulness, symptom management self-efficacy) from baseline to hospital discharge and after the 6-session protocol, compared to Usual Care. Dr. Fisher will receive advanced training and expert mentorship in behavioral sleep and cancer symptom management and behavioral intervention development for inpatient and outpatient settings, and randomized trial designs and statistical methods for optimizing behavioral treatment regimens to improve the transition from inpatient to outpatient settings. This training will help Dr. Fisher pursue a future sequential multiple assignment randomized trial assessing insomnia and symptom management strategies that are responsive to challenging treatment (i.e., inpatient, outpatient) and heterogeneous symptom demands faced by hematologic cancer patients. Findings could inform adaptation of other psychosocial interventions for the inpatient setting, and establish a new model of systematic symptom management for various cancer and hospitalized populations.

NIH Research Projects · FY 2024 · 2024-07

ABSTRACT Current pharmacologic therapies for TMD pain are largely ineffective and plagued with side effects because their mechanisms of action to TMD pain have not been validated. Validation of potential pain targets for TMD pain can facilitate the development of mechanism-based approaches. Emerging evidence suggests that lysophosphatidic acid (LPA)/LPA receptor (LPAR) signaling is a promising target for spinally-mediated neuropathic pain. However, whether it contributes to trigeminally-mediated TMD pain, which involves anatomically and functionally unique target tissues and distinct etiology, is not known. In addition, there are several roadblocks which hamper the translatability of LPA/LPAR to pain therapeutics: 1) this potential pain target has been rarely validated in human tissues; 2) its mechanisms in pain, particularly where and how it drives pain, remain poorly understood; and 3) its addiction liability has not been evaluated. The objective of this project is to identify and validate LPA/LPAR in trigeminal ganglion (TG) sensory neurons as a novel mechanistic target for the treatment of TMD pain. Our preliminary results revealed that LPA levels in the plasma and TGs are elevated in mouse models of chronic TMD. In line with results from mice, we also found that LPA in plasma is increased in TMD patients and, importantly, positively correlated with pain intensity ratings. In addition, immunostaining analysis showed that LPAR are localized in both mouse and human TG sensory neurons. Systemic inhibition of LPA/LPAR or local inhibition of LPA/LPAR in TG neurons-innervating TMJ tissues attenuated mechanical pain and masticatory pain in mouse models of TMD, while they did not show addictive effects. Moreover, electrophysiological recording revealed LPA/LPAR can sensitize PIEZO2, a mechanical transducer, in response to mechanical stimuli. Therefore, we hypothesize that LPA/LPAR in TG neurons drive TMD pain via PIEZO2 ion channel. This central hypothesis will be tested in experiments that seek to: 1) determine the contribution of elevated LPA to TMD pain; 2) dissect the contribution of LPAR in TG sensory neurons to LPA-driven TMD pain; and 3) examine whether LPA/LPAR in TG neurons drive TMD pain via PIEZO2 ion channel. The proposed experiments will include rigorous validation using complementary clinically-relevant animal models, pain measures, human tissues and replication of key experiments across laboratories. We will also perform extensive experiments evaluating the addiction liability of LPA/LPAR. Success completion of this project will substantively advance our understanding of TMD pain mechanisms. Importantly, the proposal is clinically significant because it validates LPA/LPAR as a mechanistic target with exciting potential to prevent chronic TMD pain.

NIH Research Projects · FY 2025 · 2024-07

NOTE: You must submit in Word format, not PDF, for eRA to update all the systems. The 2021 Food and Drug Administration (FDA) approval of the glucagon-like peptide 1 (GLP-1) receptor agonist, semaglutide (Wegovy), as an anti-obesity medication (AOM) is ushering in a radical shift in the treatment of obesity. Semaglutide is far more effective than prior rarely used AOMs and additional highly effective AOMs are expected in coming years. Considering that over 80 million Americans live with obesity (2020 prevalence of body mass index ≥30 kg/m2 among adults was 41.9%), obesity is a major health problem in the United States. AOMs are poised to become an important tool in population weight management but we have yet to understand how best to implement AOMs equitably and effectively in everyday practice. By carefully examining clinics within health systems that demonstrate varying use of AOMs, we will gain greater understanding of the barriers and facilitators to AOM use at various levels, including patient, provider, health system, and payer. Armed with these insights, we will be better equipped to develop effective strategies for optimizing the use of AOMs to maximize their population health benefits. We will engage a diverse array of stakeholders in a multi-site collaboration to detail the current state of AOM prescribing and implementation and to design tailored interventions based on best practices to optimize AOM access across health care settings. Our specific aims are to: Aim 1: Use data from 2009-2023 from the multi-site STAR PCORnet Network to understand the demographic, clinical and provider characteristics of eligible patients that are associated with AOM receipt. Aim 2: Identify key factors influencing AOM use at the patient, provider, and system levels. In-depth qualitative interviews will complement Aim 1 insights and help inform the development of a typology of implementation contexts specific to AOMs using the Tailored Implementation for Chronic Diseases framework. Aim 2a: Identify how patient attitudes towards AOMs and the steps required for obtaining an AOM prescription affect demand and access by conducting interviews with selected patients in multiple health systems. Aim 2b: Determine how health care provider and leader attitudes towards AOMs and their understanding of the obesity evaluation and treatment processes are barriers and facilitators to AOM use in three large health systems. Aim 2c: Determine how regional and national payers’ attitudes towards and understanding of the clinical and economic evidence for AOMs impact AOM coverage decisions. Aim 3: Design a Roadmap for selecting and designing implementation strategies to optimize AOM use that can be tailored to national, regional, and local barriers and facilitators; and then assess the feasibility, acceptability, and appropriateness of this Roadmap.

NIH Research Projects · FY 2025 · 2024-07

ABSTRACT This K38 award is designed to support Dr. Sonali Bracken’s research training and accelerate her path to an independent research career in the field of autoimmunity. Dr. Bracken is a clinical rheumatologist at Duke University with a Ph.D. in Immunology. Her long-term goal is to improve the health and longevity of patients with autoimmune, fibroproliferative disorders through the development of B cell-targeted therapies. Through this award, Dr. Bracken will develop expertise in the mechanisms of fibrosis, expand her proficiency in fundamental immunological laboratory techniques, and build foundational skills in data analysis and laboratory management. Her research progress and career development will be overseen by a multidisciplinary mentorship team headed by both Dr. Stefanie Sarantopoulos, an expert in bone marrow transplant and B cell signaling, and Dr. Scott Palmer, an expert in the field of lung fibrosis and transplantation. Dr. Bracken will also benefit from a wealth of resources available through Duke University that are aimed at training physician scientist leaders. The objective of this application is to delineate immune pathways that contribute to lung fibrosis in patients with chronic graft-versus-host disease (cGVHD). cGVHD is a leading cause of morbidity and mortality after allogeneic hematopoietic stem cell transplantation that results from multiorgan inflammation and fibrosis. In up to twenty percent of patients with cGVHD, fibrosis impacts the lungs and can cause respiratory failure. B cells are known contributors to the pathogenesis of cGVHD. The central hypothesis of this application is that B cells and fibroblasts undergo crosstalk that leads to bidirectional cellular activation and ultimately promotes lung fibrosis. This hypothesis will be investigated via two aims, the first of which will examine the mechanisms by which hyperactive Toll Like Receptor 7 signaling in B cells drives fibroblast activation in the lung. This will be accomplished through 1) co-culture assays using cGVHD patient B cells and primary human lung fibroblasts 2) immunofluorescence microscopy in explanted cGVHD patient lung tissue samples and 3) use of a well-characterized cGVHD mouse model that permits selective deletion of Toll Like Receptor 7 signaling pathway components in donor B cells. The second aim will examine the role of the fibroblast extracellular matrix component hyaluronan in activating cGVHD B cells from the lung through the CD44 receptor using in vitro stimulation assays. It will also examine the differential effects of high- and low-molecular weight hyaluronan on lung cGVHD severity using a mouse model. Altogether, these experiments are expected to provide important insights about the role of B cells in promoting fibrosis in lung cGVHD. Ultimately, this knowledge can be utilized to therapeutically target specific points of B cell-fibroblast crosstalk that are critical for promoting fibrosis in cGVHD. It is likely that the knowledge gained from this proposal will also be relevant to mechanisms that drive lung fibrosis in autoimmune connective tissue disease. Furthermore, this proposal will position the candidate to submit a K08 Career Development Award during the final year of the award period.

NIH Research Projects · FY 2026 · 2024-07

Summary of Work Decades of research have strongly linked disruptions in the serotonin (5HT) system to mental health disorders such as depression, and social and communication difficulties. Despite this link a gap remains in understanding the etiologies of many of these disorders. Beyond its role in neurotransmission, 5HT is a critical morphogenic signal during neurodevelopment, with known roles in cell proliferation, migration and differentiation, and in programmed cell death. We have recently determined that a maternal high saturated-fat diet (mHFD) throughout pregnancy in mice causes bacterial endotoxin accumulation in fetal placenta and brain, driving a central immune response and leading to sex-specific behavioral abnormalities in offspring. Measurement of 5HT levels in mHFD offspring revealed a male-specific decrease in fetal brain that persisted into adulthood. Maternal dietary intervention with tryptophan (the precursor to 5HT) rescued normal brain 5HT levels and behavior only in mHFD males. Microglia colonize the developing dorsal raphe nucleus (DRN) where 5HT cell bodies are localized starting as early as embryonic day (E)10 and thus are likely to shape this brain region as it develops. Strikingly, in male offspring only, we found that mHFD increased microglial phagocytosis of 5HT neurons in the E14.5 DRN, whereas either restoring normal 5HT levels via tryptophan supplementation of the dam's diet or conditional knockout (cKO) of the innate immune receptor toll-like-receptor 4 (TLR4) in microglia prevents this overeating response in male microglia and restores normal behavior. These data point to microglia as a critical effector cell between maternal inflammatory signals and subsequent neural development. Our goal is to determine the mechanisms by which microglia target 5HT cells for removal in males but not females in mHFD conditions, and to determine if maternal diet alters specific DRN circuits in males vs females underlying the different behavioral abnormalities.

NIH Research Projects · FY 2025 · 2024-07

The impact of Wnt signaling on hematopoietic stem cell aging and its influence on fracture repair Tuyet Nguyen tuyet.nguyen@duke.edu Alman Laboratory Duke University Abstract Age-related fractures are a current problem with a high mortality rate and, as the United States aged population increases, will become a necessary problem to address in the near future. In order to find solutions for this impending dilemma, it is crucial to understand how bone heals and how this process changes with age. Under homeostatic conditions, bone health is maintained through dynamic relationships mediated in part by the Wnt signaling pathway, especially so during a fracture injury. Wnt signaling is also a known regulator in maintaining hematopoietic stem cells (HSCs) quality, but the role that HSCs play during a fracture injury has not been well explored. The bone marrow environment and the cells that make up the endosteal and perivascular niches are known to be important for postnatal HSC maintenance. However, during a fracture injury, both niches are disordered, and bone regeneration must proceed properly for the re-establishment of the microenvironment to restore the proper cellular HSC regulatory mechanisms. Our lab and others have shown that Wnt signaling is tightly regulated during the fracture healing process and that these signaling patterns become dysregulated with age. Nonetheless, it remains unclear how fracture injury- and age-specific changes to the Wnt pathway affect HSC differentiation and how this relationship in turn regulates fracture healing. This proposed work intends to address the gap in understanding of how HSCs affect the bone fracture repair process to develop better targeted therapeutics that best decrease fracture-related complications.

NIH Research Projects · FY 2024 · 2024-07

ABSTRACT One in two Black men who have sex with men (MSM) in the United States will acquire HIV in their lifetime, an inequity that has worsened over time despite Black MSM engaging in fewer sexual risk behaviors, such as condomless anal sex, than White and Hispanic/Latino MSM. This disparate HIV incidence is especially prevalent in early adulthood, making it crucial to understand factors surrounding poor sexual health outcomes of young Black MSM (YBMSM), ages 18-29 years. YBMSM are often impacted by multiple, intersecting systems of oppression, resulting in intersectional discrimination and a variety of experiences that can adversely impact their sexual health. The goal of the proposed research and training fellowship is for the applicant to acquire the skills and expertise necessary to become an independent, mixed methods researcher focused on sexual health equity among sexual and gender minoritized (SGM) populations. The proposed research and training will be conducted at the Duke University School of Nursing, supported by Sponsor Dr. Marta Mulawa and Co-Sponsor Dr. Rosa Gonzalez-Guarda. Specific training goals include advancement of theoretical and pragmatic knowledge of intersectionality and SGM sexual health, mixed methods integration, and development of scientific dissemination skills rooted in community engagement. These goals will be accomplished through a variety of workshops, mentorship activities, and execution of the proposed research that strives to understand the heterogeneity of intersectional discrimination experiences among YBMSM and their sexual health. This study’s aims are to: 1) identify latent subgroups of YBMSM with different patterns of intersectional discrimination experiences due to various reason(s) (race/ethnicity, physical appearance, sexual orientation, and education/income level); 2) determine the relationship between the identified latent subgroups of discrimination with latent subgroups of sexual health, determined by multiple indicators (pre-exposure prophylaxis (PrEP) awareness, lifetime PrEP use, lifetime HIV and STI testing, recent STI testing, and condomless insertive and receptive sex); and 3) contextualize how intersectional discrimination experiences may shape sexual health among purposively sampled YBMSM participants (n = 20) based on identified discrimination subgroups, using semi-structured individual interviews. To achieve these aims, an explanatory sequential (QUAN à qual) mixed methods design will be used, analyzing data from a subsample of YBMSM ages 18-29 from a large dataset (R01MD013623), which will inform subsequent in-depth interviews. By combining quantitative and qualitative strands of data, the proposed study will thoroughly examine and contextualize the variation in YBMSM experiences with discrimination and sexual health, providing a critical foundation for future tailored interventions focused on mitigating sexual health inequities. The sexual health equity focus of this study closely aligns with the National Institute of Nursing Research’s mission, focusing on sexual health promotion, including HIV prevention, in the context of YBMSM population health.

NIH Research Projects · FY 2025 · 2024-07

ABSTRACT This training grant application seeks funding for the Duke Research Training Program in Surgical Oncology in the Duke University Department of Surgery. The new submission includes a structural reorganization of our long-running program in order to be more relevant and responsive to the evolving training needs of surgical scientists in surgical oncology. The program has been designed to provide future surgeon-scientists with the research methods and skills necessary to pursue independently funded academic careers that will improve the health and outcomes of patients with premalignant or malignant conditions, with a focus on local/regional disease. The training program will combine the substantial academic rigor of the Duke University School of Medicine with the Duke Department of Surgery's long-standing commitment to training the next generation of surgical researchers. The program will be led by a team of surgeon-scientists with a history of funded research and with expertise in surgical oncology. Supplemented by non-surgeon mentors with expertise in basic, translational, and clinical research, this multidisciplinary team spans the breadth of surgical oncology research to address research of local/regional disease: Tumor Invasion and Metastasis, Biomarkers of Prognosis and Treatment Selection and Regional Cancer Immunotherapy. The program will support 4 research fellows each year (2 each year for 2 years); program participants will consist of surgical residents recruited from within and outside of the Duke Surgical Residency Program. Trainees will select two mentors: a primary non-clinician scientific mentor from a highly experienced and diverse group of 14 researchers who will direct their two-year research fellowship and a senior tenured clinical surgical oncologist who will guide their career throughout residency training to their initial academic faculty appointment. Lead by their mentors, the trainees will each develop and execute a research project, which will be the basis of a future career development or independent research award application. A robust research infrastructure and substantial resources provided both by the Department of Surgery and the Duke Cancer Institute will provide 100% of the necessary support for the trainees, thus facilitating their conduct and publication of original investigations without obligations for clinical service. Specific instruction in the technical aspects of surgical oncology investigation will be provided, as will mentorship in scientific writing, publication, ethics, and clinical time management. The unifying objective of the program will be to train the future national leaders in academic surgical oncology.

NIH Research Projects · FY 2025 · 2024-07

PROJECT ABSTRACT. Despite significant advancements in treatment of children diagnosed with congenital heart defects (CHD), outcomes are inconsistent across the US. Studies have demonstrated that Parental Participation (PP), the act of parents’ performing caregiving activities for their hospitalized child, is pivotal in reducing complication and mortality in children with CHD. PP includes typical parent activities (e.g., comforting, diapering) and healthcare activities (e.g., medication administration, decision making). PP directly contributes to development of parenting confidence (PC), and leads to positive short and long-term outcomes for children and parents. Further research is needed to understand the mechanisms by which PP influences PC development. Each family’s unique life circumstances can positively or negatively impact PP. Factors which affect health, and by extension PP, include family structure, resources (income, insurance, access to transportation), and healthcare environment experiences. Despite the demonstrated benefits of PP and PC, there is paucity of research on the impact of family structure and resources on PP and PC in CHD care. A more nuanced understanding of individual factors is desperately needed to discern the ways unique family structure and external factors influence PP and PC in the CHD population. This mixed methods study seeks to examine the relationships among family structure, resources, PP and PC in CHD care among parents of children with CHD (n=110). The aims are to: Aim 1. Examine the influence of family structure, resources (income, insurance, access to transportation), and interpersonal experiences with providers in in the healthcare environment (HEE), and PP on PC using structural equation modeling (SEM) of data obtained via cross-sectional survey. Aim 2: Describe parental perceptions of how family structure, resources, HEE and PP affect development of PC in caring for their child with CHD using content analysis of narrative interviews among a group of parents purposively subsampled to encompass differing levels of PP and PC. Aim 3. Construct a comprehensive model of PP and PC, including the influence of resources, in a representative population of US parents using mixed methods integration of data from Aims 1 and 2. Without a more complete understanding of the impact that family resources and HEE have on PP and PC in CHD, creation of targeted interventions will fail to meet families’ individualized needs. Results from the proposed study will be foundational to informing explorations of: (1) additional influences on PP and PC in CHD care, (2) children’s perceptions of PP, and (3) creation of multi-level family support interventions to enhance PP in pediatric hospital care.

NIH Research Projects · FY 2025 · 2024-07

Enter the text here that is the new abstract information for your application. This section must be no longer than 30 lines of text. Community health, including the conditions in which people are born, grow, live, and age, contribute to up to 80% of population health outcomes. Nurses, as the largest and most trusted segment of the healthcare workforce, are uniquely positioned to lead national efforts addressing population health. However, nurse scientists responsible for generating evidence for care models have not typically received specialized research training in addressing community health. Additionally, a lack of access to education in nursing science in certain geographical regions in the U.S. limits the profession's ability to engage all populations in research. Our proposed training program, Nurse LEADS (Training in Nurse-LEd models of care ADdressing Systems of Care and Community Health), is designed to provide innovative training to nurse scientists at the intersection of population and community health and nurse-led models of care. Trainees will develop skills in digital health, advanced analytics, engagement science, and multisector partnerships as essential methodological approaches and tools for promoting population health. Specifically, Nurse LEADS aims to: 1) recruit and retain pre- and postdoctoral trainees (N=10) in nursing science for advanced research training in community and population health and nurse-led models of care; 2) support trainees in contributing to emerging theoretical frameworks and methodological approaches for developing and scaling nurse-led models of care addressing community and population health; 3) develop trainee methodological expertise in leveraging digital health and advanced analytics for conducting cutting-edge research evaluating nurse-led models of care addressing population and community health; 4) and apply engagement science and multisector partnerships in the development of nurse-led models of care addressing population and community health. Trainees will be supported by mentoring teams that include mentors addressing digital health, advanced analytics, and community and population health from nursing and other interdisciplinary backgrounds. Trainees will participate in career development activities, monthly Nurse LEADS seminars, three courses involving experiential learning practicums, tailored learning experiences drawing from seminars, workshops, and courses from participating departments at Duke, and training in the responsible conduct of research. Additionally, postdoctoral trainees will be required to complete pilot research contributing to a nurse-led model of care addressing population and community health and mentor predoctoral trainees. This novel training will enhance the capacity of nurse scientists across to the U.S. to create novel, evidence-based models of care to improve population health.

NSF Awards · FY 2024 · 2024-07

Nanoparticles are increasingly used in medicine, materials, and agriculture. These nanoparticles come into contact with humans during manufacturing or during use by consumers. In any biological system, proteins adsorb on the surface of nanoparticles forming a coating of proteins on the surface of the nanoparticle, often referred to as a protein “corona.” The specific proteins that adsorb on the nanoparticle surface determine the subsequent interactions of the nanoparticles with cells. Understanding the nanoparticle properties that influence the protein corona is essential for determining the toxicity associated with human exposure to nanoparticles and developing new nanomedicines and nanosensors. This research aims to predict protein-nanoparticle interactions based on nanoparticle and protein properties using machine learning combined with mechanistic biophysical experiments. Understanding protein-nanoparticle interactions is vital for industrial and environmental nanoparticle exposures, as well as for therapeutic and diagnostic applications. In addition, this research provides an ideal training platform for students to address fundamental questions of nanoscience using machine learning, providing training relevant to future academic or industry jobs. This research project aims to predict which proteins will adsorb on the surface of nanoparticles and train students in a highly interdisciplinary environment. The research team will first characterize the protein corona as a function of nanoparticle properties and develop a machine-learning workflow for prediction. The team will vary nanoparticle core composition, ligand, diameter, zeta potential, surface area, and hydrophobicity to sample a wide parameter space. Proteomics will be used to characterize the adsorption of serum proteins on the nanoparticles. The team will utilize a set of controlled protein features and biophysical assays (isothermal titration calorimetry and nuclear magnetic resonance) to test the predictions from machine learning. Well-defined protein classes will be used to determine whether corona behavior follows expected predictions made by machine learning. The team will then extend these studies by probing the robustness of machine learning predictions. Challenging mixtures of proteins will be tested, and the observed nanoparticle coronas will be compared to predictions obtained using optimized algorithms. The outcomes of this research will include the proteomics data (shared through ProteomeXchange), machine learning algorithms (shared on GitHub), and a template for recruiting and mentoring undergraduate researchers. TThe ability to predict protein-nanoparticle interactions based on nanoparticle properties will promote the development of nanoparticles for a range of applications and help to determine safe exposure limits. This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.

NSF Awards · FY 2024 · 2024-07

Technical and Non-technical Abstract This proposal seeks support for the International Soft Matter Conference (ISMC2024) and a preceding Junior Investigator Workshop, which will take place in Raleigh, NC, July 29 – August 2, 2024, and July 27 to July 29, 2024, respectively. We expect 800+ participants to attend. This conference is organized by the recently formed Soft Matter Association of the Americas and is promoted by the IUPAP Working Group 15 – Soft Matter. The conference is meant to bring together scientists from different subfields of soft matter (polymers, colloids, biological systems) with different expertise (chemists, physicists, biologists, engineers) and is the first large-scale such conference organized in the Americas. The goal is to exchange ideas and techniques to accelerate progress in each area and soft matter science. Another objective of ISMC-2024 is to raise the international visibility of soft matter research in the US. A satellite Young Investigator Workshop for students and postdoctoral fellows will take place over 2.5 days before the International Soft Matter Conference. This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.

NIH Research Projects · FY 2025 · 2024-07

Monogenic disorders individually are rare but in aggregate are common, with estimates of up to 1 in 40 individuals afflicted. In monogenic cardiovascular (CV) disease, early identification of at-risk individuals has proven utility for prevention. Unfortunately, there is substantial clinical variability not only in identification of monogenic CV diseases but also in therapeutic interventions for these patients, in part because of their underdiagnosis. As such, there is a need for development of more targeted approaches for identification of monogenic CV disorders, but that go beyond traditional diagnostic models that result in underdiagnosis. There is an opportunity and need to integrate cutting-edge, high-throughput phenotyping approaches with genetics to identify patients at high risk, or already showing evidence of monogenic CV disorders, and determine if this approach can improve the care of these patients. The overall objective for this proposal is to develop, validate and determine clinical utility of a precision genetic testing approach guided by machine learning (ML)-based models. We hypothesize that ML electronic health record (EHR), genetic and imaging algorithms coupled with precision genetic testing will lead to enhanced diagnosis of hypertrophic cardiomyopathy (HCM) and transthyretin amyloidosis (ATTR-CM). We will accomplish this objective through the following aims: Aim 1. Refine, validate and determine generalizability of imaging-based deep learning (DL) algorithms for HCM and ATTR-CM using echocardiograms across four health systems caring for diverse patients (Duke, MUSC, Mayo Clinic, Cedars-Sinai); Aim 2. Aim 2. Develop, validate and determine generalizability of an EHR-based computable phenotype for HCM and ATTR-CM in four health systems; Aim 3. Identify HCM and ATTR-CM genetic VUS with high evidence for pathogenicity using a ML- algorithm; and Aim 4. Determine feasibility and clinical utility of a precision genetic testing approach integrating a DL-imaging algorithm, an EHR computable phenotype and genetic testing. This proposal holds great potential for demonstrating clinical utility of this approach, with an output of a coordinated system that could be scaled within other health systems.

NIH Research Projects · FY 2025 · 2024-07

Psychiatric and neurodevelopmental conditions in children are common, often co-occurring, and can lead to lifelong challenges that impact quality of life. Moreover, psychiatric disorders that typically do not fully manifest until adulthood, such as schizophrenia, have their roots in development. The relevance of brain development to understanding psychiatric and neurodevelopmental conditions underscores the importance of supporting a pipeline of investigators trained in research that characterizes when and how differences in brain development manifest. The Duke-North Carolina Central University (NCCU)-Interdisciplinary Postdoctoral Training Program in Child Psychiatric and Neurodevelopmental Conditions (DN-IPT) will focus on research training in developmental approaches aimed at improving the diagnosis and treatment of child psychiatric and neurodevelopmental conditions including research on developmental antecedents to adulthood psychiatric disorders. The DN-IPT will enroll three new postdoctoral (MD, MD/PhD, and PhD) fellows per year to become independent researchers through a 2–3-year course of training. The DN-IPT will provide Trainees with focused, rigorous, in-depth training in a) our central theme of an interdisciplinary, developmental neuroscience research approach; and b) one or more of five research methodologies to interrogate this theme: (1) brain imaging; (2) computational approaches; (3) digital health; (4) interventions; and (5) preclinical models. A key strength of the DN-IPT is the partnership between Duke University School of Medicine (DUSM) and North Carolina Central University (NCCU), which is co-located with the DUSM in Durham, NC. The strong DUSM-NCCU partnership is reflected in DN-IPT Faculty Mentors and Trainees at both institutions, joint trainings and seminars, student research internships, and Program Directors (MPIs) at both institutions. In addition, the DN-IPT will add needed geographic variety to NIMH T32 programs. Fewer than 10% of the NIMH-funded T32 programs are in US Southern states (while nearly 40% of the US population live in the South), limiting the recruitment and engagement of promising trainees. Our concurrent focus on both child psychiatric and neurodevelopmental conditions is a unique and synergistic strength of the DN-IPT in light of the high degree of co-occurrence of these conditions and their combined impact on a wide range of outcomes. Finally, the DN-IPT will help fill the concerning gap in child psychiatrist-scientists. We are particularly well positioned to recruit and train child psychiatrists with a child psychiatry residency that includes physician scientists, strong institutional support to train physician scientists, and robust representation of child psychiatrist-scientists in the DN-IPT. In sum, the DN-IPT will train the next generation of developmentally oriented researchers, setting the stage for advances in the diagnosis and treatment of child psychiatric and neurodevelopmental conditions.