Duke University

NIH Research Projects · FY 2023 · 2023-04

Abstract In many cognitive processes, information is processed in a parallel manner across many brain regions. This is thought to make our cognitive abilities highly tolerant to perturbations or neuron-loss because disrupted processes are compensated by other redundant neurons coding the same information. Yet, it remains poorly understood how interconnected networks of neurons are organized into redundant representations to produce robustness. We recently discovered that persistent activity in mouse frontal cortex during short-term memory is remarkably robust to perturbations. The two hemispheres of cortex are organized into redundant modules where each one can independently maintain persistent activity. When one suffers a perturbation, signals from the other hemisphere help restore the activity. Modularity and redundancy may be a general organizing principle of information processing and storage in cortical circuits. Understanding the neurobiology of this novel and potentially fundamental organizing principle will have deep implications for design of neural manipulation strategies and understanding behavioral manifestation of chronic neurodegeneration. In the proposed research, we will establish and validate a novel framework that combines computational modeling, population recording, and targeted optogenetic perturbations to identify, probe, and chronically track modular organization of cortical circuits. Our goal is to dissect redundant modular organizations within and across brain areas, obtain a deeper understanding of how multiple redundant modules coordinate information to support robust behavior, and how such modular organization is shaped by learning to manifests in robust behavior.

NIH Research Projects · FY 2026 · 2023-04

Abstract In many cognitive processes, information is processed in a parallel manner across many brain regions. This is thought to make our cognitive abilities highly tolerant to perturbations or neuron-loss because disrupted processes are compensated by other redundant neurons coding the same information. Yet, it remains poorly understood how interconnected networks of neurons are organized into redundant representations to produce robustness. We recently discovered that persistent activity in mouse frontal cortex during short-term memory is remarkably robust to perturbations. The two hemispheres of cortex are organized into redundant modules where each one can independently maintain persistent activity. When one suffers a perturbation, signals from the other hemisphere help restore the activity. Modularity and redundancy may be a general organizing principle of information processing and storage in cortical circuits. Understanding the neurobiology of this novel and potentially fundamental organizing principle will have deep implications for design of neural manipulation strategies and understanding behavioral manifestation of chronic neurodegeneration. In the proposed research, we will establish and validate a novel framework that combines computational modeling, population recording, and targeted optogenetic perturbations to identify, probe, and chronically track modular organization of cortical circuits. Our goal is to dissect redundant modular organizations within and across brain areas, obtain a deeper understanding of how multiple redundant modules coordinate information to support robust behavior, and how such modular organization is shaped by learning to manifests in robust behavior.

NIH Research Projects · FY 2026 · 2023-04

Non-alcoholic steatohepatitis (NASH) is a major global health concern that continues to rise at an alarming rate driven by the tide of the obesity pandemic. It is well appreciated that NASH significantly raises risk for development of hepatocellular carcinoma, cirrhosis, and acute liver failure as well as type 2 diabetes and cardiovascular disease. However, there are currently no approved therapies for the treatment or reversal of NASH. Our foundational work defining the molecular pathways linking disturbances in branched-chain amino acid (BCAA) metabolism to the etiology of metabolic disease recently identified a novel regulatory node that exerts a powerful influence on hepatic lipid deposition in obese and lean animals. We discovered that the branched-chain α-keto acid dehydrogenase (BCKDH) kinase, BDK that inhibits branched-chain α-keto acid (BCKA) oxidation robustly stimulates de novo lipogenesis (DNL), by phosphorylating the lipogenic enzyme ATP citrate lyase (ACLY) on its activating serine. Likewise, we found that the BCKDH phosphatase, protein phosphatase M1K (PPM1K), that promotes BCKA oxidation, dephosphorylates ACLY on its activating serine. Accordingly, adenoviral mediated overexpression of BDK in liver of lean healthy Wistar rats was found to be sufficient to raise hepatic DNL by 2.5 fold. Whereas, treatment of genetically obese Zucker Fatty rats with the BDK inhibitor, BT-2, or adenovirus expressing recombinant PPM1K lowered circulating BCKA, reduced phosphorylation of ACLY, and remarkably prompted a 40% reduction in liver triglyceride content in these severely obese animals without altering food intake, body weight, adiposity, or physical activity. Subsequent, studies in our lab have identified an additional effect of BT2 to lower expression of the fatty acid transporter, CD36, in liver. Thus, our current working model is that modulation of the hepatic BCKA regulatory network exerts robust effects on lipid content due to its dual effects on CD36-mediated lipid uptake and ACLY-mediated DNL. Beyond these mechanisms, it remains unclear whether the BCKA themselves exert any direct or synergistic effects on hepatic lipid metabolism. Importantly, our recent medRxiv preprint demonstrates that circulating BCKA and liver BDK expression are strongly associated with NASH status in a cohort of 288 bariatric surgery patients with severe obesity that are discordant for NAFLD and NASH. In the current proposal, we will leverage our newly developed mouse models, established molecular/pharmacologic armamentarium, and novel insight to resolve the molecular mechanisms connecting the BCKA regulatory network to the pathogenesis of NASH by completing three specific aims: 1) Characterize the relative contribution of hepatic BDK, PPM1K, and BCKA to NASH progression. 2) Evaluate the therapeutic potential of small molecule inhibitors of BDK for reversing NASH. 3) Define the mechanisms connecting the BCKA regulatory network to hepatic lipid content. The successful completion of the studies outlined in specific aims 1-3 will define the BCKA regulatory network as an important modulator of NASH progression with strong translation relevance for the treatment of NASH in humans.

NIH Research Projects · FY 2025 · 2023-04

PROJECT SUMMARY/ ABSTRACT This is an application for a K01 Mentored Research Scientific Development Award. The goal of the proposed project is to provide the candidate with the advanced skills needed to establish an independent research program examining the visual health needs of stroke survivors also living with dementia. To facilitate this long-term goal, the candidate proposes a comprehensive training plan, combining formal coursework and meetings overseen by her mentors, participation in applied training experiences and involvement in seminars and workshops. Specific training goals include: (1) gain advanced knowledge in the epidemiology and mechanisms of post-stroke dementia, (2) learn neuropsychological and clinical assessment of dementia, (3) acquire skills and training in clinical research methodology and statistical analysis, using both cross sectional and longitudinal data and (4) productively participate in career advancement and leadership development activities. The training plan will be executed in coordination with the set of research activities mentioned above, which are based on preliminary data collected by the applicant. The preliminary data show a lack of research on whether the presence of specific types of vision impairment and ocular deficits increase the risk of post-stroke dementia. The candidate will expand on these findings by using data from the Atherosclerosis Risk in Communities stroke cohort to complete the following aims: (1) characterize the prevalence and outcomes associated with vision impairment(s) among stroke survivors with and without dementia; (2) determine how pre-existing vision impairments impact the development of dementia, among those with stroke; and (3) determine the effect and downstream consequences of post-stroke vision impairment in persons without pre-existing vision impairment. The primary hypotheses include that: (1) the odds of developing dementia are higher for stroke survivors with pre-existing vision impairment, compared to stroke survivors with normal vision; (2) stroke survivors with vision impairment preceding the stroke are more likely to develop dementia earlier, compared to stroke survivors with normal vision; and (3) the impact of post-stroke vision impairment on dementia development is stronger for those with functional impairment, compared to those without functional impairment. The expected findings will provide critical insight into the types of vision impairment and ocular deficits experienced by people with post-stroke dementia, including more information on the significance of distinguishing between pre- and post-stroke visual impairments and the expected differential impact on dementia. Results from this research will be used to develop a subsequent R01 research proposal that will facilitate the candidate’s transition into an independent researcher focused on analysis of existent data and prospective enrollment to optimize the independence and community participation of stroke survivors with vision impairments and dementia.

NIH Research Projects · FY 2026 · 2023-04

PROJECT ABSTRACT/SUMMARY The ability of brown adipose tissue (BAT) to expend energy through a process called adaptive thermogenesis makes it an attractive target for intervention in obesity; however, the observation that BAT mass diminishes in human obesity raises concerns about its ability to clinically impact body weight when fully activated. Energy-storing white adipose tissue (WAT) can also adopt a “brown-like” thermogenic phenotype; however, there are potent molecular brakes on thermogenic gene program in white adipocytes that help maintain its energy- storing phenotype. Since WAT is present in far greater mass than BAT, activation of the thermogenic gene program in white adipocytes may be a more viable strategy for intervention in obesity; however, the mechanisms controlling the establishment and maintenance of the energy-burning vs. energy-storing adipocyte lineages remain undefined. ZFP423, a member of the C2H2 family of zinc finger proteins, is a physiologically regulated transcription factor that functions to maintain the energy-storing white adipocyte phenotype by suppressing the thermogenic gene program characteristic of brown/beige fat cells. ZFP423 physically interacts with the brown adipocyte determination factor, EBF2, in white adipocytes to prevent EBF2-dependent chromatin remodeling and PPARg occupancy at key thermogenic genes. The experiments that I propose to conduct as part of my PhD training in the Duke University Medical Scientist Training Program will utilize advanced approaches in biochemistry, molecular biology, and mouse genetics. This work, conducted under the mentorship of Dr. Rana Gupta at the Duke Molecular Physiology Institute, is designed to 1) address the hypothesis that the ability of ZFP423 to directly recruit the NuRD complex to EBF2 is essential for its ability to suppress thermogenesis in white adipocytes (Aim1), and 2) test the hypothesis that genetic disruption of the ZFP423-EBF complex in mice is sufficient to permit thermogenic WAT remodeling and prevent the development of obesity and metabolic dysfunction. The overall goal of my proposed research is to further define the critical protein-protein interactions leading to the suppression of the thermogenic gene program by ZFP423 in white adipocytes. Successful completion of this work will highlight the importance of transcriptional “brakes” on thermogenic gene expression in adipocytes and may suggest a strategy to unlock the thermogenic capacity of WAT to promote weight loss and/or improve nutrient homeostasis.

NIH Research Projects · FY 2026 · 2023-04

SUMMARY Gut microbes are associated with disorders of behavior, including those related to food intake and appetite. Obesity and hyperphagia can be transferred from donor to germ-free recipient mice, simply by microbial transplants. However, the correlative effects seen in mice have yet to be translated to the clinic. There is a critical need to determine how microbial signals alter host behaviors. Specifically, it is unknown how a microbial stimulus arising in the GI lumen is converted into a neural signal reinforces behavior. This gap in our knowledge is a significant problem because knowing how microbial ligands and GI sensory function interact will allow for rational design of gut-based therapies to treat disorders of food intake and promote emotional well-being. Our laboratory recently discovered a neural circuit linking the gut lumen with the brain stem in one synapse. Formed between neuropod cells and vagal neurons, this neural circuit transduces luminal stimuli to the brain in milliseconds (Kaelberer et al., 2018). Moreover, in the proximal small intestine where nutrients are abundant, this neural circuit is necessary for an animal to distinguish sugar from sweeteners (Buchanan et al., 2020). On this basis, our hypothesis is that colonic neuropod cells synapse with vagal neurons to communicate reward from bacterial stimuli. The objectives for this proposal are to define if colonic neuropod cells sense bacterial ligands, transduce bacterial signals onto vagal neurons, and modulate reward behavior. Our rationale is that by elucidating the mechanisms of bacterial sensory transduction from gut to brain, gut microbial therapeutics could be developed to treat disorders of food intake linked to diet and gut microbes.

NIH Research Projects · FY 2024 · 2023-04

The pathophysiological basis of selective neurodegeneration in Parkinson's disease remains controversial. Recent genetic and biochemical analyses have uncovered aberrant LRRK2 kinase activity as a salient feature of late-onset Parkinson's disease (PD) of both familial and idiopathic origin. Familial LRRK2 mutations are generally associated with elevated kinase activity. Identifying the pathophysiological processes that regulate LRRK2 kinase could provide a critical window to understand the pathogenesis unique to PD. LRRK2 is recruited and activated at enlarged lysosomes induced by lysosome stressors, chloroquine (CO) and LLOMe. We hypothesize that LRRK2 recruitment to the stressed lysosome is part of the lysosome stress response that acts to return lysosome to the basal states. LRRK2 association with stressed lysosomes is typically transient Remarkably, the LRRK2 association with stressed lysosomes becomes dramatically enhanced in PD-associated Vps35-D620N mutant cells. This finding suggests that LRRK2 becomes excessively activated by the lysosomal stress in Vps35-D620N cells. Thus, stress-induced LRRK2-lysosome association and activation are tightly regulated, and this regulation is disrupted by a mutation that causes familial PD. A small focused chemical inhibitor screen for additional regulators of LRRK2-lysosome association identified PKD. PKD, similar to LRRK2, is activated by lysosomal stresses, while its inactivation led to aberrant LRRK2-lysosome association and activation. This proposal aims to identify the molecular entity that recruits LRRK2 to stressed lysosomes and characterize the role of PKD-signaling pathway in LRRK2 activation and pathogenic toxicity. This proposal's completion could provide a biochemical mechanism underlying pathogenic LRRK2 activation, identify PKD as a novel regulator of LRRK2, and ascertain lysosomal stress as a pathophysiological trigger to late-onset PD

NIH Research Projects · FY 2025 · 2023-04

PROJECT SUMMARY ABSTRACT Coordination of cell behaviors is essential for growth in embryonic and juvenile animals, as well as during regeneration of tissue lost by damage or disease. This is particularly challenging for stratified tissues, such as skin, during rapid phases of growth in embryonic development and adult regeneration. Here, multiple cell layers would have to communicate effectively and grow together to ensure stratification remains unaffected. How skin cell layers behave and coordinate their growth when challenged with rapid expansion requires research attention but has been limited by the availability of tools and platforms for quantitative live imaging. In preliminary studies, we have developed tools to visualize and manipulate cell behaviors and signaling in embryonic zebrafish epidermis, as well as a platform to perform quantitative live imaging of adult epidermis during regeneration. To understand the mechanism of coordination between epidermal layers, we will: 1) test the role of tissue tension and MAPK mediated mechanochemical feedback in regulating growth of embryonic epidermis during axial elongation and 2) test the role of tissue geometry in coordinating epidermis growth during adult regeneration following scale plucking and corneal abrasion. This comprehensive analysis of skin growth during development and regeneration of complex tissues will inform strategies for control of repair in human conditions of tissue damage or disease. The project draws on 1) my previous training in cell and developmental biology, 2) live imaging technique I have established to perform in toto imaging of embryonic and adult zebrafish tissues, 3) the quantitative skill set I will acquire during my training to analyze this data and 4) training on spatial transcriptomics to define signaling pathways activated during regeneration. For successful completion of these aims, I have assembled a mentoring committee – Dr. Stefano Di Talia and Dr. Kenneth Poss, whose combined expertise in quantitative biology, zebrafish genetics and regeneration biology will train me to become an expert on these topics. In addition, the advice and input I will receive from my collaborators – Dr. Christoph Schmidt, Dr. Terry Lechler and Dr. Brigid Hogan - on tissue mechanics, epithelial and skin biology and career development will further my ability to achieve the goals of this project and help launch my independent research career. I am confident that the additional training I will receive during this award will help me achieve my long-term goal of establishing a high-quality research group as an independent investigator

NIH Research Projects · FY 2026 · 2023-04

Duke University Maternal-Fetal Medicine Units (MFMU) Network Clinical Center The Duke Clinical Center will be a new center that participates in the full scope of the Network, enrolling patients at Duke as well as a Wake Forest University (WFU) satellite site. Duke has a long history of participation in the MFMU Network, first as a clinical center, and most recently as a satellite center. In addition to conducting trials in the MFMU Network, the Duke Perinatal Research Center (DPRC) has vast experience in enrolling for randomized trials and cohort studies with NIAID and CDC Networks. The Duke Clinical Center will bring special strength in developing new research protocols, particularly in the areas of infectious diseases in pregnancy and health disparities in preterm birth. The team has a strong track record in clinical trials collaborations, recruitment, retention, and follow up that will contribute to the Network’s goals of enhancing rigor and reproducibility, and data sharing. The Center has large-scale outpatient facilities as well with an established infrastructure for enrolling patients at both high-risk clinics as well as in collaboration with generalist obstetrics partners in low-risk clinics. The Duke Clinical Center, supported by Clinical and Translational Science Awards (CTSAs) at both Duke and WFU, will promote an environment fostering a respectful climate for all investigators, patients, and participants. The team has a strong history of collaboration with specialists in pediatrics, pharmacology and lactation and will leverage those collaborations to bring forward innovative, high-quality science to the MFMU Network. The proposed specific aims for the Duke Clinical Center are Aim 1. Oversee and manage operations of the Duke Clinical Center – provide the infrastructure, oversight, expertise, and resources to conduct Duke Clinical Center studies, including contributions from the WFU satellite site (and any future MFMU Network-designated sites); administrative, scientific, fiscal, and data management; communication, collaboration, and coordination processes within and between sites. Aim 2. Maximize recruitment and retention of study participants, using innovative strategies, such as community-based partnerships, bilingual research staff, and conduct of community engaged research and qualitative methods for enrolling subjects in Network studies. Aim 3. Design and implement high-impact research protocols in collaboration with the Data Coordinating Center and other Network sites – contribute innovative research specifically in the areas of infectious diseases, perinatal pharmacology, preterm birth, and perinatal epidemiology; ensure rigorous collection of reproducible, high-quality data; and leverage institutional resources to maintain robust collaboration between the investigators and clinical research teams.

NIH Research Projects · FY 2026 · 2023-04

Granulomas are complex immunologic structures formed in tissues in response to infection. The general function of a granuloma has been elusive because many infections that stimulate granuloma responses do not resolve. Often, granulomas are described as immunologic responses that wall off an infectious agent that cannot be cleared by the immune system. Basic understandings of the fundamentals of a granuloma have been elusive because mouse models where granulomas form are rare or complicated. We have discovered a novel bacterial infection model where the murine immune system forms a granuloma. When mice are infected by Chromobacterium violaceum, the immunologic response fails to clear the bacterium from the liver within the first several days. Then a granuloma forms around the infected lesion, and this complex immunologic response successfully sterilizes the infection and returns the organ to homeostasis typically within 7-14 days post infection. Therefore, we have discovered a novel infectious model where basic granuloma biology can be elucidated. C. violaceum first infects hepatocytes and perhaps Kupffer cells in the liver. This rapidly stimulates a neutrophil swarm within the first day post infection. However, the neutrophil swarm fails to eradicate the infection, and the neutrophils themselves appear to become replicative intracellular niches for the bacterium. Three days post infection the neutrophil swarm dies and forms a central necrotic core of the lesion. Macrophages begin to appear at the periphery of the lesion at 3 days post infection and form a thick macrophage zone that surrounds the necrotic core by day 5-7. Thereafter, the bacteria are killed through the action of inducible nitric oxide synthase, the granuloma is sterilized, and shrinks over the next week. Granuloma burdens are sterilized between 7-21 days post infection. This all occurs in the absence of T cells or other adaptive immune cells. In this grant, we use this novel granuloma model to explore the importance of pyroptotic cell death in the granuloma.

NIH Research Projects · FY 2026 · 2023-04

Abstract Action selection computations are at the core of goal-directed behavior. Models of action selection suggest that appropriate actions are selected through competition between potential choice options. Choice competition is thought to occur across a multi-regional network that span frontal cortex, basal ganglia, and their downstream circuits where neuronal population encoding potential choice options mutually inhibit each other to provide opponent control of choice activity. Yet, how these brain regions interact to mediate this process and the loci of choice competition remain unresolved. We recently identified a frontal cortico-basal-ganglia-superior colliculus network responsible for action selection of directional licking during decision-making. Distinct neuronal populations in this multi-regional network encode opposing choice options for lick direction and exhibit push-pull dynamics prior to a licking movement, reflecting choice competition. Remarkably, activating or suppressing the superior colliculus is sufficient to bidirectionally control the push-pull choice competition dynamics within the network, implicating the superior colliculus as a key network node that can mediate choice competition. These data suggest a working model in which circuits within frontal cortex and basal ganglia encode competition choice options and they influence downstream superior colliculus in a topographically confined fashion to drive opponent control of choice activity for specific actions. Leveraging a suite of recently developed technologies, this proposal aims to precisely define a mesoscale cortico-basal-ganglia-colliculus network for action selection (Aim 1 and 2) and directly probe the interactions of frontal cortex, basal ganglia, and superior colliculus to resolve the loci of choice competition (Aim 3). The outcome will test longstanding theories of action selection and elucidate their neural circuit implementations.

NIH Research Projects · FY 2026 · 2023-04

ABSTRACT Bacteroides vulgatus (Bvu) is one of the most common members of the gut microbiota across diverse human populations and has been strongly associated with multiple human diseases including the inflammatory bowel diseases (IBD). However, there exist fundamental gaps in our understanding of the genetic and phenotypic diversity within the Bvu species complex, as well as how Bvu strains mechanistically contribute to host inflammatory phenotypes. Our long-term goal is to understand how gut microbes impact human health and disease. Our preliminary studies in the human-derived Bvu strain CL09T03C04 identified putative genetic determinants for Bvu fitness and competition in the mouse gut and also associated these genes with metabolites identified by mass spectrometry. Using gnotobiotic mice, we have also established that different Bvu strains have variable impacts on intestinal inflammation and immunity. These results and other diverse associations between Bvu and gut inflammation in humans and animal models could be explained in part by genetic diversity among Bvu strains. Yet, there remains a paucity of well-annotated genetic information associated with this species, and strain-level variation across the Bvu species complex is almost completely unexplored. The objective of the proposed research is to define the relationships between Bvu genetic variation with host inflammation and gut microbial ecology. We will test the central hypothesis that Bvu uses distinct genetic and metabolic traits to colonize the gut and modify host inflammation, and that the variable presence of those traits in Bvu strains explains their divergent host responses. In Specific Aim 1, we will test the working hypothesis that regulation of distinct lipid metabolites is required for in vivo survival and competition in Bvu strain CL09T03C04. In Specific Aim 2, we will test the working hypotheses that the ability of different Bvu strains to promote or restrict gut inflammation is mediated by distinct genetic traits, and that gut inflammation alters Bvu fitness. The expected outcomes will vertically advance the field in several ways. First, they will provide the first in-depth understanding of genetic and phenotypic diversity in the Bvu species complex, including identification of genes, pathways, and metabolites responsible for Bvu’s ability to colonize the gut and to impact and adapt to gut inflammation. Second, they will identify pro- and anti-inflammatory Bvu strains and affiliated mechanisms that may explain prior association of the Bvu species complex with both exacerbation of and protection against IBD-associated inflammation. These results are expected to have a positive impact because they could lead to the development of new Bvu-directed prognostic markers and therapeutic approaches to modify gut microbial ecology and inflammation, potentially improving diagnostic and therapeutic management of IBD and other human diseases.

NIH Research Projects · FY 2026 · 2023-04

ABSTRACT. The ongoing epidemic of suicide among former U.S. military personnel—17 deaths every day— lies at the core of a 20-year trend of increasing suicide rates in the U.S. The rate of suicide in veterans is about 1.5 times that of the civilian population, due to veterans' unique burden of medical, psychological, and social- environmental risk factors compounded by easy access to lethal means. To date, veteran suicide research and prevention efforts have focused almost entirely on the population served by the Veterans Health Administration (VHA). Meanwhile, most veterans do not seek VHA care but prefer private-sector health services. Since 2005, suicides among veterans outside the reach of VHA have increased at more than double the rate seen among VHA users (57% vs. 28%, respectively). This study's primary objective is to develop efficient longitudinal predictive algorithms for suicide and firearm-related suicide among military veterans who utilized non- VHA health care, by analyzing the largest database ever assembled of linked civilian medical record data pertinent to veteran suicide risk. Too little is known about veterans receiving care outside the VHA, including the nature and severity of their health conditions, their patterns of healthcare utilization, and their unique risk factors for all suicide and firearm-related suicide. Filling these gaps in knowledge is crucial to the goal of meaningfully reducing suicide in the veteran population overall. To that end, our multi-disciplinary team of nationally distinguished researchers will assemble and analyze an unprecedented longitudinal database of linked VA and Department of Defense data, health records, social indicators, and death records of veterans receiving health care from 5 large civilian health systems in North Carolina and Utah. The database will yield an estimated 3.8 million person-year observations, including approximately 900 firearm-involved suicides and 1,190 total suicide deaths. We will analyze these data to describe the demographic and health characteristics of veterans who utilize non-VHA healthcare services, their patterns of healthcare utilization, their mortality outcomes, and their incidence of suicide deaths, by method. We will use machine learning methods to develop specific risk algorithms for predicting all suicides and firearm-related suicides among veterans who utilize non- VHA healthcare, to identify veterans at elevated risk of suicide. Utah-based collaborators will use linked VHA data to identify and describe risk patterns for veterans who combine VHA and non-VHA healthcare. Finally, we will conduct a series of key informant interviews to better understand barriers and facilitators to integrating this type of algorithm into civilian health system workflows. In summary, the proposed work will fill critical gaps in the literature by leveraging large-scale, real-world data sources to yield novel knowledge of suicide risks, while informing prevention efforts aimed at reducing veteran suicide. We will also gather implementation information to inform how large civilian health systems will be able to use this information to identify and intervene with the veterans who are at greatest risk of suicide within their patient populations.

NIH Research Projects · FY 2025 · 2023-04

ABSTRACT Nanoparticles enable the delivery of therapeutics to the desired tissue and thereby improve efficacy and safety. However, only about 30 nanoparticle therapeutics have been FDA approved, and none of these 30 nanoparticles use advanced targeting functionality. Key challenges that impede broader nanoparticle deployment are the complexity of nanoparticle synthesis protocols, a drug loading capacity commonly below 10%, and a one-size-fits-all approach in material optimization. Novel drug-excipient co-aggregates (Reker et al, Nat Nanotechnol 2021) address these shortcomings through facile synthesis, drug loading of up to 95%, and by using machine learning for the rational design and optimization of new nanoparticles. However, the functionalization of these novel materials for actively targeted drug delivery is not yet established, limiting their deployment to only a narrow set of tissues and indications. The here presented research will address the unmet need for novel technologies to enable the functionalization of drug-excipient co-aggregate nanoparticles. Specifically, we will develop novel experimental (aim 1) and computational (aim 2) protocols to functionalize drug-excipient nanoparticles with antibodies and validate their targeting capabilities in vitro and in vivo. This project will (1) prototype machine learning for targeted nanoparticle development, (2) for the first time functionalize drug-excipient nanoparticles to qualitatively enhance the targeting capabilities of highly loaded nanoparticles, and (3) generate a set of novel, carefully characterized therapeutic nanoparticles with potential for further clinical development. Through rapid synthesis and machine learning-guided design, the here proposed platform can rapidly expand the nanomedicine toolbox and streamline nanoparticle development, evaluation, and manufacturing. Through our modular approach to “mix-and-match” nanoparticle components, we expect the rational selection of antibodies, drugs, and excipients to enable the design of precision nanoparticles for personalized drug delivery.

NIH Research Projects · FY 2025 · 2023-03

Project Summary DNA replication problems collectively known as replication stress are a major sources of genomic instability in cancer cells and also a vulnerability of cancer that can be targeted therapeutically. The recent success of PARP inhibitors in the treatment of BRCA mutant tumors provided an exciting example of targeting cancer cells by exploiting replication stress. However, our current understanding of the replication stress in cancer cells is still very limited. Although we know that many different oncogenic events in cancer cells can cause replication problems, we still don't fully understand whether these oncogenic events affect DNA replication in similar or distinct ways. Furthermore, we also know little about how DNA replication is altered by different oncogenic events, and whether altered replication can give rise to distinct cellular vulnerabilities. Understanding the basic molecular features of replication stress, the major causes of replication stress in cancer cells, and the different vulnerabilities resulting from altered replication will greatly enhance our ability to detect and exploit replication stress in cancer therapy. I have a longstanding interest in understanding the replication stress response in human cells. In particular, my lab has extensively studied the functions and regulation of the ATR checkpoint pathway, the master regulator of replication stress response in human cells. Our work has contributed significantly to the current models of stress sensing and signaling during DNA replication. From recent studies by us and others, it has become gradually clear that different oncogenic events in cancer cells can generate distinct problems in DNA replication. Furthermore, RNA transcripts, the products of transcription, have both positive and negative impacts on DNA replication and repair. Our studies also revealed that replication stress not only exerts cell autonomous effects on the genome, but also cell non-autonomous effects in cell populations. Based on these new findings, we propose to systematically define and characterize different types of replication stress in cancer cells, understand how RNA affects replication and repair in the genome, and explore the cell non-autonomous effects of replication stress in tumor microenvironments and cancer therapy. These studies may provide us a much more comprehensive understanding of the molecular underpinnings of replication stress in cancer cells, their impacts on the genome of cancer cells and cell populations in tumor microenvironments, and the cancer cell-specific vulnerabilities that they give rise to. The new concepts and findings from these studies could have transformative impacts on the research of cancer and cancer therapy.

NIH Research Projects · FY 2026 · 2023-03

Abstract Cryptococcus is one of the most important HIV/AIDS-associated pathogens, causing >220,000 infections, >180,000 deaths, and >15% of all HIV/AIDS-related deaths annually. The ability of C. neoformans to survive at mammalian body temperature and in the presence of other host stress conditions is essential for virulence. We identified the protein phosphatase calcineurin as a major molecular determinant required for Cryptococcus thermotolerance and virulence. In response to temperature stress, calcineurin is activated by Ca2+- calmodulin and acts as a serine/threonine phosphatase. Calcineurin plays broad roles in cryptococcal virulence and is necessary to survive heat, cation, alkaline, and cell wall stress. We have further demonstrated calcineurin plays conserved roles in virulence of other human pathogenic fungi (Candida, Aspergillus, Mucor), and others have shown calcineurin is critical for virulence of Leishmania, Plasmodium, and plant fungal pathogens. However, calcineurin is conserved across eukaryotes, and calcineurin inhibitors are potent immunosuppressants in humans and thus difficult to utilize as antifungal drugs. Studies are in progress developing less immunosuppressive analogs as candidate therapies. Thus, calcineurin is a general, conserved virulence factor in eukaryotic microbial pathogens that can be targeted for therapy, and elucidation of the roles and mechanisms of calcineurin signaling cascades can identify fungal-specific targets and is of general importance. We have achieved several key advances elucidating calcineurin roles in Cryptococcus pathogenesis. We discovered heat and other stresses induce calcineurin to re-localize from the cytoplasm to P-bodies/stress granules, sites of mRNA post-transcriptional/translational control. Via phospho-proteomic studies, we identified calcineurin targets including the transcription factor Crz1 and proteins that localize to P-bodies/stress granules and mediate mRNA processing, stability, and translation. Additionally, we identified stress-response genes regulated by calcineurin-Crz1, as well as mRNAs regulated by calcineurin but not Crz1 through RNA-seq analysis. These findings support our hypothesis that calcineurin controls a bifurcated signaling cascade promoting stress survival and pathogenesis. In one branch, calcineurin stimulates Crz1 nuclear localization and gene expression promoting stress survival and virulence. In a second, less-studied branch, calcineurin undergoes heat-induced re-localization to P-bodies/stress granules and acts on targets governing mRNA processing, stability, and translation, promoting pathogenesis post-transcriptionally. We propose two aims to test this hypothesis. In Aim 1, we will identify, validate, and characterize high temperature specific calcineurin interactors as substrates and effectors via TurboID-proximity labelling and Crz1 ChIP-seq analysis. In Aim 2, we will define the importance of calcineurin re-localization and action on P-body/stress granule targets that enable Cryptococcus to surmount host stress and infect normal and immunocompromised hosts. These studies will elucidate conserved stress-responsive virulence networks of eukaryotic pathogens as therapeutic targets.

NIH Research Projects · FY 2026 · 2023-03

PROJECT SUMMARY Acute kidney injury (AKI) is a major health problem, afflicting 1.2 million hospitalized patients annually in the US. Maladaptive renal repair after AKI promotes development of chronic kidney disease (CKD), leaving affected patients at high risk for dialysis dependency, cardiovascular events, and mortality. Studies show that males are disproportionately and more severely affected by AKI than females, including COVID-19-associated AKI. However, the molecular mechanisms underlying this sexual dimorphism remain poorly understood. Moreover, there are no targeted therapies that interrupt this devastating disease process in both sexes. Using single-cell transcriptomics and mouse genetics, our ongoing studies found that the female sex confers marked protection against ferroptosis, a distinct, non-apoptotic form of regulated cell death and a critical driver of maladaptive repair after AKI in mice and humans. Ferroptosis is triggered by the inability of glutathione peroxidase 4 (GPX4) to remove toxic lipid peroxides from cell membranes, leading to the accelerated accumulation of toxic lipid peroxides (ferroptotic stress) and cell rupture. Acute ischemic and toxic kidney injuries reduce GPX4 in proximal tubular (PT) cells, thus making these cells vulnerable to ferroptosis. Severe AKI also induces pathologic transcriptional alteration of PT cells into an inflammatory phenotype and prevents their recovery to a healthy state (impaired plasticity). Our data show that in males but not in females, genetic deletion of Gpx4 promotes the accumulation of inflammatory PT cells and triggers their death by ferroptosis. To advance these clinically impactful lines of investigation, we will test our overarching hypothesis that sexual dimorphism in resilience to ferroptosis underlies sex differences in clinical outcomes after AKI. We further hypothesize that uncovering the mechanisms of how sex hormones regulate ferroptosis sensitivity will enable identification of targetable downstream pathways that improve AKI outcomes for both sexes. Directly testing these hypotheses, we will integrate unbiased single-cell transcriptomics, genetic mouse models, pharmacological studies, and human kidney organoids with two Specific Aims. In Aim 1, we will determine sex-dependent mechanisms by which ferroptosis promotes maladaptive repair at single-cell resolution using our tubule-specific, doxycycline-inducible Gpx4 knockout mouse model. We will also investigate the therapeutic effects of ferroptosis inhibitors to enhance renal repair in our murine kidney injury models in vivo and in human in vitro AKI models using organoids. In Aim 2, we will test our hypothesis that sex hormones regulate the sensitivity to ferroptosis and PT cell plasticity after AKI using gonadectomy and genetic inhibition of estrogen receptor signaling. The results of these studies will provide compelling preclinical mechanistic evidence for how ferroptotic stress governs PT cell fate. Our studies will identify new therapeutic targets to enhance renal ferroptotic stress resilience and promote healthy PT recovery from injury, thereby interrupting the AKI to CKD transition in both sexes.

NIH Research Projects · FY 2025 · 2023-03

ABSTRACT Adolescence is a time of increased risk and reward seeking behaviors, and 74% of adults with a substance use disorder initiated use by 17 years of age, with many drugs of abuse acting through the dopamine (DA) system. This makes understanding DA system development in adolescence of great importance to uncover the etiology substance use disorders. In the rat, adolescence is a critical window of circuit refinement in the nucleus accumbens (NAc), a dopamine (DA) rich brain region associated with reward. Microglia, the resident immune cell of the brain, not only provides neuroimmune support but prunes synapses and receptors. We recently demonstrated in rats that dopamine d1 receptor (D1r) peaks in adolescence and declines into adulthood, and this decline occurs via a microglial-dependent phagocytic mechanism in males but not females. Importantly, this downregulation of D1r in the NAc mediates termination of adolescent social play behavior in males. It is not known what regulates microglial pruning behavior in the NAc. It is known that microglia phagocytosis across brain regions due to chromatin remodeling altering transcriptional accessibility of required genes. Moreover, microglial phagocytosis of synapses has been demonstrated to be dependent on neuronal activity. My central hypothesis is that NAc microglial chromatin reorganization throughout adolescent development regulates genomic accessibility and expression of phagocytic genes, mediating D1r phagocytosis directing social behavior in males. I predict this occurs in a DA activity-dependent manner. To test these hypotheses, in Aim 1 I will characterize genomic accessibility and gene expression with microglia, correlating phagocytic gene accessibility expression through across adolescent development. This will provide a novel baseline characterization of microglia through development and between sexes, potentially identifying sensitive periods of dynamic gene regulation. In Aim 2 I will determine if dopaminergic signaling to the NAc is required for typical microglial phagocytic activity and chromatin organization, impacting social behavior. This will demonstrate whether microglial pruning of dopamine receptors during adolescence is dependent on neuronal activity and has consequences for behavior. Collectively these data allows for powerful future directions investigating effects of drugs of abuse on microglial development and function

NIH Research Projects · FY 2026 · 2023-03

ABSTRACT Humans diverge from other primates in numerous ways including their neuroanatomy and cognitive capacities. Human-specific features are particularly prominent in the cerebral cortex, which has undergone an expansion in size and acquired unique cellular composition and circuitry. Many of these features arose through modifications to cortical development, explained by human-specific gene expression. However, how human-specific gene expression explains divergent brain development is poorly understood. This proposal aims to fill that gap by investigating how non-coding regulatory loci impact human-specific brain development. Specifically, we focus on human accelerated regions (HARs), which are ultra-conserved sequences which have rapidly acquired mutations in the human lineage. HARs frequently physically associate with neurodevelopmental genes, and at least 50% of HARs have enhancer activity in human neural cells. Further, HARs are broadly associated with neurological disorders. Yet, biological functions for HARs in brain development remain largely unknown. Our group discovered HARE5, which shows divergent human-chimpanzee (Hs-Pt) enhancer activity in the developing mouse brain, due to just 4 mutations over 600 conserved nucleotides. HARE5 activates expression of Fzd8, a receptor in the WNT signaling pathway which is implicated in brain size and neurological disease. We have generated humanized HARE5 mouse models which exhibit expanded progenitor and neuron number and enlarged brains. We have additionally discovered new HARs, which like HARE5, are predicted to impact WNT signaling. This proposal will test the central hypothesis that evolutionary modifications of HAR enhancer activity modulate WNT signaling to control neural progenitor dynamics in the developing brain. Our proposal leverages our expertise and unique genetic tools, including mouse models, and human and non-human primate iPSCs and organoids. We will investigate mechanisms of HARE5 function in mouse models (Aim 1) and in cortical organoids generated from human and non-human primate iPSCs (Aim 2). We will then test roles for 12 WNT-associated HARs in neurogenesis (aim 3). Upon completion of this study, we will gain valuable insights into the developmental underpinnings of human cognitive capacities which can inform the basis for neuropsychiatric diseases.

NIH Research Projects · FY 2026 · 2023-03

Neuromodulatory nuclei detect and transform brain network activity into simpler signals, then send neurotransmitters back out to large-scale brain networks to change their function. Such nuclei are centrally implicated in mental disorders and adaptive resilience, and their regulation remains an untapped resource for interventions. The purpose of this grant is to understand how neuromodulatory nuclei detect and in turn influence distributed patterns of brain activity to impact behavior. To understand their regulation and effects on brain function, the investigative team has developed novel neuroimaging, behavioral, and analytic methods. These methods include: training participants to endogenously self-regulate dopaminergic midbrain, isolating distinct streams of information in the midbrain over multiple timescales, distinguishing behavioral contexts and network effects associated with univariate activation in neuromodulatory nuclei, and finally relating midbrain activation to memory-conducive states in medial temporal lobe memory systems. Our team has recently developed whole-brain analyses of real-time fMRI during midbrain neurofeedback and machine-learning tools for characterizing nonlinear latent dynamics from high-dimensional data. Now, with these tools, we can relate midbrain activation to whole brain states. We hypothesize 1) that distinct distributed spatiotemporal patterns precede and follow midbrain univariate activation, specify it uniquely among neuromodulatory nuclei, and distinguish sustained from transient midbrain responses; 2) that the evolution of these patterns over the training session will predict learning to upregulate midbrain, and 3) that endogenous midbrain regulation will predict brain and behavioral effects we and others have previously shown to be associated with midbrain activation and dopamine function. If the aims of this project are achieved, we will have introduced a multi-level model of the neural states that support midbrain activation, a complement of methods for regulating midbrain noninvasively, and an improved understanding of its impact on learning and motivated behavior. Reliable cognitive strategies for dynamically and selectively fine-tuning neural networks to suit behavioral contexts will lay the foundation for a wide array of interventions across educational and clinical applications.

NIH Research Projects · FY 2026 · 2023-03

ABSTRACT O2 uptake in the lung and O2 delivery peripherally depend on the efficient matching of blood flow to regional O2 availability in the lung and O2 consumption in tissues. To achieve this matching, red blood cell (RBC) hemoglobin allostery regulates not only trans-erythrocytic O2 flux but also RBC export of vasoactive mediators that respond to O2 demand. RBCs export vasoregulatory ATP basally and in response to O2 deficit. This RBC-based vascular control of the uptake and delivery of O2 may be disrupted by endogenous (e.g., in sepsis) and exogenous (via storage for transfusion) RBC injuries. Septic persons with moderate anemia are frequently transfused, but infrequently benefit. Yet conversely any anemia is a negative risk factor. Lung morbidity is frequent after RBC transfusion, possibly due to impaired RBC ability to export ATP, disrupting O2 uptake via pulmonary RBC- endothelial adhesion. We show in septic mice (cecal ligation/puncture, CLP) that the RBC’s ability to produce and export ATP is impaired. We will test the hypothesis that the O2-transport dysfunction in sepsis is mediated in part by impaired export by RBCs of vasoregulatory ATP, a dysfunction compounded by transfused RBCs, exacerbating acute lung injury (ALI) and hypoxemia, by achieving these Aims: Aim 1. Determine the role of RBC ATP export in mortality and ALI in a mouse model of sepsis and transfusion. Exchange transfusion of CLP RBCs into healthy mice exposed to hypoxia drives mortality. RBC ATP export takes place via pannexin 1 (Px1). We will determine the role and mechanism of depressed RBC ATP export via Px1 in the mortality, ALI, and O2 transport responses to sepsis (CLP or severe influenza) and transfusion in mice using genetic and pharmacological approaches. Aim 2. Determine the influence of augmenting transfusate RBC ATP content and/or export on organ function and O2 transport in septic mice. RBC ATP export can be augmented via clinically available approaches: hypoxic RBC storage; transfusate incubation with PIPA (phosphate, inosine, pyruvate, adenine) solution that preserves stored-RBC ATP and DPG; or using an activator of RBC pyruvate kinase (PKR), which augments RBC ATP with little effect on DPG or P50. We will test these approaches to augment or preserve RBC ATP content on ATP export in mice transfused during sepsis. Aim 3. Determine the influence of human sepsis on RBC vasoregulatory function ex vivo, and the functional influence of candidate modulators of ATP content and export in septic RBCs. We validated a novel RBC cryopreservation scheme with superior phenotype fidelity. We built a unique biobank of RBC specimens from septic children and adults. We prospectively sampled over 150 patients with severe sepsis; most subjects have ALI. We will determine the influence of translation-ready lead candidates identified in Aim 2 to augment RBC ATP export on key RBC respiratory functions: vasoactivity, anti-adhesivity, and O2 transport. We will model the effects of transfusate intervention in admixed septic and stored RBCs. Our novel focus on disrupted signaling by RBCs will produce novel, practical, and relevant insight into respiratory dysfunction in sepsis and transfusion.

NIH Research Projects · FY 2026 · 2023-03

Ubiquitylation is a covalent posttranslational modification that influences a tremendous number of normal and disease-related cellular functions. The neuronal precursor cell-expressed developmentally downregulated 4 enzyme (Nedd4) is the founding member of a family of HECT-type E3 ubiquitin ligases that regulate proteostasis in various conditions including cancers and neurodegenerative disorders. In addition to its importance in cancer, Nedd4 has also recently emerged as a significant regulator of a-synuclein proteotoxicity, and may be a target for treating synucleinopathies, neurodegenerative disorders characterized by the accumulation of aggregated forms of the protein a-synuclein in both neuronal and non-neuronal cells in the brain. NAB2 is an N- arylbenzimidazole small molecule discovered from phenotypic screening that reverses a-synuclein associated toxicity in cellular models of a-synuclein-associated PD, including ER-to-Golgi trafficking disruption. Recently we elucidated the mode of action of NAB2, finding that it bound tightly to the E3 ubiquitin ligase Nedd4 (Kdapp = 42 nM) and expands the substrate specificity of Nedd4. We determined that NAB2 binding to Nedd4 triggers the ubiquitylation of new substrates, such as the trafficking-associated proteins such as TFG, TRAPP1 subunits, and RER1. We hypothesize that Nedd4 signaling influences a new pathway that regulates trafficking processes in response to a-synuclein-associated toxicity. The proteoform state of Nedd4 that responds to a-synuclein toxicity and binds NAB2 is also not known. In addition, the location of the NAB2 binding site within Nedd4 also is not known. In this proposal we wish to test the hypothesis that NAB2 acts on Nedd4 alone or as ‘molecular glue’ to facilitate communication between Nedd4 and potential substrates. We wish to understand how NAB2 interacts with NEDD4, and how this interaction affords Nedd4 a gain of function activity to ubiquitin modifiy non PxY-containing substrates like TFG. If successful, these studies will better illuminate the role Nedd4 plays in proteotoxicity signaling. In addition, the degree to which Nedd4 activity can be modulated by small molecules is important, given the important role Nedd4 ubiquitination plays in cancer pathobiology and neurodegenerative disorders. These studies will hopefully add to our fundamental knowledge of the role that E3 ligases play in proteotoxicity signaling, and may inspire the future discovery and development of therapeutics that may address some of the causes of synucleinopathies.

NIH Research Projects · FY 2026 · 2023-03

ABSTRACT. Concussions occur at an alarming rate among U.S. schoolchildren, with one in five children experiencing a concussion by age 16. The number of children visiting emergency departments for concussions annually has increased by 50% over the past decade, with an estimated cost to the healthcare system of $1 billion/year. Compared to adults, children experience longer and more severe postconcussive symptoms (PCS). Severity and duration of PCS, however, vary considerably among children, complicating clinical care and return to learn and play. Persistent PCS including physical, emotional, and cognitive symptoms, result in increased school absenteeism, social isolation, and psychological distress. Early PCS diagnosis and access to evidence-based return-to-health and -school interventions are strongly linked to positive health and academic outcomes. Yet models to identify children at high risk for persistent PCS are lacking. PCS have been linked to inflammatory processes occurring within the injured brain. Preliminary evidence suggests that fatigue, another symptom likely contributing to poor outcomes, is also a biological byproduct of pediatric concussions. Importantly, even though 73% of children report continuous fatigue after concussion, this symptom is rarely studied along with other PCS. Prior research has focused on the relationship between inflammatory biomarkers and PCS severity but has not examined this relationship longitudinally. Acute symptom severity alone, however, is a poor prognostic of clinical outcomes in concussed children. Symptom severity immediately postinjury does not explain why at least 25% of children still experience PCS after 1 year or why even children who may appear asymptomatic still report academic and social challenges months after concussion. To identify which children are at high risk for persistent PCS and poor health, academic, and social outcomes, research tracking PCS trajectories and describing school-based impacts across the entire first year postinjury is critically needed. This proposal will 1) define novel PCS trajectory typologies in a racially/ethnically diverse population of 500 children with concussion (11–17 years, near equal distribution by sex), 2) identify associations between these typologies and patterns of inflammatory biomarkers, 3) develop a risk stratification model to identify children at risk for persistent PCS; and 4) gain unique insights and describe PCS impact, including fatigue, on longer-term academic and social outcomes. We will be the first to use NIH's symptom science model and patient-reported outcomes to explore the patterns of fatigue and other physical, cognitive, psychological, emotional and academic responses to concussion in children over a full year. Our model will enable clinicians and educators to identify children most at risk for poor long-term health, social, and academic outcomes after concussion. This work is critical to meeting our long-term goal of developing personalized concussion symptom- management strategies to improve outcomes and reduce disparities in the health and quality of life of children.

NIH Research Projects · FY 2026 · 2023-03

PROJECT SUMMARY/ABSTRACT An effective malaria vaccine would be transformative for malaria elimination campaigns. A major challenge to malaria vaccine development is that most immunogenic parasite antigens also exhibit extremely high polymorphism. As a consequence, monovalent vaccines have lower efficacy against mismatched variants due to imperfect cross-protective immunity. Additionally, signatures of naturally-acquired protective immunity, which inform vaccine design, are not clearly legible in most field studies, where the background of parasite diversity and accumulated lifetime exposure can bury functional responses among biomarkers of exposure. Understanding how natural exposure to protein variants confers protection is essential for designing vaccines that can overcome parasite diversity and provide robust protection. Additionally, linking infections with parasites harboring variant haplotypes to subsequent immune responses against those specific variant epitopes would support this conclusion and could identify cross-reactivity or cross-protection patterns and inform multivalent vaccine target screening and design. Parallel analysis of parasite antigenic variation and variant-specific host antibody responses in a multi-year longitudinal study of a consistent cohort offers an unprecedented opportunity to triangulate variant positions and epitopes within polymorphic malaria antigens that contribute to protective immunity. I will leverage densely-sampled longitudinal parasite genotype data (36 months of observation in over 500 participants) and samples collected as part of an ongoing, NIH-funded cohort study and combine this rich sampling structure with high-dimensional serological measurements, molecular epidemiology, and data science to develop in silico approaches for epitope screening. Specifically, I will: (1) correlate protective clinical reinfection phenotypes with P. falciparum CSP C-terminal amino acid positions and epitopes in silico, (2) compare cumulative parasite haplotype exposure profiles to position- and epitope-specific seroreactivity against field- derived CSP sequences, and (3) measure and compare protection conferred by non-CSP antigen candidates and variants in a naturally-exposed population. Upon completion of these aims, I will have developed new data science-driven approaches for screening polymorphic antigens for epitopes and vaccine targets, which could inform rational vaccine design for malaria elimination campaigns. The proposed work builds upon the PI’s strengths in malaria molecular epidemiology and serology and serves as a bridge to in silico vaccinology. It builds on existing collaborations, resources, and a supportive institutional environment. The proposed projects and career development plan offer extensive training opportunities in epidemiology, immunology, informatics, and translational research, which will position the PI to launch an independent career aimed at reducing the burden of malaria and training the next generation of scientists at the intersection of sero- and molecular epidemiology, bioanalytical chemistry, and data science.

NIH Research Projects · FY 2025 · 2023-02

ABSTRACT Spine pain consistently ranks first or near the top in global rankings of disease burden, and epidemiological data suggest the burden is worsening. The number of low back surgeries has increased by 300% over the past 2 decades, accounting for approximately 30% of spine-related costs in the US. While it can provide cost- effective pain relief to some patients, up to 25% of those who undergo spine surgery will develop persistent pain requiring additional surgery, imaging, or other invasive interventions. Moreover, many patients will experience persistent opioid use, which carries significant risks of misuse, addiction, and overdose. Clinical practice guidelines strongly recommend the use of multimodal – or ‘mind and body’ – treatments for effective pain management after surgery. This approach combines interventions with analgesic or physical therapeutic inputs alongside interventions with psychological or behavioral inputs to better address the multifaceted risk factors for persistent pain and opioid use following surgery. Integration of Mindfulness delivered via mobile app (mHealth) with auricular Acupuncture (AA) in individuals undergoing Spine Surgery (I-MASS) is a highly promising multimodal treatment approach given the distinct yet complementary mechanisms by which mindfulness and AA influence pain after surgery. Establishing the effectiveness of I-MASS requires a rigorously designed pragmatic trial comparing it to usual medical care in adults who undergo spine surgery. However, trials of this size and scope require careful preparation. This proposed mixed methods R34 project is designed to answer important preparatory questions regarding the feasibility and acceptability of I-MASS through the following Specific Aims: 1) Conduct interviews with patient and care delivery stakeholders to refine and finalize the I-MASS intervention protocol by integrating mHealth mindfulness training and AA for use in patients age 18-80 undergoing spine surgery; 2) Conduct a single-site, exploratory randomized controlled clinical trial to assess the feasibility and acceptability of I-MASS in patients undergoing single-level laminectomy, discectomy or fusion; and 3) Use feasibility trial results to develop and submit a competitive research proposal to NIH for a multi-site, pragmatic, randomized comparative effectiveness clinical trial designed to rigorously evaluate I-MASS compared to mHealth mindfulness, AA, and usual care augmented with standard education. The results of this R34 project will provide the information needed to successfully execute on such a study and create new knowledge regarding the feasibility and acceptability of a highly innovative non-pharmacological multimodal approach designed to improve the lives of patients undergoing spine surgery.