Univ Of North Carolina Chapel Hill

NIH Research Projects · FY 2026 · 2024-12

PROJECT SUMMARY/ABSTRACT Executive function (EF) is a critical ability, and low levels of EF are a transdiagnostic risk factor for psychopathology. EF is composed of dissociable components (e.g., inhibition, updating, shifting) that have distinct developmental trajectories, and that may be differentially related to psychopathology. Therefore, characterizing neurocognitive trajectories of distinct components of EF and how they relate to future psychopathology is a public health imperative. The main goal of this proposal is to identify trajectories of neural biomarkers that predict EF and psychopathology in a dimensional sample of youth with varying degrees of risk for psychopathology. Influential theories suggest that transdiagnostic risk for psychopathology is associated with brain network properties of EF-related networks. Crucially, EF-related brain regions and the EF-related brain networks that underlie psychopathology change across development, highlighting the need for longitudinal research to identify when and how neural markers related to EF alter within an individual. To address these fundamental knowledge gaps, we capitalize on the UNC Early Brain Development Study (EBDS), a unique and innovative longitudinal study that has followed children, enrolled prenatally, with rich neural and phenotypic data collected at birth, 1, 2, 4, 6, 8, 10, 12, 14, and 16 years. We propose to conduct novel data collection in 354 participants from this cohort at 18-19 years that includes careful assessment of transdiagnostic psychopathology and completion of tasks separately probing distinct components of EF while undergoing fMRI scans. Critically, EBDS is enriched for infants at high risk for future psychopathology (mothers with psychiatric diagnoses; preterm births), with ~40% of participants considered high risk at enrollment. Thus, we have an unparalleled ability to chart neurocognitive trajectories from birth through adolescence in a sample of participants that is heterogeneous in terms of risk for psychiatric outcomes. We leverage theoretical and computational models of the networks underlying distinct EF components to assess how within-network coherence and integration with other task- relevant networks changes throughout development, with a focus on the two periods that are most important for shaping both EF and mental health outcomes: early life and early adolescence. We propose to implement groundbreaking new methods to use fMRI data to quantify trajectories of neuroplasticity across these two sensitive periods. Finally, we will examine how interactions from birth between brain development and environmental context results in increased risk for (or resilience against) psychopathology in emerging adulthood. The specific aims of this proposal are: 1) to characterize neural and behavioral trajectories of EF from infancy to emerging adulthood; 2) to establish how neural trajectories relate to functional brain organization during EF tasks in emerging adulthood; and 3) to determine how and when EF-related neural trajectories diverge across psychopathology- and environment-related risk levels. This research will provide groundwork that can lead to early identification and, ultimately, targeted intervention in youth at risk for future psychopathology.

NIH Research Projects · FY 2026 · 2024-12

Abstract Macrocyclic peptide therapeutics (MPTs) have risen as a powerful tool for targeting “undruggable” proteins of interest. This class of compounds can mimic protein-protein interactions, disrupting shallow interfaces that would be otherwise difficult to target with small molecule drugs. Many naturally occurring MPTs contain non-canonical amino acids (ncAAs) in their core scaffolds, such as modified sidechains, backbone alkylations, β-linkages, etc. Including diverse building blocks in MPTs can confer greater specificity and binding affinity towards a target. Two primary techniques are used for including ncAAs into peptides, flexizyme and orthogonal tRNA synthetases (ORSs). While flexizyme can charge any tRNA with any pre-activated ncAA, this non-specificity prohibits utilization in situ, necessitating purification of charged tRNAs and limiting the maximum number of replaced codons to ~10. Conversely, ORSs are capable of catalytically recharging tRNAs with ncAAs in situ, but are typically limited to a single tRNA and a narrow scope of structurally similar ncAAs, requiring lengthy engineering campaigns to modify tRNA and/or ncAA specificity. Recently, a new class of chimeric ORSs has been reported, where a tRNA recognition domain (RD) is tethered to a catalytic domain (CD) by a flexible linker, allowing independent engineering of both domains. Here, I propose to combine the best aspects of both ncAA incorporation systems by engineering a system of modular chimeric tRNA synthetases (MoChi-RS) to allow “plug-and-play” swapping of tRNA recognition and catalytic function. Candidate tRNA-RD pairs were sampled from nature using a custom bioinformatics pipeline leveraging sequence similarity network analysis, AlphaFold, and genome-wide tRNA searching. These candidates will be assayed for co-orthogonality and engineered for diversity to allow tandem multi-codon replacement. In parallel, catalytic domains from reported ORSs, such as those capable of charging β-amino and α-hydroxy acids, will be screened and engineered for enhanced activity and modularity. Additionally, generation of a new flexizyme-mimetic catalytic domain will be targeted using in vivo selection, deep sequencing, and machine learning guided engineering. Finally, these developed tools will be used in an mRNA display campaign to search for novel and stable binders to the SH2 domains of Spleen-associated tyrosine kinase (SYK), a cytosolic kinase implicated in neuroinflammation, Aβ accumulation, and gliosis in Alzheimer’s disease.

NIH Research Projects · FY 2026 · 2024-12

Project Summary/Abstract Chronic musculoskeletal pain is a persistent, debilitating condition with high societal costs. Traumatic stress exposures (TSE) often precede the onset of chronic pain, and affect >90% of individuals in their lifetime. While repeated incidents of acute physical injury can lead to chronic pain, many individuals without serious physical injury report enduring musculoskeletal pain following TSE, termed chronic post-traumatic pain (CPTP). Despite high rates of CPTP, risk factors and mechanisms driving CPTP are poorly understood, impeding the development of promising therapeutic strategies to prevent or treat CPTP. To address this knowledge gap, I will perform a series of studies aimed at elucidating biopsychosocial mechanisms underlying the transition from acute pain following TSE to CPTP. Specifically, I will examine how one particularly influential epigenetic mediator type, DNA methylation, influences CPTP development by building on my recently published data showing that increased DNA methylation levels in the pro-opiomelanocortin (POMC) gene predict CPTP development. Through a series of mentored, didactic, and experiential trainings in statistical analysis of large longitudinal datasets, molecular and cell culture studies, and translational research design, I will be well positioned to accomplish two main study aims. One aim will examine whether stressful life events experienced prior to TSE increase POMC promoter methylation levels that prime individuals for CPTP persistence, and the mechanism by which this occurs. The other aim will assess whether increased POMC methylation levels influence downstream gene expression and function, and ultimately CPTP severity. Aims will be accomplished using complementary human cohort and molecular and cell culture studies. Overall, this F31 training award will provide me with a strong foundation in the skills needed to build a successful independent academic research career focused on identifying biopsychosocial mediators of complex human disorders such as CPTP, and the proposed studies have the potential to identify novel therapeutic targets for the prevention of CPTP.

NIH Research Projects · FY 2024 · 2024-12

PROJECT ABSTRACT Formerly incarcerated people are highly vulnerable to drug overdose and suicide deaths upon release from incarceration, yet there are few interventions to address these concerns. Existing programs in the criminal legal system, such as post-release supervision (PRS), can be improved to help acclimate individuals to life back in the community. While PRS helps individuals reintegrate into the community, it also significantly increases their risk of reincarceration. Moreover, systematic and individual racism in the criminal legal system has led to overrepresentation of racially minoritized people in prison and among individuals receiving PRS. Augmenting the length of the PRS sentence can allow optimization of PRS’s benefits to harms. My study proposes a way to reduce suicide and overdose mortality risk among the formerly incarcerated by providing evidence-based recommendations to modify existing PRS policies. The objectives of this proposal are to (1) determine and understand predictors of post-release supervision (PRS) assignment length, (2) establish how to optimize NC’s existing PRS program to reduce suicide and overdose mortality among formerly incarcerated people through altering their the PRS assignment length, and (3) identify optimal PRS terms that minimize the difference in risk of suicide and overdose mortality and reincarceration rates between white and racially minoritized groups, without increasing rates for any racialized group. To accomplish these aims, I will apply advanced causal inference methods to a linked dataset containing administrative and death records for all persons released from prison between January 1, 2000 and December 31, 2021. The completion of the proposed aims will significantly advance our understanding of interventions aimed at reducing post-release mortality, as well as provide an evidence-base for future PRS policy to reduce racialized disparities in not only PRS sentencing but also post-release suicide and overdose mortality outcomes among formerly incarcerated people. The training plan outlined in this proposal will equip the applicant, Monica Swilley-Martinez, with critical knowledge on the intersection of criminal legal system involvement and racialized health disparities, necessary skills in advanced epidemiologic methods and social and injury epidemiology, and experience with longitudinal analysis using large population-based administrative data. This plan will prepare her to successfully complete the proposed aims and to progress into a role as an independent, interdisciplinary epidemiologist working at the intersection of criminal legal system involvement and racialized disparities in the US. The applicant is incredibly well supported by an interdisciplinary group of epidemiologists and health disparities researchers, with the requisite expertise to support her doctoral research and prepare her for the next phase of her career.

NIH Research Projects · FY 2026 · 2024-12

PROJECT SUMMARY / ABSTRACT Cardiomyocytes (CMs) generate contractile forces to pump blood throughout the body. Contraction begins at the sarcomere and is coordinated by actin-myosin filament interactions. Coordinated CM contraction is maintained by adaptive responses to external stimuli. During postnatal heart development, changes in environmental oxygen levels and metabolites require CMs to undergo drastic remodeling to sustain adult functionality. Numerous of these changes are driven by transcriptional networks and RNA-processing mechanisms. Alternative splicing is an RNA-processing mechanism that allows single genes to produce more than one transcript, and potentially different protein isoforms with distinct roles in specific cells and tissues. Previously, our group demonstrated that the RNA-binding protein (RBP) called Fragile X messenger ribonucleoprotein 1 autosomal homolog 1 (FXR1) is regulated by alternative splicing in a tissue- and developmental stage specific manner: Fxr1 exon 15 is skipped in all fetal tissues but is highly included only in adult striated muscles. Recessive mutations in FXR1 exon 15 are linked to congenital multi-minicore myopathy, an inherited neuromuscular condition apparent at birth where individuals often experience cardiac failure. Others have demonstrated that sarcomere RNAs undergo local translation in CMs. During local translation, instead of protein production occurring in the perinuclear region, large cells like CMs shuttle the translational machinery, mRNAs, and RBPs to the intracellular compartment wherein the coded protein functions. FXR1 regulates the translation of numerous sarcomere mRNAs and localizes to domains far from the nucleus and endoplasmic reticulum. I hypothesize that FXR1 controls the organization and contractile capacity of adult CMs via regulation of local translation and inclusion of exon 15. First, I will establish FXR1's role in local translation at the sarcomere in cultured cardiomyocytes (AIM 1). Second, I will determine the role of FXR1 in the activation mechanosensitive transcriptional changes and signaling cascades in cultured cardiomyocytes (AIM 2). Third, I will identify the consequences of the developmentally regulated and striated muscle specific Fxr1 exon 15 on cardiac morphology and function by using our unpublished mouse model where exon 15 was deleted via CRISPR/Cas9 editing (AIM 3). My research will provide novel insights on the role of FXR1 in cardiac biology, which will have potential in the development of therapies for cardiovascular diseases. After completion of my F31 fellowship, I will have received multidisciplinary training from my sponsor, co-sponsor, and collaborators at the University of North Carolina at Chapel Hill, which will aid in my development as an independent cardiovascular researcher.

NIH Research Projects · FY 2025 · 2024-12

PROJECT SUMMARY/ABSTRACT This application is being submitted in response to the Notice of Special Interest (NOSI) identified as NOT-RM- 24-013. Angiogenesis is central to cancer development; together with Angiosarcoma and Hemangioma, Kaposi Sarcoma (KS) is the most angiogenic cancer in humans. KS is the most common cancer in people living with HIV worldwide. In the USA today, KS is concentrated in underrepresented minorities (URM) of black race or Hispanic ethnicity as well as in underserved and marginalized populations. The current frontline regimen for KS was developed in the 1980s. Despite its discovery over 25 years ago, no proper, immune-competent animal model existed for KS or aggressive angiosarcoma until last year, when we published a novel genetically engineered mouse model (GEMM) funded by RO1 CA250080. This novel GEMM fills a gap that has hampered novel therapy and vaccine developments for these cancers. The last experiment in our manuscript describes the first drug evaluation in this new cancer model. We propose repeating this experiment with an independent CRO to establish a repeatable, robust, and rigorous basis for the field. This will yield a best practices manual for drug testing in this model.

NIH Research Projects · FY 2026 · 2024-12

PROJECT SUMMARY AND ABSTRACT Following treatment with platinum-doublet cytotoxic chemotherapy and a PD1 inhibitor, treatment options for recurrent/metastatic (incurable) HNSCC are limited in efficacy. CSPG4 is a cell surface proteoglycan that we and others have shown to be highly overexpressed in HNSCC. We developed a CAR-T encoding the CD28 endodomain and have shown in vitro and in vivo activity. We now propose to conduct a phase I, single center, open-label study in adult patients with HNSCC that is platinum and PD1 refractory. We propose a modified 3+3 design with doses of 5 × 105, 1 x 106 and 5 x 106 cells followed by a dose expansion cohort of 9 more patients at dose to better characterize safety, to provide pilot data on efficacy, and to provide samples for correlative analysis. To fully characterize the impact of CAR-T on both tumors and T cells, we will collect pre- and post- treatment biopsies as well as serial blood samples. We will model changes in both the CAR-T cells and non-CAR T cells through qPCR, flow cytometry for markers of exhaustion (CD57, PD1, LAG-3), metabolomic profile, and stemness. We will utilize TCR-seq to demonstrate the clonality of non-CAR T cells in tumor, comparing pre-treatment biopsy to post- treatment biopsy as well as to blood at serial time points. Further, we seek to study how to overcome tumor escape mediated by heterogeneity in CSPG4 expression. We have reported a bystander mechanism of tumor killing by CAR-Ts associated with CD95 expression in tumor cells and Fas-L expression by activated CAR-Ts and observed that TNFα released by CSPG4.CAR-Ts upon antigen engagement induces the upregulation of CSPG4 in tumor cells. We will assess CSPG4, CD95 and TNFα expression and co-localization. Finally, we will discover the extent to which iC9.CSPG4.CAR-T cell therapy induces epitope spreading in treated patients, including analysis of T cell responses to the full landscape of HPV antigens and neoantigens. This will both increase our understanding of mechanisms of CAR-T efficacy and provide rationale for combination of CAR-T therapy with T cell antigen-directed therapy (e.g. therapeutic neoantigen vaccination and/or TCR-T therapy).

NIH Research Projects · FY 2026 · 2024-11

SUMMARY ABSTRACT Clostridioides difficile causes antibiotic-associated disease ranging from mild diarrhea to potentially fatal pseudomembranous colitis and is one of the most common causes of nosocomial infections in the U.S. C. difficile disease is largely mediated by the toxins TcdA and TcdB, which damage the intestinal epithelium and elicit inflammation. How C. difficile adapts to the intestinal environment to elicit virulence factor production is unclear. The expression of the genes encoding TcdA and TcdB is linked to expression of genes for flagellum biosynthesis and motility through SigD, a sigma factor encoded in the flgB operon. Factors that affect expression of the flgB operon therefore impact both motility and toxin production. Transcription of the flgB operon is subject to complex regulation. The signaling molecule c-di-GMP inhibits transcription of flgB, resulting in loss of flagella and reduced toxin production. In addition, a reversibly invertible ‘flg switch’ sequence upstream of flgB modulates expression and results in phase variation of flagella and toxins. This phase variation occurs stochastically and enables the generation of a phenotypically heterogeneous population consisting of flagellated, toxigenic bacteria and aflagellate, nontoxigenic bacteria and serves as a bet-hedging strategy to ensure survival. We have shown that flagellum and toxin production is coupled during infection of mice and preventing flg switch inversion alters infection outcomes. Recent work demonstrated that a c-di-GMP hydrolase also undergoes phase variation and modulates flagellar motility. These findings link c-di-GMP signaling and phase variation and point to a previously unknown strategy for coordinated modulation of virulence factors and development of phenotypic heterogeneity. The goal of this project is to define the interplay between the stochastic and regulatory mechanisms underlying the heterogeneous expression of flagella and toxins. We propose to use molecular genetics, single-cell analyses, and an animal model of C. difficile disease to address fundamental questions: Is phase variation of flagella and toxins regulated beyond stochastic inversion of the flg switch? Do certain environments result in coordinated phase variation of flagella and toxins with other factors? What is the impact of flagellum and toxin phase variation on C. difficile fitness during infection? Completion of the proposed studies will provide much needed mechanistic information on how C. difficile controls production of key virulence factors and the impact on C. difficile fitness in the intestinal environment.

NIH Research Projects · FY 2026 · 2024-11

ABSTRACT The clinical treatment of autoimmune diseases traditionally uses immunosuppression to curtail the pathogenesis of the autoimmune disease. An alternative for general immune suppression, is antigen specific tolerance. However, there is currently no antigen specific tolerance therapy in the clinics. We have recently discovered serendipitously that degradable microparticles comprised of the biopolymer acetalated dextran (Ace-DEX) can specifically bind to the surface of B cells both in vitro and in vivo. The binding of this biomaterial microparticle to B cells is due to the protein corona that is uniquely generated by Ace-DEX. The binding of this specific biomaterial to the B cell surface results in the generation of the tolerogenic cytokine IL-10. Uniquely this phenomenon is not observed when the microparticles are fabricated through emulsion, but only when they are fabricated through a spray drying technique. In comparison to other biomaterials, such as poly lactic-co-glycolic acid (PLGA) the observed phenomenon is significantly less compared to Ace-DEX. We observed less binding to B cells and diminished production of IL-10, indicating that our observed effect is biomaterial specific. Further, in the treatment of an animal model of MS, Experimental Autoimmune Encephalomyelitis (EAE), we show that administration of Ace-DEX MPs encapsulating Myelin Oligodendrocyte Glycoprotein (MOG) bound to B cells can drastically decrease the clinical score of EAE. The degree of reduction of clinical score for our treatment in the EAE model was greater than observed in other published antigen specific EAE treatments that used biomaterial particle systems. Further it is significantly improved in comparison to microparticles of other biomaterials (i.e. PLGA). At peak disease we show a drastic decrease in the symptoms of mice with EAE. In this grant we propose three specific aims. In aim one we will focus on biomaterial particle synthesis and characterize the protein corona on the surface of the microparticle to determine the protein(s) responsible for Ace-DEX MPs binding to B cells. We will additionally fully characterize the phenotype of the B cells most influenced by our Ace-DEX biomaterial MPs by using RNA-seq. In the second aim of our proposal, we will optimize our proposed therapy. This includes exploring the route of administration, B cell dose, MP dose, route, and other pharmaceutic parameters. Additionally, we will explore the biodistribution of our adoptively transferred B cells and the attached MPs. Also, we will look at general toxicity of our therapy, as well as the general immune suppression of our proposed therapy. Finally, in the third aim, we will attempt to elucidate the mechanism of action of our proposed therapy. This includes using in vitro methods exploring the interaction of B cells with other cells from the immune system. Additionally, we propose in vivo various knockout mice to explore the mechanism of our novel immunotherapy. Overall, the goal of our proposal is to elucidate the interaction between microparticles comprised of the biomaterial Ace-DEX and B cells.

NIH Research Projects · FY 2026 · 2024-11

PROJECT SUMMARY / ABSTRACT Many people with HIV (PWH) are living to older ages with the availability of efficacious and tolerable antiretroviral therapy, especially when diagnosed and linked to care early after infection. But healthy life expectancy among PWH is limited by comorbidities, including mental health, substance use, and age-related conditions affecting PWH at younger ages. Hospitalizations among PWH merit study as these sentinel events are valuable for understanding disease burden, trends in morbidity, health disparities, and healthcare utilization and needs. Hospitalizations are also a sensitive marker of overall health and serve as an indicator of high risk for exacerbation of HIV-related and comorbid conditions. Predicting hospitalization risk with a risk score can combine HIV-related clinical status, comorbid conditions, and social determinants of health (SDOH) into one measure, and can lead to interventions that prevent hospitalizations, alter clinical progression, and improve patient health. We do not yet adequately understand hospitalization causes or predictors of hospitalization among PWH. Therefore, in Aim 1, we will develop and implement a data-driven algorithm, incorporating a standardized adjudication protocol, for assigning validated hospitalization causes. We will use these validated causes to estimate trends and patterns in cause-specific hospitalization rates across calendar years and patient characteristics. In Aim 2, we will develop hospitalization risk scores for use in outpatient HIV care, using new innovative interpretable machine learning algorithms with integrated clinical, patient reported outcome and SDOH data. In Aim 3, we will assess feasibility, acceptability, and usefulness of using hospitalization risk scores as a clinical support tool in outpatient HIV clinical care via formative research. Stakeholders will be engaged through focus groups and semi-structured interviews. Stakeholder perspectives will be sought from patients, clinical providers, hospital and clinic administrators, epidemiologists, computer, data, and implementation scientists, and an ethicist. These aims have potential to improve the health of PWH across the lifespan, leveraging advances in epidemiology and data science and translating these to support HIV outpatient clinical care.

NIH Research Projects · FY 2026 · 2024-11

I aspire to be a principal investigator at a research-focused institution where I can study how RNA mediates gene regulation during early development. To this end, the activities proposed in this fellowship were designed to provide me with training in mechanistic aspects of RNA biology, developmental biology, computational analysis, scientific writing, and oral communication, which together will play essential roles in helping me establish a career in academic research. The overarching goal of my research is to delineate mechanisms by which long non- coding RNAs (lncRNAs) recruit chromatin-modifying (i.e., epigenetic) enzymes to regulate gene expression. Every step of development relies on dynamic gene regulation. As such, understanding how cells direct epigenetic enzymes to specific loci is essential to untangling the mechanisms that define early development. It has become clear that recruitment of epigenetic modifiers can be mediated by lncRNAs, the most potent of which, Xist, silences one of two X chromosomes in a process called X chromosome inactivation. However, it is not clear how lncRNAs encode the ability to recruit epigenetic modifiers. As the most powerfully repressive lncRNA known, Xist is an ideal model for decoding how lncRNAs recruit epigenetic modifiers and serves as a paradigm to understand other lncRNA-enzyme relationships. Xist-mediated silencing enzyme recruitment requires RBPs that are abundant in the cell, such as heterogeneous nuclear ribonucleoproteins (hnRNPs). Yet, paradoxically, hnRNPs bind thousands of other RNAs without contributing to transcriptional repression. The underlying sequence features and molecular interactions that allow Xist to exploit non-repressive RBPs to recruit epigenetic modifiers remain elusive. By focusing on a member of the hnRNP family, hnRNPK, which Xist requires to recruit the silencing enzyme complex Polycomb Repressive Complex 1 (PRC1), my research will 1) define the RNA sequence features that enable RNA to recruit PRC1 to chromatin and 2) determine how RNA and intrinsically disordered protein domains promote interactions between hnRNPK and PRC1. By defining the underlying RNA sequence features and the molecular interactions that enable PRC1 recruitment by RNA, I will identify a paradigm that will guide studies of other lncRNAs, RBPs, and silencing enzymes, which themselves are critical for embryonic development. These experiments will provide critical training in RNA biochemistry, genomics, computational biology, and quantitative microscopy, essential skills for studying RNA-mediated molecular mechanisms.

NIH Research Projects · FY 2025 · 2024-09

Project Summary/Abstract Alzheimer’s disease (AD), the most common cause of progressive dementia in adults over the age of 65, is a devastating disorder without effective treatment options. Available drugs treat late-stage symptoms rather than addressing disease-causing pathways. There is an urgent need for new protein targets that potentially act via previously unexplored mechanisms to halt AD progression. Human protein kinases represent a highly tractable class of targets that have largely been examined with respect to oncology, but which hold great promise in areas such as neurodegeneration. Protein kinase casein kinase 2 (CK2) is highly expressed in the mammalian brain and has many validated substrates that are critical in neural cell homeostasis and signaling processes across synapses. These roles have indicated that CK2 is a key regulator of neuronal function and that it may represent a novel target to treat neurodegenerative diseases like AD. Through extensive evaluation of our first library of pyrazolopyrimidines, we identified SGC-CK2-1 as a potent, selective, and cell-active CK2 chemical probe. Remarkably, despite years of research pointing to CK2 as a key driver in cancer, SGC-CK2-1 did not elicit a significant antiproliferative phenotype when tested in nearly 180 cancer cell lines. SGC-CK2-1 also does not demonstrate toxicity in human stem cell-derived neurons/microglia at doses required for CK2 inhibition. Guided by crystal structures and published data, we have developed a medicinal chemistry plan to address the metabolic liabilities of SGC-CK2-1 and develop it into a probe that is suitable for in vivo use. Part of this strategy involves also adding functionalities into our CK2 inhibitors that improve their blood–brain penetrance. Calculations and predictive software models will aid medicinal chemistry efforts and help prioritize compounds to be made. Many of these simulations will be corroborated with experimental data, including kinetic solubility, lipophilicity, microsomal stability, and CNS pharmacokinetic data, which will increase our confidence in their utility. Optimized CK2 inhibitors will be profiled in stem cell-based assays that model key pathogenic signaling pathways in AD related to neuroinflammation, a process we have shown to be at least partially regulated by CK2. Our lead CK2 chemical probe candidates will be dosed in a 3xTg mouse model of AD to validate CK2 target engagement in vivo. All publications that have attempted to characterize CK2 function using a CK2 inhibitor have used a sub- optimal compound, most often CX-4945 or TBB, that suffers from potent inhibition of off-target kinases and other liabilities, including broad antiproliferative activity, that preclude its use in AD. Despite these issues, CX-4945 has been dosed systemically in humans for oncology indications, which confirms that clinical inhibition of CK2 is tolerated. Development of a potent and selective in vivo probe targeting CK2 that lacks broad antiproliferative activity will enable confirmation of its putative role in AD for the first time.

NIH Research Projects · FY 2025 · 2024-09

ABSTRACT Diabetes affects over 37 million people in the US with the disease burden disproportionately borne by American Indian, African American, Hispanic/Latino, and rural subgroups (our priority populations). Despite progress in diabetes treatment, glycemic and cardiometabolic (e.g., blood pressure) outcomes are not improving. Healthy eating, physical activity, medication adherence, and self-monitoring of blood glucose are essential self-care practices. While Diabetes Self-Management Education and Support (DSMES) programs are effective at improving these self-care practices, they are significantly under-utilized nationwide, with only 5% of newly diagnosed Medicare beneficiaries and 6.8% with private insurance accessing DSMES within one year of diagnosis. Innovative implementation strategies are needed to bridge the gap between research and practice. Prevention Research Centers (PRC) are well positioned to lead this effort. We propose building on our long experience in the PRC Network to: 1) continue growing our prevention research capacity; 2) support a core research project to identify more effective strategies for implementing, scaling, and sustaining DSMES, with a focus on eliminating health disparities/inequities; and 3) contribute to and learn from PRC Network partners to improve public health service delivery in partnership with state and local health departments; community and tribal organizations; and national organizations. Together, we will put feasible evidence-based interventions into national practice, addressing health equity as the highest priority. Our core research project will focus on understanding how to implement DSMES more equitably in those at highest risk by examining contextual factors and key drivers of DSMES utilization, such as reimbursements, referral policies/practices, and willingness of persons with diabetes (PWD) to participate. We propose a 3- phase study to address implementation challenges for rural residents in NC with high diabetes prevalence. Phase I: Understand complex determinants of uptake and sustained DSMES use in priority populations to adapt program delivery. Use systems and implementation science to understand barriers and facilitators of DSMES uptake, prioritize key leverage points for change, assess organizational readiness for DSMES implementation, and identify cultural adaptations for DSMES materials. Phase II: Test the effects of adapted DSMES program implementation. Use a hybrid trial Type 3 effectiveness-implementation design (12 sites: 6 health departments + 6 Federally Qualified Health Centers/similar primary care clinics and 240 PWD [20 participants per site]). Phase III: Disseminate and translate research products to state and national audiences through established partnerships and stakeholder support. With program staff and PWD, conduct a final review of the adapted DSMES to anticipate and address potential implementation, dissemination, and translation challenges and develop a DSMES Toolkit companion guide and marketing plan for widespread dissemination.

NIH Research Projects · FY 2025 · 2024-09

Abstract Arthritis, a highly prevalent, debilitating, and costly chronic disease, affects 53.2 million adults in the United States, with over 32 million having osteoarthritis (OA), the most common form. OA is managed mainly in primary care settings; and evidence-based (EB) guidelines promote self-management strategies, such as physical activity (PA), weight management, and Arthritis-Appropriate, EB Interventions (AAEBIs) as first line interventions to improve OA symptoms. Health Care provider (HCP) counseling for these interventions improves patient engagement, yet counseling rates remain inadequate, and the programs are underutilized. This issue is compounded among underrepresented populations such as Blacks, Latinos, and rural citizens, who are not only more negatively impacted by arthritis but also experience disparities in healthcare for arthritis management strategies. To address the gap in HCP referrals to and patient engagement in first line EB behavioral interventions for OA, as well as address disparities in arthritis-related experiences and management, there is an urgent need for an efficient and practical framework for engaging patients with arthritis in AAEBIs. The overall goal of this proposal is to respond to SIP-24-009 as follows: 1) To establish an Arthritis Management & Wellbeing Research Network Collaborating Center that will participate in the Arthritis Management & Wellbeing Research Network (AMWRN). The Collaborating Center will also address a stated research priority to pilot test, evaluate, and translate OACareTools+, an innovative and efficient intervention developed by the OAAA, that represents an HCP-informed and inexpensive solution for integrating HCP screening, counseling, and referral to increase engagement of diverse patients with arthritis in AAEBIs. 2) To establish an Arthritis Management & Wellbeing Research Network Coordinating Center (Component B) that will coordinate arthritis research, translation, and dissemination activities. Coordinating Center responsibilities include a) Facilitating the AWMRN through providing leadership, forming and supporting an AWMRN Community Advisory Group, establishing and facilitating AMWRN working groups, and coordinating Advisory, Brainstorming, and Consultative sessions; b) Developing and executing a comprehensive dissemination plan; c) Evaluating AMWRN activities and impact. Together, the efforts from these Components will support the work of the AMWRN to identify and promote awareness of arthritis-related research priorities and findings, conduct and disseminate research, and translate science into actionable, scalable public health practices to benefit diverse adults with arthritis.

NIH Research Projects · FY 2025 · 2024-09

Abstract Lipids circulate in the blood in lipoproteins including chylomicrons and very low-density lipoproteins (VLDLs). Lipoprotein Lipase (LPL) is the main enzyme that hydrolyzes the triglycerides from circulating lipoproteins into free fatty acids that can be taken up by cells. Without LPL, dangerously high levels of lipoproteins circulate in the blood, which can lead to cardiovascular disease, amongst other diseases. LPL inhibitors, known as angiopoietin-like (ANGPTL) proteins have key roles in the regulation of lipid metabolism. ANGPTL3 is a potent inhibitor of LPL. ANGPTL8 can form a complex with ANGPTL3 which results in even greater inhibition of LPL. ANGPTL8 is only found in the bloodstream in complex with ANGPTL3. However, where this complex forms, and why ANGPTL8 requires ANGPTL3 for secretion remains a mystery. This proposal aims to understand why ANGPTL8 is unstable when it is not in a complex with ANGPTL3, as well as visualizing the ANGPTL3/8 complex trafficking dynamics.

NIH Research Projects · FY 2025 · 2024-09

PROJECT SUMMARY/ABSTRACT Systematic reviews (SRs) of interventions might report inconsistent results and conclusions about patient safety, and they might differ from other sources of patient safety information such as real-world evidence (RWE) and drug labels. SRs underpin clinical guidelines by the US Preventive Services Taskforce, professional societies, and national insurers. Guidance says that SRs should address both harms and benefits of interventions, yet most SRs are designed to assess benefits and consider harms as secondary outcomes. Moreover, guidance for conducting and reporting SRs includes scant advice about the different types of data, and different study designs, for harms compared with benefits. In a preliminary study, we found that 70 SRs reached different conclusions about the harms of a single drug, and conclusions in SRs were not consistent with the drug label. Inconsistency suggests that some conclusions about harms in SRs might be wrong. In this study, we propose to use innovative methods, including natural language processing (NLP), to assess the consistency of methods, results, and conclusions about patient safety in >19,000 SRs published from 2004— 2024. Advances in NLP have created new opportunities for evidence synthesis using models that can identify and interpret text for extraction (e.g., from journal articles). Specifically, we will leverage state-of-the-art NLP tools and methods, including those based on large language models, to extract and synthesize evidence on harms from SRs, RWE studies, and drug labels at a granularity that has not been attempted previously. Then, we will compare SRs that include the same drug (we estimate there are >4,000 overlapping SRs), and we will compare SRs with RWE and drug labels. We will investigate whether SRs use methods for assessing harms that might lead to inconsistent conclusions about patient safety. We will also investigate whether SRs use methods that lead to differences compared with RWE and drug labels. For example, SRs often exclude RWE. Moreover, SRs are usually limited to one health problem; by comparison, drug labels include harms that could occur when people take the drug to treat different health problems. Highlighting specific drugs for which SRs might misrepresent risk of harm, and identifying why certain conclusions might be wrong, could immediately help patients and healthcare providers make better-informed decisions. Using our findings, we will develop improved guidance for synthesizing and reporting harms in SRs, which should ultimately improve conclusions about patient safety in SRs and clinical guidelines. Specifically, we aim to answer the follow questions: Aim 1. Are results and conclusions about patient safety in SRs of the same drug consistent? Aim 2. Do SRs use RWE, and do the results and conclusions of SRs address harms found in RWE? Aim 3. Is information about harms in SRs consistent with information in drug labels? Aim 4. What recommendations could improve the synthesis and reporting of harms in SRs?

NIH Research Projects · FY 2025 · 2024-09

PROJECT SUMMARY/ABSTRACT For more than 20 years, the Cancer Prevention and Control Research Network (CPCRN) has been a national leader in developing and implementing effective interventions that decrease the burden of cancer in diverse and medically underserved communities. Since 2004, the University of North Carolina (UNC) has hosted both the CPCRN Coordinating Center and a Collaborating Center (Comprehensive Cancer Control Collaborative of North Carolina (4CNC)). 4CNC's work in the last cycle included co-leading 6 work groups, producing 161 peer- reviewed publications (41 cross-center publications), and completing a successful core project which subsequently led directly to a multicenter NCI-funded R01. The Coordinating Center's work included shepherding more than 200 members through a workgroup formation consensus process, supporting workgroup communication and functioning, sharing resources, and implementing, evaluating the implementation of the strategic plan of CPCRN, and coordinating the publication of a 21-article supplement in Cancer Causes & Control featuring 118 unique CPCRN members as authors. UNC as the Coordinating Center demonstrated our ability to achieve these functions, while maintaining stability during the COVID19 pandemic and despite significant turnover in network membership between funding cycles. Given our strong history of supporting collaboration while embracing new members and innovative ideas, we are well prepared to guide the Network through another transition because of our long history as committed stewards of the CPCRN's mission, vision, and action plan. The overarching goal of the Network and the UNC Collaborating Center and Coordinating Center is to reduce the burden of cancer through the development, dissemination, and implementation of community-engaged, evidence-based interventions. Our specific aims are to: (1) Develop and pilot test the Pharmacy-Assisted Cessation of Tobacco and Screening (PACTS) intervention to increase access to lung cancer screening shared decision-making in medically underserved populations through integration with pharmacy-based tobacco cessation programs. (Collaborating Center); (2) Lead and collaborate in community-engaged, cross-center projects to improve cancer prevention and control (Collaborating Center); (3) Facilitate and support collaborative research linkages among Network members, Network Affiliates, Scholars and national, state, and local community partners to advance the implementation of proven cancer prevention and control strategies in practice and policy (Coordinating Center); and (4) Evaluate and disseminate the products and impact of Network activities (Coordinating Center). The expected long-term impact of this work is the significant reduction in cancer burden and cancer health disparities achieved through collective network contributions to science, practice and policy that extend beyond what any individual center could achieve on its own.

NIH Research Projects · FY 2025 · 2024-09

ABSTRACT Vaccine hesitancy, or the state of being conflicted about or opposed to getting vaccinated, is a “top 10” threat to public health, according to the World Health Organization. In the United States, vaccine hesitancy among parents has recently emerged as a particular concern because exemptions to kindergarten vaccination mandates have increased almost 50% since the onset of the Covid-19 pandemic. At the same time, national vaccination coverage among kindergarten-age children has fallen. For example, the proportion of kindergarteners vaccinated against measles has dropped below the 95% needed to prevent community-level transmission to 93%, with even lower coverage found in states such as Georgia (88%), Wisconsin (87%), and Idaho (81%). Despite the public health importance of vaccination mandates, surprisingly little is known about why parents are filing exemptions more often or what communities can do to support parents in ways that prevent exemptions. School-based interventions are a promising way to address this research gap because they can influence vaccine hesitancy and behavior by addressing vaccine-related perceptions, social norms, and practical issues like vaccine accessibility. Thus, we propose to partner with school communities in Georgia, Wisconsin, and Idaho to develop an intervention to prevent vaccine exemptions. In Aim 1, we will characterize multilevel drivers of exemptions to kindergarten vaccination mandates. Working with 9 school communities with high exemption rates, we will use ethnographic methods, including observations and in-depth interviews, to understand the reasons for rising exemptions. In Aim 2, we will develop a multilevel intervention to reduce vaccine exemptions, in partnership with school communities. Using the participatory method of group concept mapping, we will collaborate with parent partners and our school health advisory board to prioritize targets for our intervention. Together, we will develop intervention components drawing from evidence-based strategies for increasing vaccine uptake. In Aim 3, we will pilot the vaccine exemption intervention in partnership with school communities. We will iteratively deliver and adapt our intervention in our 9 study schools over two years. Our multimethod evaluation will examine pre/post- intervention changes in intermediate outcomes related to vaccine perceptions, social norms, and practical issues. To guide future implementation efforts, we will also evaluate implementation outcomes such as acceptability, reach, and delivery cost. Exploratory analyses will assess changes in exemption rates and vaccination coverage. The proposed study is designed to further the ARISe network’s goal of advancing the science of immunization services by providing actionable data and scalable solutions to the growing problem of exemptions to kindergarten vaccination mandates. If successful, this research will lay the groundwork for a future cluster randomized effectiveness-implementation trial to scale up our intervention and further evaluate its impact on exemption rates and vaccination coverage.

NIH Research Projects · FY 2025 · 2024-09

Project Summary/Abstract Despite significant advances in omics studies and laboratory observations, identifying the causal mechanisms for late-on- set Alzheimer's disease (AD) and AD-related dementia (ADRD) remains a challenge due to their multifactorial inheri- tance, which is heterogeneous across subjects and populations. In dementia studies, only a subset of relevant data is typi- cally collected from each participant, resulting in a biased exploration of AD pathogenesis. To address these limitations and respond to the NOT-AG-21-045 call for proposals on harmonizing complex data sets relevant to AD/ADRD, we pro- pose the development of a comprehensive AD-related knowledge graph (AD-KG) platform. This platform will inte- grate and harmonize data from multiple curated resources, literature, and a large-scale AD-related database with multiple types of high-dimensional data, including imaging, genetics, and clinical variables, from different studies with different missing-data patterns. Our inspiration for this proposal comes from the success of knowledge graphs (KGs) as a foundation for cognitive systems in industry, such as Microsoft XiaoIce. We propose to achieve four aims: Aim 1: Con- struct a dynamic AD-KG by utilizing multiple curated resources, literature, and individual data across different domains and studies for AD. Aim 2: Develop an omics knowledge graph (OKG) platform for harmonizing, imputing, and repre- senting AD-related multi-omics data. Aim 3: Develop a neuroimaging knowledge graph (NKG) platform for presenting, imputing, and representing AD-related neuroimaging data and a neuroimaging omics knowledge graph (NOKG) platform for neuroimaging-omics association maps. Aim 4: Analyze data from the large-scale AD-related database and verify the effectiveness of the newly developed AD-KG for clinically transformative research. The construction of OKG, NKG, and NOKG will complement the development of AD-KG. By developing a comprehensive AD-KG platform that integrates diverse data sources and types, we can facilitate more comprehensive research in AD and ADRD, leading to the develop- ment of new diagnostic and therapeutic approaches. Achieving these aims will offer unique analytic and data science ca- pabilities necessary for AD-related cognitive systems and greatly enhance cognitive techniques through innovative use of semantics and graphs to address complex data modeling, blending, and analytic challenges. To achieve our proposal aims, we have formed a team of experts in cognitive systems, knowledge graphs, statistical genetics/genomics, AD genetics, neuroimaging analysis, neuroscience, and statistics. Clinically, achieving these aims will enhance the identification of new genes and genetic pathways, leading to risk and protective factors for AD and inspiring novel therapeutic approaches. We plan to share our AD-KG, new cognitive tools, and AD-KG-based structured data with the research community through NIAGADS and other NIA infrastructure.

NIH Research Projects · FY 2024 · 2024-09

Project Summary/Abstract One of the fundamental scientific problems in neuroscience is to have a good understanding of how cognition and behavior emerge from brain function. Tremendous strides have been made over the past decade to elucidate the biological mechanism that creates remarkable oscillatory patterns of functional fluctuations. From a data science perspective, functional neural activities manifest geometric patterns, as evidenced by the evolving network topology of functional connectivities (FC) even in the resting state. Since the co-activation of spontaneous functional fluctuations is often encoded in a symmetric and positive-definite (SPD) matrix, it is more reasonable to put the spotlight on the geometric patterns of evolving functional connectomes on the Riemannian manifold of SPD matrices, instead of using Euclidean operations. In this regard, we will develop a novel computational model to understand the control mechanism underlying functional dynamics through the lens of cutting-edge manifold, control theory, and machine learning technologies. The overarching goal of our project is to establish a new underpinning of the relationship between analytic measurement of control mechanisms and cognitive functions, which allows us to understand the mechanism of how the human brain works and discover new imaging biomarkers with great mathematics guarantee. To do so, we define a trajectory of the complex neural system to be the temporal path on the Riemannian manifold that steers the human brain traverses through diverse cognitive states. In this regard, we will first develop a deep end-to-end model to uncover the characteristic equation of dynamical systems from the time series of FC matrices in Aim 1. The backbone of our deep model is a data-driven linearization process that projects high-dimensional manifold instances to a subspace such that the nonlinear dynamic mechanism of evolving SPD matrices on the manifold can be dissected using a well-studied linear model on the latent vector space. Furthermore, we integrate the notion of optimal control into the deep model, which allows us to (i) uncover the multi-frequency oscillatory functional network modes for brain state transitions and (ii) measure the controllability for not only the whole brain but also each brain region. We will address the following scientific questions in Aim 2 using the existing unprecedented amount of human connectomes: (i) What is the relationship between brain controllability and visual working memory? (ii) In what control mechanism does each brain region contribute to the altered functional dynamics associated with auditory verbal hallucinations (AVH)? (iii) What is the statistical power associated with the identification of disease-specific connectomes using the newly established system-level understanding of functional dynamics? Successfully executing this project will shed new light on elucidating the working mechanism that links brain function and cognition, which is instrumental in understanding cognitive control in the neuroscience field. We will release the software to facilitate other human connectome studies.

NIH Research Projects · FY 2025 · 2024-09

ABSTRACT Glioblastomas rank among the most lethal of all human cancers. Current therapy includes maximal surgical resection, followed by combined radiotherapy and oral chemotherapy (temozolomide), and adjuvant temozolomide. However, current glioblastoma therapy offers only palliation. Median survival for glioblastoma patients has been reported to be 15-21 months, but these data are derived from patients with favorable age and performance status. Glioblastoma ranks among the human cancers most thoroughly studied, yet precision medicine efforts have demonstrated very limited efficacy. Like many cancers, glioblastomas display altered metabolism that promotes tumor growth, often through the generation of metabolites that promote epigenetic reprogramming. In the current proposal, we focus on the role of specific essential amino acids that appear to the preferentially taken up by brain tumor cells. Upon cellular entry, amino acids can undergo catabolism to generate bioactive intermediates that can alter the chromatin landscape and modulate tumor- immune interactions. Based on this background, we investigated differential expression of metabolic pathways and amino acid levels between glioblastoma cells and neural stem cells, revealing critical selective dependencies in tumor cells due to both altered gene expression and genetic lesions. As a result, glioblastoma cells suppress the anti-tumor immune response. In the proposed studies, we will investigate the molecular and cell biology mechanisms through which selective amino acid metabolism regulates brain tumor growth and immune interplay. Systems to be used include patient-derived cultures, organoids, and xenografts to determine the molecular determinants of amino acid catabolism and epigenetic reprogramming. To translate these efforts into novel preclinical paradigms, we propose to use dietary manipulations that have been developed for treatment of inborn errors of metabolism, including those that affect the brain. These dietary interventions can potentially be combined with other therapies, including targeted therapies and immune checkpoint inhibitors, to target glioblastomas. Collectively, the proposed studies will lay the foundation for improved understanding of tumor metabolism in brain tumor biology with possible application to oncologic care.

NIH Research Projects · FY 2025 · 2024-09

The increasing availability and scale of omics data have revolutionized our ability to understand complex biological processes underlying health and disease. Such biologically informed insights are aligned with the notion of precision medicine and have the potential to improve diagnoses, prevention, and treatment. In the oral health domain, multiple omics data layers (e.g., genomics, metagenomics, transcriptomics, metabolomics), intended to capture aspects of otherwise unobservable biology, are increasingly being collected in oral health studies. However, methods for powerful and informative integration of information gained from these multiple data layers remains elusive. The focus of this proposal, early childhood caries (ECC), is the most common non-communicable childhood disease. ECC is defined as dental decay in children under the age of 6. It remains a clinical and dental public health problem and confers substantial and multi-level human and economic impacts. The advent of precision oral health care, based upon a new, microbially-informed understanding of ECC, is expected to shed light onto mechanistic aspects of the disease processes and reveal new ways to prevent it. We propose to develop new statistical methods and machine learning (ML) strategies that handle high dimensionality and excess zeros in comprehensive integrative analyses of metagenomics (MTG), metatranscriptomics (MTX), and metabolomics (MTB) and apply them to characterize the ECC-related supragingival biofilm dysbioses, biochemical activities, and their interactions in a community-based sample of 300 preschool-age children, enrolled in a large-scale investigation of early childhood oral health in North Carolina. We propose to develop statistical methods to jointly identify regulatory modules across MTG, MTX, and MTB associated with ECC. Furthermore, we seek to develop interpretable machine learning approaches to predict binary (e.g., case status) or quantitative ECC experience (e.g., dmfs index) using MTG, MTX, and/or MTB. We anticipate that our study will provide novel insights into the microbial basis of ECC, identify microbial and biochemical disease biomarkers, highlight potential targets for prevention and treatment, and establish a powerful research platform that can be extended to characterize other microbiome-related diseases.

NIH Research Projects · FY 2025 · 2024-09

Abstract: 3D human neurocircuits to determine the role of microglia in AUD and Alzheimer’s neuronal pathology. Altered neuronal metabolism, neuronal activity, and neurodegeneration are key features in both alcohol use disorder (AUD) and Alzheimer’s disease (AD). AUD and AD are linked, with alcohol related brain damage (ARBD) being one of the strongest risk factors for AD. However, the mechanisms underlying altered neuronal metabolism in these diseases, and its impacts on neuronal activity and neurodegeneration are unknown. We reported that proinflammatory microglia promote ARBD and alcohol-enhancement of AD pathology. We now find that microglia promote lipid accumulation in neurons with alcohol. Therefore, we hypothesize that alcohol alters neuronal activity and survival to promote AUD and AD through a novel microglia- neuronal metabolic link. In AUD and AD, brain glucose metabolism is reduced. ARBD correlates with this reduction, suggesting metabolic changes promote pathology. Recent studies suggest microglia may also contribute. Proinflammatory microglia undergo a glycolytic burst that can produce high levels of lactate and express the lactate exporter MCT4. We hypothesize that the proinflammatory microglia induced by alcohol deliver excess lactate to neurons, causing a metabolic imbalance that alters neuronal activity and promotes neurodegeneration. Alcohol (i.e. ethanol) is metabolized by oxidative and non-oxidative pathways (OME and NOME) to produce acetate and fatty-acid ethyl esters (FAEEs) respectively. Acetate is converted to lipids through acetyl-coA. Microglia, but not neurons, have OME machinery. Thus, we hypothesize microglial OME releases acetate to disrupt neuronal lipid metabolism. We recently found that accumulation of neuronal lipids caused by alcohol promotes AD pathology. Amyloid-β (Aβ) is normally degraded within neurons by lysosomes. Ethanol increased neuronal lysosomal lipid to cause lysosomal damage and prevent neuronal degradation of intraneuronal Aβ. Inhibition of proinflammatory microglia prevented neuronal lipidosis, identifying microglia as regulators of AD-promoting changes in neuronal metabolism. However, the mechanism underlying this microglia- neuronal link in AD are unknown. Given the impact of ethanol on microglial activation, and consequences of ethanol metabolism, we hypothesize energetic metabolites produced by microglial glycolysis as well as microglial ethanol metabolism combine to produce neuronal lipidosis, lysosomal dysfunction, altered neuronal activity, and neurodegeneration associated with AUD and AD. We propose to employ novel human 3D reciprocal brain circuits (h3D-rC) to test the role of microglia in neuronal metabolism and activity (Aim 1-2), alcohol-induced neurotoxicity (Aim 1) and Aβ accumulation (Aim 2). These reciprocal circuits are formed using human IPSC- derived neurons grown in proprietary microfluidic culture platforms (XonaTM) that enable the bidirectional growth of axons between two distinct compartments and mimics the three dimensional and multi-cellular features found in vivo; it also reproduces the dynamics caused by both outgoing projections and inputs from other brain regions.

NIH Research Projects · FY 2024 · 2024-09

ABSTRACT The impact of genetic testing for disease prevention hinges on cascade screening, the process of systematically identifying and testing relatives in families with a genetic condition. Lynch syndrome is a genetic condition that confers an increased lifetime risk of cancer. Unfortunately, only half of first-degree family members with Lynch syndrome receive cascade screening, representing a missed opportunity in cancer prevention. Let's Talk is a novel intervention to promote and support cascade screening in families with Lynch syndrome. Developed using intervention mapping, a 6-step, stakeholder-engaged methodology for developing theory-based interventions, the workbook intervention addresses barriers to cascade screening through information chunking, guided practice, planning coping responses, and gain frame messaging for patients, their provider and family. Preliminary data have demonstrated that the content of Let's Talk, in a paper-based format, is acceptable to patients with Lynch syndrome, and all patients reported that they would recommend its use to someone recently diagnosed with Lynch syndrome. In addition, all patients in our usability study endorsed the development of an interactive, online version, which could improve dissemination, given changes in genetic counseling workflows due to COVID-19, and could facilitate ongoing patient support through follow- up messaging. Thus, the overall objective of this project is to (1) adapt and refine an interactive online format for Let's Talk based on patient preferences and user feedback, and (2) pilot test Let's Talk to assess its feasibility by measuring implementation (primary) and effectiveness outcomes. The expected outcomes of this project will move the field forward in tackling challenges associated with cascade screening in Lynch syndrome and other hereditary conditions. This work will provide foundational data for a future R01 application to test the effectiveness and implementation of Let's Talk for increasing cascade screening uptake and identification of relatives with Lynch syndrome across diverse care settings.

NIH Research Projects · FY 2025 · 2024-09

ABSTRACT Clinical virology is predicated on the workflow of analyzing small sample volumes (to minimize patient discomfort, storage, and fit legacy infrastructure) for a single analyte, i.e., virus, with utmost precision. The human virome project (HVP) does not share these restrictions. The HVP priority tissues of urine, stool, saliva, and blood can be acquired from healthy people in a 50 – 500 ml sample size. For instance, the Red Cross makes normal plasma available in 500 ml bags, and NGS allows for the characterization of all human viruses in a single reaction. This proposal responds to RFA-RM-23-018 with the development of two novel tools: AIM 1, a virus purification pipeline that utilizes larger volumes to achieve < 1 genome copy/ ml sensitivity; AIM 2, a single virion detection pipeline to provide an accurate denominator of how many intact virions a given NGS sequence set is representing. We hypothesize that Viral Direct Counts (VDC) akin to bacterial direct counts will become the essential parameter for integrating the studies in the HVP.