Univ Of North Carolina Chapel Hill

NIH Research Projects · FY 2024 · 2021-08

ABSTRACT Cardiovascular disease (CVD) is the leading cause of death for U.S women, annually killing >400,000 women. Compared to whites, non-Hispanic Black and Latina women are at higher CVD risk. Despite the burden of CVD in women, risk factors specific to women are understudied and thus not considered in current CVD risk prediction or prevention strategies. Early detection of subclinical disease is key to CVD risk stratification and prevention. Since prenatal and postpartum care is the sole health care access point for most U.S. women, pregnancy represents a critical opportunity to measure CVD risk and implement innovative strategies to address this critical gap in women’s health care. Furthermore, CVD risk factor trajectories begin in utero and in early life, so pregnancy is also an opportunity to identify CVD risk in children. Our long-range goal is to identify and disseminate obstetric care practices that mitigate CVD risk for women and their children. The objective of this prospective, multicenter study is to estimate CVD risk in healthy and medically complicated pregnant women and their infants. We will also examine the relationships among personal, social, and ecological factors and CVD risk for 3 years postpartum. Our primary outcomes are maternal and infant central pulse wave velocity (PWV), a validated measure of arterial stiffness (vascular aging) that predicts CVD, independent of other established CVD risk factors. We will enroll a cohort 840 pregnant women of diverse race/ethnicity and socioeconomic status: 420 healthy and 420 women with preeclampsia, gestational diabetes, and/or suspected fetal growth restriction. We will measure maternal and infant PWV, cardio-metabolic (e.g., blood pressure, lipids, adiposity, HbA1c) and inflammatory (e.g., hs-CRP, IL-6, adiponectin) markers of CVD risk, and assess personal, social, and ecological factors at 34-40 weeks’ gestation, delivery, 6 months, 18 months, and 3 years. The study aims are the following: 1) Measure arterial stiffness by PWV during and after pregnancy; 2) Measure infant/child PWV following healthy and complicated pregnancies; and 3) Identify maternal and infant modifiable risk factors associated with CVD risk measured by PWV. To date, no studies have longitudinally measured CVD risk in pregnant women and their infants, nor ascertained the effect of biologic, personal, social, and/or ecological factors on CVD risk. Using a noninvasive measure of arterial stiffness, we propose to determine CVD risk in a cohort of mother-infant dyads. Our interdisciplinary study team of experts in CVD, high-risk pregnancy, exercise and sports physiology, CVD epidemiology, public health, and cardiology are well poised to complete the proposed aims by using a synthesis of expertise to achieve our common, shared goal of mitigate CVD risk for women and their children. We are proposing an innovative paradigm shift in the goals of prenatal care to use pregnancy as a time in a woman’s life, particularly if she is at high risk for CVD, to identify and mitigate early markers of CVD for herself and her offspring.

NIH Research Projects · FY 2024 · 2021-08

PROJECT SUMMARY Over the past few decades, viral hepatitis has become a leading cause of death globally, causing more deaths each year than malaria, HIV/AIDS, or tuberculosis. When considering Hepatitis B (HBV), this large burden of disease is largely driven by childhood infections, as 90% of infants infected with HBV will develop chronic hepatitis with lifelong sequelae. Childhood HBV infection occurs through vertical transmission (from mothers to children during childbirth) and through horizontal transmission (between members of the same household or community). In sub-Saharan Africa (SSA), where HBV remains endemic, children are vaccinated against HBV at 6, 10, and 14 weeks of age. This schedule does not protect against vertical transmission, and an estimated 1% of newborns (367,250 infants) in SSA continue to be infected with HBV at birth each year. Administration of the monovalent HBV vaccine at birth has been shown to have up to 95% protective efficacy against vertical transmission in the WHO Western Pacific region. However, few studies have been conducted to characterize the potential impact of providing a birth dose of HBV vaccine in sub-Saharan African settings. Our partners for this project, the Ministry of Health in the Democratic Republic of the Congo (DRC) are particularly interested in understanding whether to adopt a national HBV birth dose intervention. This translational study will provide estimates of the effectiveness and impact of a 4-dose HBV vaccine series (including a birth dose) in the DRC. The proposed research will utilize previously collected data and dried blood spots from two trials in Kinshasa Province, DRC: the Birth Dose Immunogenicity Study and the Continuous Quality Improvement Study. Using advanced epidemiological methods and mathematical modeling, this proposal aims to 1) compare the proportion of infants who achieve protective immunity to HBV at 12 months of age by vaccine dose series and mothers' HBV and HIV status and 2) model the impact of adopting a national 4-dose HBV vaccine series, including the birth dose, on the incidence of HBV in children under 5 in the DRC. The results will provide valuable estimates of the immunogenicity and potential impact of an HBV birth dose that will inform vaccine policy in the DRC and greater sub-Saharan African region. Through the completion of these research aims, the trainee will gain a unique set of skills in advanced epidemiologic methods, mathematical modeling, and vaccine intervention research. Expert mentors in vaccinology, immunology, modeling, and epidemiology will support the trainee's successful completion of the proposed research, associated training plan, and MD/PhD degree at the University of North Carolina at Chapel Hill. This F30 fellowship will aid the applicant's development as a future interdisciplinary physician-scientist practicing at the intersection of infectious disease, infant health, and interventional epidemiology.

NIH Research Projects · FY 2026 · 2021-08

PROJECT ABSTRACT RNA binding proteins (RBPs) are important regulators of gene expression, playing a role in every aspect of RNA processing. Despite their importance, our understanding of RBP-RNA interactions remains incomplete. While canonical well-folded RNA-binding domains (RBDs) have been extensively characterized, emerging evidence highlights the critical role of intrinsically disordered low-complexity domains (LCDs) in RNA recognition, particularly of structured elements like RNA G-quadruplexes (rG4s). This discovery challenges the conventional binding models: instead of structured proteins binding to unstructured RNA, we observe structured RNA elements binding to unstructured or disordered proteins. My research aims to explore: i) the mechanisms of RBP LCD-RNA interactions, ii) the functional implications of these interactions, iii) how disease-causing mutations within RBPs impact function, and iv) how LCDs vary in function across tissues. Together, our studies aim to define generalizable principles of RNA recognition by RBPs, elucidate how mutations and isoform diversity reshape RNA regulatory networks, and provide mechanistic insight into RBP-linked developmental disorders. We propose to achieve these goals using highly multi-disciplinary approaches including biochemistry, molecular biology, computational biology, and relevant animal models.

NIH Research Projects · FY 2024 · 2021-08

TOWARD TRANSLATION OF NANFORMULATED PACLITAXEL-PLATINUM COMBINATION The goal of this proposal is to obtain pre-clinical data to enable the translation of a novel nanotechnology-based drug combination to treat triple negative breast cancer (TNBC). TNBC accounts for ∼10-20% of breast cancers and is associated with relatively poor prognosis, earlier disease recurrence and higher number of visceral metastases. Chemotherapy, in particular with anthracyclines and taxanes, remains the backbone medical management for both early and metastatic TNBC but a significant proportion of patients with early-stage TNBC unfortunately develop metastatic disease. Combination treatments using platinates and taxanes were shown to increase pathologic complete response rates in TNBC and improve survival in neoadjuvant treatment settings. We propose to use nanotechnology to improve the treatment of TNBC by co-delivering platinum and taxane drugs in the same nanoparticle to attack cancer cells in a synergistic fashion and produce greater antitumor effect. To address poor miscibility and drug loading of platinates and taxanes in many nanoparticles, we propose to use a high capacity polymeric micelles (PMs) of poly(2-oxazolne) (POx) block copolymers to incorporate drugs. In preliminary work we developed POXOL-CP PMs, a combination of PTX and hydrophobic cisplatin prodrug co-loaded in POx block copolymer micelles that has shown pharmacological synergy of solubilized drugs, better delivery of both drugs to tumors and improved efficacy in several animal models compared to the small molecule agents or their combination administered separately. The goal of this proposal is to obtain additional pre-GLP data for our new combination nanotherapeutic in rodent and non-human primate (NHP) models, develop validated assays and procedures for POXOL-CP PMs, further demonstrate its safety and efficacy and establish path for translation of POXOL-CP PMs to the clinic for TNBC patients. The project addresses the following aims: 1) Manufacture reproducible, stable, and safe POXOL-CP PMs, validate its safety and improved drug delivery to tumors in a mouse model of TNBC; 2) Demonstrate activity of POXOL-CP PMs compared to standard of care in Orthotopic Syngeneic Transplant (OST) and Genetically Engineered Mouse Models (GEMM) of TNBC that recapitulate the human disease. 3) Assess safety and PK profiles of POXOL-CP PMs in rat and NHP models. We will follow Good Experimental Practice (GEP) in data keeping and recording and develop Standard Operating Procedures (SOP) and follow guidance of a clinical and translational panel. If successful the results of this project will allow forming data package to support the Good Laboratory Practice (GLP) and Good Manufacturing Practice (GMP) work and compete for NCI Experimental Therapeutics (NExT) program, and/or other resources to advance development of POXOL-CP PMs on a path to the clinic to improve treatment outcomes for patients with TNBC.

NIH Research Projects · FY 2025 · 2021-08

ABSTRACT Glioblastoma’s (GBM) invasive nature is part of the reason this primary brain tumor results in near 100% mortality. Even with surgical resection, radiation, and chemotherapy, the median survival remains of only 12-15 months. Tumor invasion make complete surgical resection difficult leading to local recurrence within 2 centimeters of the original tumor in 90-95% of patients. Most systemically delivered chemotherapy agents are ineffective against GBM because they cannot reach the brain at therapeutic concentrations due to the blood- brain barrier. The blood-brain barrier is a highly selective and semi-permeable membrane that separates the circulating blood from the brain tissues as a protective mechanism. The capillaries that line the blood brain barrier have especially restrictive tight-junctions that significantly reduce permeation of systemically administered chemotherapeutics to brain tissues. A promising strategy to avoid the blood-brain barrier and reduce dose- limiting toxicities observed with systemic delivery is to administer drugs directly to the brain by implanting them within the cavity left after GBM resection. One way to achieve this it to load drug into a biodegradable polymer which allows for controlled temporal release of drug as the polymer degrades. Gliadel®, a biodegradable polymeric wafer that delivers carmustine into the resection cavity, is a clinical example of this type of therapy, and increased patient survival by 10-18 weeks. However, the use of more efficacious drugs, facilitated by recent advancement in cancer genotyping, could greatly improve the success of interstitial therapy. This could lead to personalized chemotherapeutic selection where one or more drugs can be co-administered based on a patient’s tumor-specific genetic mutations. In addition, our preliminary data suggests that the release rate of drugs from the polymer can greatly affect outcomes. Drug release rate can be controlled via polymer degradation rate as well as formulation of the drug within the polymer. We hypothesize that more potent chemotherapies loaded into biodegradable polymers tailored for optimal drug release rate would generate a platform that could be translated to the clinics to improved GBM therapy.

NIH Research Projects · FY 2024 · 2021-08

ABSTRACT Over the past decade, malaria elimination has re-emerged atop the global health agenda, with most countries setting goals to be malaria-free within two decades. However, major obstacles remain, including “getting to zero” in regions that have achieved pre-elimination status but remain surrounded by areas of ongoing transmission. As these regions near elimination, they are often “vulnerable” to re-introduction of malaria from nearby areas and “receptive” as they have the right ecology to support transmission. The Zanzibar Archipelago is one of these regions. Despite robust vector control and access to efficacious antimalarial treatment, its proximity to mainland Tanzania has made elimination difficult. Specifically, eliminating malaria on the archipelago requires a better understanding of why and where importation is occurring and understanding the factors that promote local transmission. This proposal will overlay genomic studies onto ongoing Zanzibar Malaria Elimination Program (ZAMEP) passive surveillance and reactive case detection (RCD) activities to identify foci of imported cases on the islands (Aim 1A), model the relationship between human travel, parasite genetics and importation (Aim 1B), determine the extent of secondary transmission from index cases (Aim 2A), and show the limits of RCD in detecting index cases and capturing parasite outbreaks (Aim 2B). Samples will be collected from every reported case on the archipelago and 10 sites on mainland Tanzania. Additionally, enhanced RCD - screening households surrounding a reported index case, both 1 and 4 weeks later - will be carried out in order to capture secondary asymptomatic cases, including those infected but with prepatent infection, as well as those yet to be inoculated by infected mosquitoes at the time of first RCD. We will deploy novel efficient high throughput sequencing methods that enable genotyping of thousands of samples on a genome-wide basis. This strategy is much cheaper than whole genome sequencing but still provides the resolution needed to use identity-by-descent analyses to infer relationships between highly related parasites. These methods will allow us to define individual and community risk factors for importation, as well as intervenable risk factors that impact the extent of local transmission arising from importation. Combined with geospatial data on human mobility patterns, we will achieve a deeper understanding of the drivers of importation and secondary transmission that will allow ZAMEP to tailor interventions at a local level. This study leverages an existing productive collaboration between leading academic institutions (UNC, Brown, Imperial, MUHAS) and ZAMEP to tackle questions cited amongst the highest research priorities for the WHO and other bodies that guide malaria research. As all malaria endemic countries will face the last mile of malaria elimination, whether now or in the future, we expect completion of the aims in this proposal to have a direct impact on global malaria policies.

NIH Research Projects · FY 2025 · 2021-08

ALDH1L1, a common enzyme in folate metabolism, converts 10-formyltetrahydrofolate (10-formyl-THF) to tetrahydrofolate (THF). This reaction is known to regulate the de novo purine biosynthesis and folate-dependent homocysteine re-methylation cycle. It could also play a key role in controlling the flux of one-carbon groups to anabolic pathways. In support of the role in the regulation of folate metabolism, we have recently shown that the loss of the ALDH1L1 gene in knockout mice causes functional folate deficiency, even when the mice had sufficient folate intake. Analysis of Aldh1l1 knockout mice also showed that the enzyme is the main regulator of glycine metabolism in the liver: KO mice have lower levels of glycine and glycine conjugates, indicating that the enzyme is involved in the folate-dependent synthesis of glycine from serine. We have further reported that human ALDH1L1 has six common non-synonymous exonic SNPs at the polymorphic loci rs3796191, rs2886059, rs9282691, rs2276724, rs1127717 and rs4646750 with the occurrence of haplotypes associated with these SNPs being remarkably different between ethnic populations. Our analysis of an established cohort of Hispanic children, Viva La Familia, has shown a significant reduction of serum glycine and increase in serine/glycine ratio in children with rs2276724 and rs3796191, indicating deregulation of serine to glycine conversion and re- capitulating our mouse findings. ALDH1L1 non-synonymous SNPs were also associated with markers of metabolic stress and adiposity in this cohort. Based on our findings, we hypothesize that non-synonymous ALDH1L1 SNPs produce enzyme variants with altered catalytic activity and/or stability that affects their ability to metabolize 10-formyl-THF and thus deregulates glycine metabolism. Accordingly, individuals with specific haplotypes have different ratios of THF/10-formyl-THF and serine/glycine, and altered levels of glycine and its conjugates, with perturbations in the metabotype representing a signature of metabolic health. This proposal will address the question of how haplotype-specific ALDH1L1 variants affect folate metabolism and the overall cellular metabotype, and how the haplotype-specific effect is modified by folate supplementation, by pursuing the following specific aims. Aim 1. Functionally characterize the ALDH1L1 enzyme variants from common human haplotypes. Aim 2. Determine the impact of major ALDH1L1 haplotypes on cellular metabolism and haplotype- specific responses to various folate supplementations. Aim 3. Link ALDH1L1 haplotypes to the folate-dependent regulation of glycine metabolism and health outcomes in humans. ALDH1L1 variants are very common in different populations but their role in folate homeostasis and in the etiology of metabolic disease is largely unexplored. It is expected that ALDH1L1 haplotypes differently mediate the metabolic response to dietary folate that might require adjustments of folate intake for individuals bearing certain ALDH1L1 SNPs. By filling this knowledge gap, the proposed research will provide mechanistic insight into the metabolic regulation by ALDH1L1 SNPs and will lay ground for the evaluation of population-specific ALDH1L1 haplotypes as a disease risk factor.

NIH Research Projects · FY 2025 · 2021-08

The vast majority of common genetic variation underlying risk for neuropsychiatric disorders resides in poorly annotated non-coding regions of the genome and likely impacts the regulation of gene expression. In order to move from a location in the genome associated with risk to a regulatory mechanism, there are several major gaps in knowledge including: (a) the causal variant(s) within the associated locus, (b) the regulatory elements impacted by those causal variant(s), (c) the cell-type(s) and developmental time period(s) at which the causal variants(s) exert their effects, and (d) the gene(s) impacted by those causal variant(s). In this proposal, we will identify genetic influences on two features of chromatin architecture (enhancer histone marks and their 30 interactions) during human cortical development in order to more completely explain regulatory mechanisms leading to risk for neuropsychiatric disorders. In a large population of post-mortem human developing cortical tissue that has previously undergone genome-wide genotyping and transcriptomic profiling, we will utilize a technique that allows us to simultaneously measure enhancer activity and its interaction profile (H3K27ac HiChIP). We will then identify genetic influences on these two features of chromatin and their co-localization with previous and growing neuropsychiatric disorder genome-wide association (GWAS) risk loci. Psychiatric disorder risk variants may exert their regulatory impact by (1) changing enhancers (H3K27ac QTLs or histone acetylation (ha)QTLs) and/or (2) chromatin interaction (interaction-QTLs). This novel class of QTLs will enhance our understanding of the molecular processes underlying human neurodevelopment and how that development is altered in neuropsychiatric disorders. Further, we will conduct two orthogonal methods to validate the impact of the genetic variants and assess their cell-type specificity. We will perform cell-type specific massively parallel reporter assays (MPRA) to validate the functional impact of haQTLs. In this assay, cloned oligos containing the enhancer associated alleles drive expression of barcoded transcripts that can be used to assess regulatory differences and identify causal variants. We will also apply a haplotype-specific chromatin imaging technique to visualize how regulatory variation impacts chromatin interactions in individual nuclei. This technique paints sections of each chromosome with allele-specific oligos in order to visualize and measure the physical interactions of the 0NA molecule. Completing the aims of this proposal will allow us to identify largely complete regulatory mechanisms impacting human brain development and risk for neuropsychiatric disorders.

NIH Research Projects · FY 2026 · 2021-07

The recent success and expanded use of the checkpoint inhibitor immunotherapies in clinical oncology has resulted in an increased incidence of a variety of immune-related adverse events (irAEs), some of which can have a lasting impact on the lives of our patients. The continued development of adjuvant immunotherapy protocols and more potent immunotherapy combinations such as the ipilimumab/nivolumab regimen is expected to increase the incidence and societal impact of these irAEs. Despite their growing prevalence, the underlying pathogenesis of individual irAEs is poorly understood and our therapeutic management of these conditions remains crude. Using a genetically engineered model of melanoma, we have found that anti-PD-1 antibody (ab) immunotherapy routinely leads to neutrophilic infiltration of the lung parenchyma and colon lamina propria, closely resembling the pathology noted in human checkpoint inhibitor-associated pneumonitis and colitis, respectively. This work further revealed that anti-PD-1 ab treatment of non-tumor-bearing mice eliminates the development of these irAEs, suggesting the presence of a tumor-intrinsic pro- inflammatory mechanism. As part of this work, we have recently identified a tumor-intrinsic PD- L1:NLRP3:HSP70 signaling axis that drives the accumulation of neutrophils in distant organs including the lungs and colon in response to PD-1 blockade. Additional studies have shown that genetic knock- out of tumor HSP70 expression and the pharmacological inhibition of the NLRP3 inflammasome suppresses the accumulation of neutrophils in these distant tissues. Based on these findings, we now hypothesize that the tumor NLRP3 inflammasome promotes the development of checkpoint inhibitor- associated colitis and pneumonitis and that NLRP3 represents a promising pharmacological target for suppressing the development of these irAEs. To address this hypothesis, we have generated a transgenic melanoma tissue-specific NLRP3-/- model to examine the role of tumor-intrinsic NLRP3 in the development of checkpoint inhibitor-induced colitis and pneumonitis. Additional studies will address a potential role for this tumor NLRP3 pathway in Th17 differentiation in these distant organ tissues and whether a small molecule inhibitor of NLRP3 would be a superior option over steroids for the management of colitis and pneumonitis in an autochthonous melanoma model undergoing anti-PD-1 ab immunotherapy. We will further utilize tumor tissue and DNA collected from patients undergoing checkpoint inhibitor immunotherapy on an active IRB-approved clinical study to determine if genetic variations of NLRP3 may contribute to the development of these irAEs. Overall, this work will provide unique mechanistic insight into the development of irAEs and identify rational therapeutic strategies and predictive biomarkers for improving the management of patients undergoing immunotherapy.

NIH Research Projects · FY 2025 · 2021-07

PROJECT SUMMARY Increasingly, genomics is being integrated into population-level cancer prevention and control approaches through precision public health. Given that the field is still emerging, there are limited opportunities for investigators to come together to form collaborations and to build capacity for research. Thus, our goal for this R13 renewal application is to convene an annual transdisciplinary conference for investigators who work in this field to support capacity building in transdisciplinary precision public health research, with a focus in cancer over the next three years. Our target audience emphasizes engaging early career investigators in cancer precision public health who are in a pivotal moment in their career for establishing professional networks and identifying research priorities. Our specific aims for the conference are to (1) increase content knowledge and methods expertise in cancer precision public health through seminars and question and answer sessions; (2) advance research priorities for cancer precision public health; and (3) maintain an ongoing professional network of precision public health researchers in cancer to facilitate future collaborations in precision public health research, training, and practice. Through this international conference, investigators from around the world will convene annually to gain new content expertise, to advance key research priorities for the field, and to establish an ongoing collaborative network to advance precision public health research. This builds on the work of our inaugural conference which established key research priorities, an ongoing working group to advance these priorities, and a network of precision public health researchers and practitioners who meet quarterly for webinars on advanced topics in precision public health in cancer. Moreover, the conference themes will reflect the research priorities identified in the 2021 conference: implementation science (2023 at University of North Carolina Chapel Hill), health equity (2024 Medical University of South Carolina) and capacity building (2025 University of Technology Sydney). Our long-term goal is to maintain a platform for early career investigators interested in precision public health to come together to support the development of the precision public health research agenda.

NIH Research Projects · FY 2024 · 2021-07

Abstract Congenital heart disease (CHD) remains the most common congenital malformation. Therefore, attaining a mechanistic understanding of cardiomyocyte formation is crucial for improving outcomes to structural heart disease. Though much emphasis in the last few years has been placed on transcription factor networks that control cardiomyocyte differentiation, these studies have mainly focused on transcriptional activation. However, there is growing recognition that alterations in transcriptional repression also lead to CHDs. Transcriptional repression involves not only cardiac transcription factors but also broadly expressed multiprotein machines that modify and remodel chromatin. Prominent among these is the Nucleosome Remodeling and Deacetylase (NuRD) complex. In this proposal we address the role of chromodomain helicase DNA-binding protein 4 (CHD4), the catalytic core component of the NuRD complex. The critical nature of CHD4 is highlighted by mutations in Chd4 being causative to CHDs. The goal of the current application is to test the central hypothesis that CHD4 functions with the NuRD complex to regulate cardiac chromatin architecture. This will be achieved by: 1) Determine whether CHD4 both represses and activates cardiac gene expression. 2) Delineate how CHD4 and NuRD are recruited to cardiac loci. 3) Establish how the human Chd4 missense mutations lead to cardiac disease.

NIH Research Projects · FY 2024 · 2021-07

Abstract Tuberculosis (TB) presents an ongoing global challenge to medical science that will only be met by multiple approaches. Due to the length of even “routine” TB therapy and the age of existing drugs – which contributes to the emergence of devastating resistant forms of the disease – the discovery of new drugs, especially those that function by new mechanisms of action, has become critical. In early 2019, a team including the present laboratory reported AU 8918 as the first high-quality inhibitor of 4'-phosphopantetheinyl transferase (PptT). PptT, which catalyzes the placement of a 4'-phosphopantetheinyl moiety onto a client carrier protein, is essential for the biosynthesis of mycobacterial fatty acids and virulence factors. PptT represents a valuable anti-TB target because (1) it is essential for mycobacterial tuberculosis (Mtb) survival in vitro and in mice, (2) it is divergent from the closest host ortholog, and (3) it is distinct from all targets of established TB drugs. In addition, its inhibition has been shown (4) to effectively kill Mtb including multi- and extensively-drug-resistant variants and (5) to block Mtb growth in mice, while (6) sparing other bacterial or mammalian cells. The primary hit compound, AU 8918, has an IC50 of 2.3 M in biochemical assays of PptT inhibition, a MIC90 of 3.1 M against Mtb in vitro, and has some physical properties features consistent with advancement as a drug candidate, but suffers from off-target cardiotoxicity likely associated with sodium channel blockade. The present proposal seeks to support an ongoing collaboration between three laboratories that share the common goal to design, synthesize, and characterize PptT inhibitors suitable for pre-clinical development. The availability of five high resolution co-crystal structures of AU 8918 and analogs bound to Mtb PptT has been leveraged to establish a robust in silico modeling protocol for the preliminary assessment of analogs. Several avenues to create novel PptT inhibitors are proposed, including (1) SAR exploration of AU 8918, (2) discovery and exploration of new scaffolds arising from bioisosteric replacements of the amidinourea subunit of AU 8918, and (3) new hits arising from an ongoing screen against PptT. We will characterize inhibitors by (1) biochemical PptT inhibition, (2) X-ray crystallography of inhibitor•PptT co-crystals, and (3) advanced biochemical characterization (including intracellular macrophage activity measurements, verification of on-target activity by knockdown/knockout studies, safety profiling against off-target liabilities, pharmacokinetic and metabolic characterization, metabolomics, and synergy studies). The final goal of the project is to identify 1–2 advanced compounds for advancement to in vivo studies in Mtb infected mice, having the following properties: (<0.1 M potency against PptT, <1 M MIC90 against Mtb, retention of positive physical properties, and lacking cardiotoxicity or activity (>30 M inhibition) at relevant Ca and Na channels.

NIH Research Projects · FY 2026 · 2021-07

Abstract: This study evaluates the effectiveness of a combination intervention providing education, employment support, resources, and mentoring on uptake of HIV prevention medication and behaviors in U.S. young adults. Approximately 1.2 million Americans are currently living with HIV, and many more are at risk of HIV infection. While new HIV diagnoses have declined in recent years, an estimated 38,000 Americans are newly diagnosed each year. Young adults represent a growing proportion of new HIV diagnoses in the U.S. and are more likely to acquire HIV infection compared to older adults due to limited education on prevention of sexually transmitted infections (STI), higher rates of sexual risk behaviors, and lower access to HIV prevention therapies. Young adults also face higher rates of economic hardship, such as unemployment, job instability, homelessness, or low wage – which are associated with higher rates of HIV. Pre-exposure prophylaxis (PrEP) is a medication that can prevent HIV infection in individuals who do not have HIV but are at risk of contracting it. Research has shown that PrEP is highly effective in preventing HIV transmission through sexual activity among individuals who are at risk of HIV infection. Yet, young adults make-up a small proportion of PrEP users in the United States. Barriers to uptake of PrEP are often economic in nature if potential users are uninsured or if, even with health insurance, potential users lack income to pay for out-of-pocket expenses relating to medications, lab monitoring, or travel to clinics. In addition, young adults experiencing economic hardship are often unaware of the benefits of PrEP, how to access it, how to pay for it, and how to discuss HIV prevention medications and behaviors with their sex partners or healthcare providers. Therefore, interventions that provide education on HIV prevention and that provide support to enhance access to employment and cost-assistance programs are needed. This study will randomize U.S. young adults to an experimental group that will receive HIV prevention education (i.e., PrEP, condomless sex), economic resources, job announcements, job readiness training, and employment mentoring or to a control group that will receive job announcements only. We will recruit sexually active young adults, aged 18 to 24, who are experiencing economic hardship. The specific aims are to: (1) evaluate the effectiveness of the intervention on condomless sex and PrEP initiation, as well as participants’ economic stability as achieved by enhanced employment; (2) assess heterogeneity of intervention effects by sex and by peer support; and (3) examine mechanisms of change and component experiences using statistical and qualitative methods.

NIH Research Projects · FY 2025 · 2021-07

Enter the text here that is the new abstract information for your application. This section must be no longer than 30 lines of text. Computational approaches based on statistical, mathematical and machine-learning principles are now permeating all areas of biological and biomedical research. Driving this explosion in biological computation are new high-throughput techniques in genomics, proteomics, metabolomics and chemoinformatics, and advances in modern imaging. Each of these fields generates complex data sets that require computational approaches to analyze and interpret. Also driving the use of computing in biomedical research is the increasing availability of high-performance computing, including graphical processing units (GPUs), that make deep learning and other artificial intelligence approaches computationally feasible. As a result, there is an increasing demand for biomedical researchers with expertise in scientific computing and data analytics and trained in statistical and mathematical modeling. To address this need, in 2007 the University of North Carolina at Chapel Hill established the Ph.D. Curriculum in Bioinformatics and Computational Biology (BCB). The mission of the BCB curriculum is to train the next generation of scientists with the computational and quantitative skills required to make important contributions to modern biological and biomedical research. To accomplish this goal, not only requires students receive training in computational, mathematical and statistical approaches, but also that they become sufficiently versed in biology and acquire skills required for multidisciplinary team science. The BCB curriculum also strives to provide students with the professional skills required to successfully transition into careers in the biomedical workforce. The specific objects of the BCB curriculum are to: 1) provide broad knowledge of bioinformatics and computational biology approaches and the computational, statistical and mathematical foundations on which they are built, 2) provide in depth training in a chosen area of bioinformatics and computational biology, 3) train students to participate in collaborative and interdisciplinary research, 4) train students to develop independent research programs and identify new research directions, 5) develop skills in oral and written communication, 6) provide students with professional training opportunities for careers outside of academics and 7) provide students with training in the Responsible Conduct of Research, and in Rigor and Reproducibility. The proposed T32 training program will support 6 BCB students during their second year of graduate training. In addition to providing didactic training and scientific research opportunities, the BCB curriculum provides professional training opportunities by sponsoring events such as “lunch and learn” sessions with representatives from the pharmaceutical and biotechnology sectors and “hackathons” with the National Center for Biotechnology Information. The University of North Carolina and BCB curriculum are provide a supportive environment for students from all academic and research backgrounds and with the training needed to successfully transition to biomedical research careers in academic, governmental, and corporate settings.

NIH Research Projects · FY 2025 · 2021-07

Abstract: Rates of sexually transmitted infections are on the rise in the United States, including those caused by Neisseria gonorrhoeae. Antibiotic resistance in N. gonorrhoeae is also increasing and has been recognized as a serious emerging public health threat by WHO and the US CDC. A vaccine against N. gonorrhoeae could help combat the spread of antibiotic resistant N. gonorrhoeae, however, an effective vaccine for N. gonorrhoeae has thus far eluded discovery. Individuals infected with N. gonorrhoeae do not develop immunity to subsequent infection, limiting our understanding of the immune responses required for protection from infection. Mass vaccination campaigns in New Zealand and other countries with vaccines against N. meningitidis serogroup B made from outer membrane vesicles have been followed by reduced reported rates of N. gonorrhoeae infections in those countries. The US FDA-approved N. meningitidis serogroup B vaccine (4C-MenB) contains both N. meningitidis outer membrane vesicles and two recombinant antigens that are highly related to N. gonorrhoeae homologs of the antigens. Our research team currently uses a unique human experimental infection model to study N. gonorrhoeae in its natural host. Because the use of the 4C-MenB vaccine is not yet widespread within the US, there is a unique and time-sensitive opportunity to test the effectiveness of this vaccine in preventing N. gonorrhoeae using our human challenge model. The proposed clinical trial will also allow us to study immune responses to the 4C-MenB vaccine and determine which responses are essential to the protective effect of the vaccine. The current proposal requests support for the implementation of the proposed clinical trial, which represents an important step in the development of an effective N. gonorrhoeae vaccines.

NIH Research Projects · FY 2025 · 2021-07

CELL CYCLE CONTROLS THAT ENSURE GENOME MAINTENANCE (COOK) SUMMARY Our research program seeks insight into the fundamental architecture and regulation of the human cell division cycle, with specific focus on DNA replication competence. Complete and efficient duplication of an entire mammalian genome requires that many thousands of DNA replication origins become licensed in G1 phase through the DNA loading of MCM helicase complexes. Loaded MCM complexes render genomic loci competent for replication initiation during S phase. Loss of normal origin licensing control causes genome instability, which can cause oncogenesis, developmental defects, and degeneration. Origin licensing control is as important for ensuring normal genome maintenance as companion mechanisms such as replication fork control and stability or DNA repair, but the regulation of origin licensing is only partly understood. For example, how is complete origin licensing achieved in cells with dramatically different G1 lengths, such as during development or after oncogene activation? How is origin licensing activity distributed in a heterogenous chromatin environment? How is origin licensing controlled during transitions into and out of the cell cycle? These unanswered questions preclude the comprehensive understanding of proliferation control needed to diagnose and treat pathologies in which cell proliferation is a hallmark. Our long-term goal is to understand how DNA replication origin licensing is governed by intracellular and extracellular pathways that control proliferation and development and to understand the outcomes of perturbations to those controls. Our current and future projects are organized into scientific questions clustered into two central goals: Goal 1) Define how MCM loading dynamics regulate G1 progression, Goal 2) Determine the molecular events that establish and maintain cell cycle exit to quiescence. In recent years, we developed innovative experimental tools and approaches using quantitative live cell and fixed single cell analyses in cultured human cells. We combine these tools with molecular genetics and biochemistry. We focus on uncovering molecular mechanisms and their inter-relationships, and then test the consequences of perturbing those mechanisms. Our prior efforts produced a consistent stream of basic scientific discoveries and advances for both the field and the scientific workforce. The impacts of success towards our central goals are to define previously unexplored mechanisms in the mammalian cell cycle and to probe the dynamics of molecular events required for genome maintenance.

NIH Research Projects · FY 2025 · 2021-07

Differences in drug metabolism between patients can significantly affect drug concentrations in the body and overall drug response (efficacy and toxicity). Advances in pharmacogenomics have improved our understanding of how variations in genes that encode drug metabolizing enzymes (e.g., cytochrome P450 enzymes) affect drug response. However, far less is known about the mechanisms and clinical consequences of genetic and non-genetic factors (biological sex, age, epigenetics, drug interactions, etc.) that affect drug disposition in patients from all backgrounds. Adequate representation of the U.S. population in both basic and translational pharmacogenomics and multi-omics studies is key to the implementation of precision medicine for all patients. Recent findings from my laboratory support the contention that genetic and phenotypic markers are needed to accurately assess individual drug metabolism capacity. The overall vision of my research program is to understand the underlying mechanisms of interindividual variability in drug metabolism and drug response to advance precision medicine for all patients. Through this Maximizing Investigators’ Research Award (MIRA R35) for Early Stage Investigators, my research program will address key questions and important challenges in the field through the following distinct and complementary projects. Project 1 will test the hypothesis that including people from different genetic backgrounds in pharmacogenetics studies will provide greater insight into the underlying mechanisms of interindividual variability in drug metabolism and response. Project 2 will test the hypothesis that the application of an integrated pharmaco-omics approach will greatly enhance the ability to precisely quantify drug metabolism capacity in individual people. Project 3 will test the hypothesis that the incorporation of data from mechanistic drug metabolism studies with genetically different populations will improve the prediction of pharmacokinetic variability using data-informed physiologically based pharmacokinetic models compared to model predictions using “reference” populations. Significance: This research promises to shift the current “one-size-fits-all” drug dosing paradigm by utilizing and integrating population-specific genetic variants and phenotypic biomarkers to accurately quantify individual drug metabolism capacity, a major predictor of drug response. My research program will increase the return on investment for precision medicine initiatives by overcoming the barriers that have limited the applicability of genotype-guided dosing. This work will lay the foundation needed to implement the right drug at the right dose for the right patient at the right time. This research represents the first comprehensive pharmaco-omics investigation in representative populations to utilize germline genetic markers as well as dynamic epigenomic, proteomic, and metabolomic biomarkers to capture drug metabolism phenotype. I am dedicated to mentoring the next generation of drug metabolism scientists.

NIH Research Projects · FY 2025 · 2021-07

PROJECT SUMMARY While most people with psychosis are not dangerous and most violence is committed by non-psychotic people, people with psychotic disorders are at increased risk for violence, and violence is associated with worse outcomes and increased stigma. Therefore, decreasing violence risk in psychosis is clinically relevant and has important public health implications. Several clinical studies suggest that clozapine is superior to other antipsychotic medications in reducing violence or aggression. However, there were numerous limitations of these studies including that most of them were observational and non-randomized, included small sample sizes, or focused on hostility, non-physical aggression, or self-harm, rather than violent acts. Further, the majority of these trials were not generalizable to outpatient, community settings. No large effectiveness study has examined the effects of clozapine on violent behavior in community settings. We propose a randomized, parallel-group, 24-week, open-label, single (rater)-blind, 7-site clinical trial to examine the effects of treatment with clozapine vs. treatment as usual (TAU) on the risk of violent acts in 280 individuals with schizophrenia at high risk for violence. This trial will be a collaboration of 7 sites, coordinated by the New York State Psychiatric Institute. The 6 additional collaborating sites contribute unique expertise and will ensure an adequate sample size for this trial. Our primary effectiveness outcome is time to violent acts as measured by the MacArthur Community Violence Interview (MCVI). We will also explore the effects of clozapine on the Point Subtraction Aggression Paradigm. While many factors may contribute to violent behavior in individuals with schizophrenia, including positive symptoms, psychopathy, impulsivity, and substance use, evidence suggests that the final common pathway for many of these disparate causal influences likely runs through behaviors captured by the Excitement Factor of the Positive and Negative Syndrome Scale (i.e., a composite of the scores of excitement, uncooperativeness, poor impulse control, and hostility). Importantly, our target (the excitement factor of the PANSS) has been validated to measure excitement-like symptoms in clinical trials in schizophrenia, is sensitive to treatment, has been linked to the neurobiology of violence in MRI and PET studies, and differentiates clozapine from other antipsychotic drugs. We will also explore the effects of clozapine vs. TAU on positive symptoms (e.g., persecutory delusions) and alcohol and substance use, and how these effects influence the risk for violent acts. To enhance the safe implementation of this study in this vulnerable population at risk of violent behaviors, we will implement clinical safety and treatment engagement protocols that rely upon standard personnel and that will be readily generalizable. This trial will provide guidance on the use of clozapine for violence in community settings and will definitively test hypotheses regarding mechanisms of its anti-violence effects. The results will be immediately relevant to practice and will impact public health because there is currently no standard approach for the treatment of violence in schizophrenia.

NIH Research Projects · FY 2024 · 2021-07

PROJECT SUMMARY/ABSTRACT Dengue is the most prevalent vector-borne virus plaguing our world. In 2010, there were an estimated 390 million infections worldwide, 25% of which were symptomatic. The pathogenesis of dengue is complex because of the existence of four serotypes. Infection with one serotype protects the individual against future infections of the same serotype, but subsequent infection with a different serotype increases the risk of symptomatic disease, which includes potentially life-threatening dengue hemorrhagic fever and dengue shock syndrome. In endemic countries, children are most at risk of infection and disease. An immunizing vaccine is crucial for population protection but large trials of live-attenuated vaccine in children show that younger age is associated with future infection and severe disease independent of other variables. Vaccination is a correlate to natural infection, where in previously unexposed individuals, antibodies that cross-react to many serotypes protect against multiple dengue serotypes but are short-lived. Long-lasting protection most likely comes from a small fraction of durable antibodies that are specific to one dengue serotype. What determines the production of these type-specific antibodies and the viral epitopes that they target is not well understood. Immunologic studies incorporating longitudinal observational data are needed to understand protective antibody responses after primary natural dengue infection in children. This study will address relationships between age, antibody quality, and dengue infection or disease. The proposed research will utilize previously collected data and sera from an ongoing longitudinal observational study, the Pediatric Dengue Cohort Study in Managua, Nicaragua. Using state-of-the-art recombinant viral techniques and epidemiologic methods in this one-of-a-kind dataset, the proposal aims to 1) compare how epitopes targeted by antibodies vary in younger and older children with known dengue serotype 2 infection and 2) assess the risk of dengue reinfection in younger and older children with prior natural dengue infection. The results will establish the variation in antibody specificity and avidity in younger and older children and inform future policy decisions regarding vaccination against dengue virus in this population and possibly other Latin American countries. Through the completion of these research aims the trainee will gain a unique set of skills in advanced epidemiologic methods, virology, and immunology research, including analysis and interpretation of complex immunologic and longitudinal data. Expert mentors in virology, immunology, and epidemiology will support the trainee’s successful completion of the proposed research, associated training plan, and MD/PhD degree at the University of North Carolina at Chapel Hill. This F30 fellowship will critically aid the applicant’s development as a future interdisciplinary physician-scientist practicing at the intersection of virology, immunology, and infectious disease epidemiology.

NIH Research Projects · FY 2025 · 2021-07

Project Summary - SEED Follow-up Autism Spectrum Disorder (ASD) is a neurodevelopmental disorder that impacts approximately 1.5% of children in the United States. Individuals with ASD experience deficits in social communication or restricted interests and repetitive behavior; but the severity and patterns vary greatly and convey lifelong impairment for some. It is unclear how the presentation of ASD changes from early childhood into adolescence or adulthood. The causes of ASD are also unknown, though substantial evidence supports the contribution of both genes and environmental factors. These gaps in knowledge exist because US studies to date have lacked the sample size, depth of data collection, or appropriate life course timing to address these questions. The Study to Explore Early Development (SEED) is now able to address these prior limitations. SEED is a large case- control study of children ages 2-5 years and their families, implemented across eight states over three phases. SEED collected detailed data on children’s core ASD symptoms, cognitive status, and presence of co- occurring conditions in early childhood, along with extensive risk factors related to maternal health and the perinatal environment as well as genomics. The SEED sample includes 2044 children with ASD, 1950 children with non-ASD developmental disabilities (DD), and 2285 population control children (POP), making this the largest etiologic study of ASD in the US. Recent ancillary studies - the SEED Teen Pilot and SEED COVID studies -- will soon add data on adolescent health and the consequences of the pandemic, respectively, for some SEED participants. The work proposed here, SEED Follow-up Studies (SEED FU), will maximize the impact of extant SEED data through analyses that characterize ASD phenotypes and assess the potential interplay between genetic and modifiable risk factors. SEED FU will also facilitate new data collection in middle childhood, adolescence and early adulthood to characterize changes in ASD phenotype across developmental stages, and the associated health, educational, and service needs across the early life course. These data will further enable prospective analyses of associations between early life factors and later childhood through early adulthood outcomes. Studying risk factors in relation to life course phenotypic subgroups may also help elucidate etiologies previously masked in ASD case-control studies. The NC SEED Team in combination with the SEED Network’s collaborative infrastructure and extensive extant data resources, will ensure the successful implementation of the SEED FU Study in North Carolina and contribute to success across the network. SEED is well-powered for making significant contributions to our understanding of the complex autism phenotype and identifying factors associated with ASD risk in the population. The knowledge gained by SEED FU will greatly advance our ability prevent adverse developmental outcomes and to support individuals with ASD and their families to ensure optimal wellbeing through early adulthood.

NIH Research Projects · FY 2024 · 2021-07

Project Summary Frontotemporal lobar degeneration (FTLD) and amyotrophic lateral sclerosis (ALS) are two progressive neurodegenerative disorders on a spectrum of disease related to the RNA/DNA binding protein TAR DNA- binding Protein of 43 kDa (TDP-43). Many patients demonstrate an intermediate phenotype of dementia with motor neuron disease (here called FTLD-ALS). The vast majority of pure FTLD and ALS cases are sporadic (sFTLD, sALS), with no family history or known genetic mutation. More than 50% of all FTLD and 90% of all ALS cases manifest a characteristic pathology in affected neurons: hyperphosphorylated, ubiquitinated inclusions of TDP-43. TDP-43 pathology is often observed in other neurodegenerative disorders, including Alzheimer’s and Parkinson’s Diseases, suggesting a common pathogenic mechanism linking TDP-43 dysfunction and neurodegeneration. TDP-43 aggregates are normally degraded by autophagy, but in FTLD-ALS this machinery fails, contributing to disease progression. In fact, some familial FTLD-ALS cases are caused by mutations in autophagy-related proteins. The mechanisms behind TDP-43 aggregation and the neurotoxicity it imparts remain poorly understood, particularly in sporadic disease. Most animal models rely on overexpression of disease- associated genetic variants; however, these may be limited in generalizability to sporadic disease. Our lab identified TDP-43 acetylated at a key lysine residue (Ac-K145) as a driver of TDP-43 pathology. Ac-K145 TDP- 43 is detected in the pathologic inclusions in sALS spinal cord. With the goal of better modeling sporadic illness, we used CRISPR/Cas9 technology to insert a K145Q acetylation-mimic mutation in the endogenous mouse Tardbp locus (TDP-43K145Q) to generate a novel model of TDP-43 proteinopathy in sporadic FTLD-ALS. TDP- 43K145Q mice show hallmark pathologies, such as age-dependent cognitive impairment and accumulation of insoluble TDP-43 in the cortex and spinal cord. This project aims to determine the role of acetylation-mimic TDP- 43 in neurodegeneration and autophagy impairment. Aim 1 will test the hypothesis that aging exacerbates the neurodegenerative phenotype in TDP-43K145Q mice, using behavioral assays of cognitive and motor function, neuropathologic assessment of cortical tissue, and electrodiagnostic studies of motor unit function. Aim 2 will test the hypothesis that autophagic flux is impaired in primary cortical neurons of TDP-43K145Q sFTLD-ALS mice, using an in vitro aging paradigm alongside pharmacologic manipulation of autophagy and biochemical and live- cell imaging techniques. The long-term goal of this project is to better understand the mechanisms behind TDP- 43-related neurodegeneration and reveal opportunities for therapeutic intervention. This work will provide me with comprehensive training in both translational and basic science research methods, and I will complement my research with mentored clinical activities caring for neurodegenerative disease patients. The top-tier research and clinical opportunities available at UNC Chapel Hill, alongside my mentor, Dr. Todd Cohen, and expert collaborators, will help launch my career as a leading physician-scientist in neurodegenerative disease biology.

NIH Research Projects · FY 2025 · 2021-07

ABSTRACT We propose to establish a Chemistry–Biology Interface (CBI) Training Program that will enable trainees at the University of North Carolina at Chapel Hill (UNC) to obtain the breadth of scientific training essential for modern, mechanistically informed chemical biology. This program draws from two historically successful programs at UNC: the Division of Chemical Biology and Medicinal Chemistry (CBMC) in the UNC Eshelman School of Pharmacy, and the Biological and Organic Chemistry Divisions in the UNC Department of Chemistry (College of Arts and Sciences). These two units have a strong and continuing tradition of collaboration, common coursework, and a shared seminar series. Although UNC has a highly regarded scientific tradition, there is no chemistry-oriented NIH training program on the UNC campus. The proposed program will bring together 25 established researchers who encompass the breadth of chemical biology, ranging from analytical bioanalysis to protein structure/function to medicinal chemistry/drug design. In addition, three promising junior faculty members will join the program as “mentored mentors”, working closely with senior colleagues as they continue to establish their programs. The program leaders, one from CBMC and one from the Department of Chemistry, are accomplished senior faculty with mentoring and administrative experience; they will provide program guidance with input from an internal steering committee and a distinguished group of external advisors. Students will be recruited from the two primary units and from a UNC umbrella biological/biomedical sciences program that has shown remarkable success in recruiting outstanding and diverse graduate students to the campus. The training program includes (1) common coursework that establishes the basis for research at the chemistry–biology interface, including responsible conduct of research and rigor/reproducibility training, (2) biweekly meetings that alternate between a journal club and a smaller discussion group focused on individual learning and professional development, (3) an program retreat that will be held before the fall semester, providing orientation and early formal training in rigor and reproducibility, and (4) a trainee-organized symposium that will become a major annual event at UNC. Work at the chemistry–biology interface has become increasingly relevant as our understanding of biology has required more molecular insights. Accordingly, the activities of the proposed program will capitalize on the diverse expertise in CBMC and Chemistry, and the extensive educational and research resources that are available at this internationally recognized institution. This program will provide trainees with a superior education from the perspective of depth and breadth, and develop well-trained PhD scholars at the interface of chemistry and biology who will play a critical role in the biomedical sciences across academia and industry.

NIH Research Projects · FY 2025 · 2021-07

PROJECT SUMMARY/ABSTRACT Cancer is a common diagnosis in the emergency department (ED) and by the time patients reach the ED, their cancer has often progressed to later stages. EDs are not intended to diagnose cancer. Training in cancer management is limited for ED physicians, and patient access to follow-up care after a visit to the ED is often difficult. Research from other western countries tells us that, compared to non-emergency settings, cancer diagnosis through the ED is an independent predictor for worse outcomes, including poorer overall survival. Very little is known about emergency diagnosis of cancer in the United States (U.S.). From a handful of studies conducted in a few cancer types, we know that up to 30% of cancer patients are diagnosed as emergencies, and low income and racial/ethnic minority patients are substantially more likely to be affected. However, across different cancer types, the burden and risk factors of cancer diagnosis as an emergency have not been studied. Furthermore, no population-based studies in the U.S. have compared survival differences in patients with cancers diagnosed in EDs vs other non-emergent settings. And among those who are diagnosed as emergencies, it is unclear why they visited the ED, rather than going to a primary care provider for their diagnosis. Our long term goal is to establish the epidemiology of emergency cancer diagnosis in the U.S. We will describe the burden of cancer diagnosis in the emergency department including the patient characteristics of those most affected and quantify disparities across vulnerable populations defined by socioeconomic status, race/ethnicity, and geographic isolation (Aim 1). We will estimate the relative importance of ED (compared to non-ED) diagnosis on patient survival, after controlling for known risk factors like cancer stage, treatment, patient age and chronic conditions (Aim 2). Finally, we will investigate modifiable drivers of disparities among patients diagnosed as emergencies by examining their pre- and post-diagnostic patterns of care to identify opportunities for prevention and improved outcomes (Aim 3). Our highly efficient study design uses epidemiologic methods to analyze high-quality, population-based SEER-Medicare data for 1.8 million, Americans who were diagnosed cancers of the esophagus, stomach, colon/rectum, liver, pancreas, lung, breast, uterus, ovary, prostate, bladder, kidney, non-Hodgkin’s lymphoma, myeloma, and leukemia. The investigative team includes experts in cancer epidemiology, healthcare delivery, cancer health disparities, medical sociology, and oncology, family, and emergency medicine. This will be the first large-scale study of emergency cancer diagnosis in the U.S. Establishing a base of evidence about this important problem, including who is affected, where, and why, will illuminate a largely unrecognized issue, and identify modifiable drivers of disparities in patients with the poorest prognoses.

NIH Research Projects · FY 2025 · 2021-07

PROJECT ABSTRACT. Disability continues to be common in adults with RA despite pharmacological advances two decades ago that reduced disease activity. Physical therapy and exercise are effective in reducing disability in adults with RA, however they are underutilized in rheumatologic care, particularly in the United States. Key contributors to this underutilization includes lack of sufficient specificity for physical therapy and exercise recommendations in treatment guidelines leaving rheumatologists unclear when to refer and lack of systematic processes for integrating rehabilitation in routine RA care. To facilitate appropriate referral to physical therapy and exercise for adults with RA, we created a model to PREserve Valued Activities In Life (PREVAIL) based on the premise that early identification of functional decline will help direct physical therapy and exercise referrals to address impairments before irreversible disability ensues. PREVAIL inserts disability screening into routine RA care and uses the results of the screening to direct a physical therapy referral matched to disability level and RA- specific exercise guidance. The objective of this research proposal is to develop and pilot test a scalable model (PREVAIL) for integrating rehabilitation into routine care to preserve function and delay disability in adults with RA. The aims will (1) define the distribution of disability levels and related functional needs in adults with RA, (2) obtain key information from patients and providers on the acceptability and feasibility of the PREVAIL model, and (3) conduct a pilot trial to determine feasibility and acceptability of the refined PREVAIL model in at least 50 adults with RA. Successful completion of this proposal will establish feasibility and acceptability, and set the stage for to integrate PREVAIL into rheumatologic care on a larger scale. My long-term goal is to mitigate disability in adults with rheumatic and musculoskeletal diseases. The objectives of this career development award are to (1) deepen my current knowledge of rheumatic disease, specifically in rheumatoid arthritis (RA) care to better understand how to integrate rehabilitation, (2) train in health services research, particularly intervention development and clinical trials, and (3) prepare to design and execute a larger clinical trial in my next phase. My mentors are experts in health services research, rheumatologic care, and RA disability measurement. Together, we developed this research proposal and career development plan to accelerate my scientific development towards my long-term goal and research independence.

NIH Research Projects · FY 2025 · 2021-07

Computational Diffusion MRI for Studying Early Human Brain Development Abstract In the first years of life, the human brain develops dynamically in both structure and function. Many neurodevel- opmental disorders are associated with aberrations from normative growth during this critical period of early brain development. The increasing availability of longitudinal baby MRI data, such as those acquired through the Baby Connectome Project (BCP), affords unprecedented opportunity for precise charting of early brain developmental trajectories in order to understand normative and aberrant growth. Dedicated computational tools are needed for accurate processing and analysis of baby MR images, which typically exhibit dynamic heterogeneous changes across time. The goal of this project is to equip brain researchers with computational tools effective for studying the early developing human brain in terms of tissue microstructure and white matter pathways using diffusion MRI. We propose three aims. In Aim 1, we will develop computational tools for effective estimation of white matter pathways in the baby brain via diffusion tractography. We will tackle the challenge of tracking through regions with low diffusion anisotropy owing to ongoing myelination in the developing brain. Our tools will allow proper characterization of complex white matter pathway patterns such as fanning and bending. This will allow solving the gyral bias problem ubiquitous in existing tractography algorithms with fiber streamlines terminating predomi- nantly at gyral crowns but not sulcal banks. Our tools will allow tracing of cortico-cortical and cortico-subcortical pathways with more uniform coverage of the cortex. In Aim 2, we will develop microstructural analysis meth- ods that are unconfounded by complex fiber configurations, such as crossing, bending, branching, kissing, and fanning, allowing more accurate and specific characterization of changes in tissue microarchitecture during early brain development. In Aim 3, we will develop techniques that will allow diffusion MRI data collected at multiple sites, which are very common in the era of big data, to be harmonized to mitigate the negative effects of inter-site variability. Unlike existing methods that harmonize derived quantities such as fractional anisotropy, our method can be applied directly to the diffusion-weighted images, allowing measurements based on microstructure and connectivity to be subsequently computed for consistent analysis. We will also develop deep learning tools for multi-shell data prediction so that diffusion MRI data collected with different numbers of shells can be harmonized. Successful completion of this project will empower the neuroscience community with computational tools to better chart the normative early development of the human brain using diffusion MRI. The developed tools will also enable quantitative brain examinations of children who are affected by neurological developmental disorders.