University Of Alabama At Birmingham

NIH Research Projects · FY 2026 · 2024-09

Project Summary The combined opioid and stimulant use epidemic is an escalating public health emergency with numerous biological and psychological drivers and consequences, which are amplified in people with HIV (PWH) and other marginalized groups. We and others have described significant immune alterations in PWH and individuals that inject opioids and/or stimulants including increased systemic inflammation and lymphocyte dysregulation, including among B cells. This heighted inflammatory state and distorted B cell function likely contribute to increased risk and severity of infections and inflammatory co-morbidities including cardiovascular, kidney, liver, and autoimmune diseases. Although anti-retroviral therapy (ART) suppresses HIV, its ability to restore immune homeostasis is incomplete, resulting in accelerated immunological aging and associated co-morbidities; subsequently development of adjunctive interventions to mitigate these complications is ongoing. Active substance use, intoxication, and related behaviors associated with injection drug use can impact HIV viral dynamics and immune competency. Among people who inject drugs (PWID) that do not have HIV, there is a high risk for acquiring HIV, clear indications of reduced effectiveness of HIV vaccines, and altered viral dynamics in the acute stage of HIV infection; these unique factors highlight the challenges of HIV vaccine development for PWID. There is an unmet need for interventions that can restore immune homeostasis in PWID in order to improve responses to pathogens and minimize inflammatory-related co-morbidities. Metformin (MTF), the most widely prescribed drug for type 2 diabetes (T2D), may be such an intervention. Animal and human studies have demonstrated MTFs ability to reduce inflammation and enhance vaccine responses. Our central hypothesis is that MTF can mitigate the inflammation and immune dysregulation that is prevalent in PWID including among PWH, restoring immune homeostasis and responsiveness. This will be addressed through a placebo controlled, randomized clinical trial of MTF in PWH and non-PWH with a history of recent injection drug use including opioids and stimulants. Assessment of Hepatitis A/B and pneumococcal vaccine responses during this trial will allow examination of adaptive responses to pathogens of concern within these populations and serve as a surrogate for assessing their potential response to a future HIV vaccine. Vaccine outcomes will provide a metric to complement the integrated behavioral and high-resolution functional analysis of systemic and mucosal inflammation and immunity, providing mechanistic insights relevant to HIV prevention and pathogenesis. Our hypothesis will be addressed through the following aims: 1) determine the ability of MTF to mitigate inflammation and improve vaccine response in PWID, 2) determine the ability of MTF to normalize B cell phenotype and function in PWID, and 3) determine the influence of MTF on mucosal inflammation and immunity.

NIH Research Projects · FY 2025 · 2024-09

PROJECT SUMMARY Global diabetes prevalence is nearing 10%, and despite advancements in treatments, compared to non-diabetic, individuals with diabetes have 2-fold higher rates of heart failure, as well as increased mortality due to cardiovascular disease. Specifically, diabetic cardiomyopathy (DCM) is a diagnosis based on cardiac insufficiency attributable only to diabetes, and characterized by the triad of cardiac hypertrophy, fibrosis, and apoptosis. We believe these are consequences of and contributors to epigenetic changes that regulate expression of genes responsible for the pathological state. Epigenetic changes are stable, yet reversible modifications to chromatin and genetic material (e.g., histones, DNA). It is an established regulator of gene expression associated with diabetes and heart failure—with the field studying the intersection of these topics still relatively young. Additionally, our prior work found that glucose can signal through a specific post-translational protein modification, O-linked -N-acetyl-glucosamine (O-GlcNAc), and building upon current literature, our lab has shown using our novel mouse model that chronically enhanced O-GlcNAc is sufficient to cause pathology associated with diabetic hearts. My work focuses on identifying and studying molecular pathways regulated by DNA methylation changes during chronic O-GlcNAc which lead to pathology. Upon RNA-sequencing, my prior analysis identified significantly increased NADPH Oxidase 4 (Nox4) with chronically increased cardiac protein O-GlcNAc. Similarly, methylation-sequencing of DNA from cardiac tissue of diabetic mice revealed hypo- methylation (an epigenetic mark associated with increased gene expression) at the Nox4 promoter associated CPG island. Nox4 is a significant producer of reactive oxygen species (ROS), and its activity is governed by levels of expression. The field of Nox4 in the context of chronic diabetic hearts is relatively young, and little is known about its regulatory mechanisms. With these opportunities and encouraging preliminary data, I seek to build upon the rigors of past research to contribute novel knowledge and develop resources to study Nox4’s regulation and role in chronic diabetic hearts. I hypothesize that with chronically enhanced protein O-GlcNAc (a key facet of diabetic hearts), cardiac Nox4 is induced via DNA hypomethylation, and its upregulation is necessary to promote cardiac dysfunction and pathology. The proposal will test the following two aims: (1) Determine the mechanism of O-GlcNAcylation initiated DNA methylation changes leading to cardiac Nox4 upregulation. (2) Establish that Nox4 depletion can prevent cardiac remodeling seen during chronically enhanced cardiac protein O-GlcNAc. In summary, this proposal will determine a new regulatory mechanism for Nox4 and provide foundational research for the development of precision therapeutics to treat underlying pathological mechanisms driving disease in diabetic hearts. This proposal will also provide the foundation for my career as a physician- scientist with the scientific reasoning, research, and translational skills in cardiovascular research/medicine.

NIH Research Projects · FY 2025 · 2024-09

Project Summary/Abstract Chronic exposure to psychostimulants leads to maladaptive long-lasting molecular and functional changes in the brain of vulnerable individuals that may contribute to susceptibility to Substance Use Disorder (SUD). Despite significant advances in understanding genetic and epigenetic factors that may underlie SUD, few effective treatment options exist. In order to advance our knowledge to therapeutic avenues, we need to overcome some of the existing technical and practical limitations of existing models, including the inability to characterize drug-induced changes nervous-system- wide with cellular resolution and the lack of in vivo high-throughput screening platforms for putative regulators and therapeutic compounds. The nematode Caenorhabditis elegans is a simple and well-characterized model organism that has led to many fundamental discoveries in conserved biological mechanisms. The genetic amenability and the compact nervous system allow us to conduct high-throughput screens and to analyze the entire nervous system with single neuron resolution, respectively. Combining advanced genetic, genomics, microscopy, and behavioral approaches, we will generate comprehensive molecular (transcriptome and chromatin landscape), behavioral, and neuronal activity atlases in response to acute vs. chronic exposure to cocaine. Leveraging these atlases, we will use high-throughput screening approaches in C. elegans to identify genetic regulators that underlie nervous-system-wide molecular and functional changes as a result of drug exposure. Finally, the genetic amenability of the C. elegans model allows us to causally examine the mechanistic roles of these regulators in drug-induced plasticity with unprecedented locus and cellular specificity. By establishing these approaches and platforms in the C. elegans model with cocaine, we can investigate other classes of drugs in the future, and open up new avenues for disease mechanism investigation and therapeutic identification for SUD.

NIH Research Projects · FY 2024 · 2024-09

PROJECT SUMMARY/ABSTRACT Data analytic tools, such as natural language processing and machine learning, are a subset of artificial intelligence that hold promise for advancing health services research (HSR) in a world of growing complexity. Though many health services researchers have some familiarity with these methodologies, the adoption and application of emerging data analytics in HSR is still in its infancy. Emerging data analytics may also provide added value to understanding and mitigating the health care inequities experienced by a number of AHRQ Priority Populations, especially women, racial and ethnic minorities, and persons in low-income, rural, and urban settings in the U.S. Deep South. The University of Alabama at Birmingham (UAB) is situated in the heart of the Deep South in Birmingham, AL and is home to several federally funded research centers who formally partner with 10 academic medical centers, universities, and historically black college and universities in Alabama, Mississippi, and Louisiana to address the chronic inequities plaguing our region. UAB and its regional partners are especially well-positioned to benefit from modern data analytics that can improve the quality, accessibility, and equity of health care in these populations. However, because many data analytic tools ‘learn’ by being ‘trained’ on real-world data that often contain inherent biases, these approaches are susceptible to perpetuating health care inequities. We therefore propose the 2025 Annual UAB Methods Symposium on April 9-10, 2025 in Birmingham, AL to disseminate timely information on modern data analytic applications in HSR and the potential biases associated with each. The Symposium will build capacity for a broad audience of HSR trainees and investigators to integrate advanced data analytics into their research portfolios and understand their limitations. The Symposium is an annual 1.5-day event and is intended for an interdisciplinary and interprofessional HSR audience across the career arc. In recent years, the Symposium has organically garnered national interest and reach. An AHRQ R13 conference grant is requested to add Travel Awards for trainees and early-stage investigators to attend in-person and increase capacity to host a national meeting and disseminate its products. Specific aims are to plan and execute a national symposium in hybrid format; disseminate information on the HSR application of geospatial analyses, natural language processing, machine learning, and microsimulation and the potential biases associated with each; and conduct program evaluation and dissemination of symposium products. The Symposium will provide a local, regional, and national outlet to highlight and disseminate emerging analytic methods and their HSR application for AHRQ Priority Populations, including women, racial and ethnic minorities, and persons in low-income, rural, and urban settings. As these groups comprise a large proportion of the populations that UAB and our regional partners serve, we are uniquely positioned to host this Symposium and translate the information disseminated into improved care for our region and beyond.

NIH Research Projects · FY 2024 · 2024-09

PROJECT SUMMARY Myopia is a global public health problem affecting over two billion people worldwide. Concerns for myopia are increasing because axial eye elongation associated with myopia is a major risk factor for several sight- threatening ocular pathologies in later life. Although optical methods based on a single visual cue—peripheral myopic defocus—have shown some potential to slow eye growth, the partial effectiveness of these methods suggests that the peripheral defocus cue alone is not sufficient to effectively restrain eye growth and myopia progression. The emmetropization mechanism also uses wavelength cues (from longitudinal chromatic aberration in broad-band light) to modulate eye growth, with an in-focus light serving as a stop signal. The wavelength cues appear more powerful than the defocus cues because they can cause the emmetropization mechanism to essentially ignore the refractive state. However, the potential of using wavelength cues to slow eye growth and myopia progression has yet to be systemically studied. In near-primates and primates, narrow- band red light (peak wavelength 636 ± 10 nm), which does not stimulate the short-wavelength sensitive cones, acts as a powerful anti-myopia stimulus, producing hyperopia and counteracting negative lens-induced myopia. Even brief periods of exposure a day produce substantial hyperopia, suggesting a temporal non-linearity of the effect that makes it feasible for clinical translation. We have recently found that exposure to amber light (wavelengths > 500 nm) also produces the same hyperopic effect in tree shrews with similar potency to red light. Unlike red filters, amber filters only minimally reduce ambient illumination and allow sufficient brightness even in typical indoor lighting conditions. The Gawne and Norton model hypothesized that longer wavelength light that avoids the stimulation of short-wavelength sensitive cones produces an image contrast that the emmetropization mechanism interprets as the eye being too long and signals to slow its growth. We aim to test this hypothesis by asking whether daily periods of amber light exposure slow eye growth and myopia progression in children in a pilot, “proof-of-concept” study. The specific aim is to determine the efficacy of amber contact lens wear for up to four hours a day in slowing myopia progression and axial elongation. We will recruit 40 myopic children aged 8 to <13 years, have them wear daily disposable, amber- tinted soft contact lenses for up to four hours daily, and measure refractive error and axial length for a year. By comparing the outcomes to the published one-year results from children wearing daily disposable single-vision and dual-focus soft contact lenses, we aim to determine whether a wavelength cue, amber light, slows childhood myopia progression and how its efficacy compares to that of the dual-focus lenses. This project will provide pilot efficacy data and potentially lead to a placebo-controlled, randomized clinical trial of a novel, wavelength-based myopia control strategy, providing an entirely new avenue for childhood myopia control.

NIH Research Projects · FY 2026 · 2024-09

Glaucoma is a progressive, irreversible, blinding condition of the eye that affects millions worldwide, and intraocular pressure (IOP) remains the only modifiable risk factor for glaucoma progression. However, we still do not understand how IOP fluctuations are controlled centrally. Our interest is in identifying central nervous system (CNS) nuclei responsible for controlling circadian IOP fluctuation with the hope that this knowledge may identify novel targets for glaucoma therapy. Our previous studies have shown that chemical stimulation of the dorsomedial hypothalamus and surrounding perifornical region (DMH/PeF) transiently, but dramatically, elevates IOP. Further, orexins are highly localized to the DMH/PeF, and orexin neurotransmitters are implicated in control of circadian rhythms. We have extensive data extending the role of the orexin neurotransmitter system in the regulation of IOP. Additionally, our studies have shown that the brainstem raphe pallidus (RP) receives projections from the DMH/PeF neurons. Further, when injected into the RP, orexins stimulated a sustained rise in IOP directly implicating the orexins and the RP in IOP regulation. While a CNS orexinergic pathway that eventually stimulates autonomic ganglia may be the most obvious pathway regulating IOP fluctuation after DMH/PeF stimulation, an alternative orexinergic pathway controlling IOP may exist. Data suggests that orexin receptors are located on the ciliary body and ciliary muscle of the eye's anterior segment. Thus, we will investigate both. We will examine the role of the RP on DMH/PeF induced IOP elevations by measuring the degree to which local orexin receptor antagonists in the RP attenuate the IOP response (Aim 1). We will further assess the degree to which orexin receptor antagonists administered directly within the anterior chamber attenuate the CNS-mediated IOP stimulation (Aim 2). We will also address mechanism of action and examine the effect of CNS-mediated IOP stimulation on the flow dynamics of the aqueous humor (Aim 2). With unique data demonstrating a role for the orexin system in attenuating CNS-mediated IOP stimulation, further exploration of the association between allelic variations of the orexin neurotransmitter and its receptors with the IOP trait is justified and appropriate. Thus, we will use a candidate gene approach and Mendelian randomization analysis to investigate the three genes encoding the orexin signaling system using the NIH All of Us database and the UK Biobank which offers genomic sequence data for over 100,000 participants with matching IOP and medical data (Aim 3). Finally, IOP and IOP dynamics in transgenic mice lacking a functional orexin peptide allele or lacking functioning alleles of either of the orexin receptors will be tested for circadian IOP rhythm disruption, as well as for significant differences in IOP elevation, in our validated CNS stimulation methodologies (Aim 4). Together, these aims establish a comprehensive approach to identify potential mechanisms of action for the orexin system in mediating IOP increases caused by stimulation of the DMH/PeF region and may provide additional insights into CNS control of IOP and its circadian dynamics.

NIH Research Projects · FY 2024 · 2024-09

Project Summary There are approximately 46 million people worldwide living with dementia according to the 2015 World Alzheimer Report, and it is estimated to increase to 131.5 million by 2050. It has been estimated that the total worldwide dementia-related healthcare cost is $818 billion, rising to $2 trillion by 2030. The most common progressive cause of dementia in the elderly is Alzheimer's Disease (AD), which is in the top ten leading causes of death in America and has no proven preventative or curative interventions. The goal of Alzheimer's research is to improve and simplify diagnosis, characterizing testing parameters that identify the earliest pathological changes in the patient, while ideally being inexpensive, non-invasive, and widely distributable to health care providers. Cognitive decline and neurological damage displaying anatomical losses are often preceded by functional and molecular changes that are harder to detect. The eye and brain are anatomically, embryologically, and physiologically linked. The retinal ganglion cells (RGCs) are like the cerebral cortex neurons but the synaptic layers of the retina are beautifully laid out, easing examination of histopathology and functional testing. There is strong evidence of retinal manifestations of AD in both post- mortem human tissue samples and the APP/PS1 rodent model of Alzheimer's disease. Functional testing like the electroretinogram (ERG) can and has identified early neurological losses in Alzheimer's models and can be immediately transferable as a technique to human subjects, Alzheimer's patients, and preclinical Alzheimer's subjects. Here we will pursue retinal testing for AD in 1) the APP/PS1 mouse model of AD to track the earliest disease indicators, 2) in young and old human subjects to define a range of normal function, and 3) in preclinical and mild cognitively impaired humans to control for early AD onset to determine specificity and sensitivity of the tests. We will use novel combinations of pattern size and contrast sensitivity as visual stimuli, and use identical ERG tests on a well-defined animal model of AD and human subjects with varying degrees of cognitive impairment. We will also investigate the structure of the unique glutamatergic ribbon synapses of the two retinal synaptic layers with the goal of identifying a mechanism behind the retinal sensitivity declines.

NIH Research Projects · FY 2024 · 2024-09

The number of primary open angle glaucoma (POAG) cases will increase by 250% by 2050, directly affecting over 7 million lives. Development of high-quality, accessible, and cost-effective strategies for eye care for these individuals is critically important. POAG is 4-5 times higher in Blacks, progresses more rapidly, and appears about 10 years earlier compared to those of European descent. This proposal evaluates a novel screening approach developed from our prior CDC-funded glaucoma detection study (AL-SIGHT), utilizing a hybrid type 2 implementation science design. This will enable evaluating feasibility of program expansion occurring simultaneously with a comparative effectiveness trial of the intervention. This implementation study will evaluate a modified streamlined version of our AI-SIGHT screening protocol by including a validated artificial intelligent algorithm to provide interpretation of ocular imaging and clinical data obtained within Federally Qualified Health Centers (FQHCs) located in medically underserved regions. Using this program within FQHC’s will facilitate potential expansion nationwide. These centers provide primary health care services for lower income people and treat more than 27 million people yearly at over 12,000 sites. Moreover, we are targeting patients at-risk for glaucoma living in areas with large Black populations. Our prior research in FQHC’s has demonstrated a higher prevalence of POAG at FQHCs than when screening in the general population. This high “pre-test” probability addresses critical concerns expressed by the US Preventative Screening Task Force (USPSTF) that population screening is not merited. Moreover, patients in AL-SIGHT demonstrated a high rate of follow-up (at 76%) to recommended eye examination due to the integration of FQHC’s into their local communities. We have developed and tested a novel multimodal telemedicine approach in our current CDC- funded AL-SIGHT study within FQHCs, with good agreement with expert diagnosis and adherence to follow-up. Patients were satisfied with the screening. Yet this approach is limited in expandability in that it still requires expert physician guidance. With the new protocol we will determine the ability of validated AI algorithms to make screening diagnoses, previously shown to provide diagnostically equivalent recommendations to physician diagnoses, reducing the cost of implementation. The study will identify POAG screening rates, adherence to follow-up care rates, cost effectiveness of the protocol, and acceptability for primary care provider and patients. If our outcomes are successful, we will develop a scalability plan for FQHCs. Our long-range goal is to reduce the personal burden of POAG in medically underserved areas.

NIH Research Projects · FY 2025 · 2024-09

Synucleinopathies, including Parkinson’s Disease (PD) and Lewy Body Dementias such as Dementia with Lewy Bodies (DLB) and Parkinson’s Disease Dementia (PDD), are a devastating group of neurodegenerative disorders that cause extensive social and economic burdens worldwide. The prevalence of these diseases is predicted to increase drastically, yet no therapies currently prevent neurodegeneration in PD, PDD, or DLB. Alpha-synuclein (asyn) is the key pathogenic protein that misfolds, aggregates, and induces pathology in PD, PDD, and DLB. Pathogenic asyn spreads from cell to cell throughout the brain, and misfolded asyn species are hypothesized to facilitate the spread of pathology by inducing the misfolding of nonpathogenic species. However, little is known about the exact processes that promote asyn propagation in PD, PDD, and DLB. The goal of this project is to allow the PI (Kacie Scholz) to develop the necessary skills in neuroscience research to study key proteins involved in asyn pathology. The primary objective of this proposal is to investigate the roles of Rab27a and Rab27b on the endocytosis and autophagic-lysosomal degradation of asyn. Previous work from the lab of Dr. Talene Yacoubian, the PI’s sponsor, has identified that Rab27b is upregulated in temporal cortical lysates from human PD and DLB subjects relative to age-matched controls, and that it acts as a mediator of asyn clearance and toxicity in asyn models. Further, our lab has identified Rab27a as a potential mediator of asyn uptake. Both endocytosis and autophagic-lysosomal clearance are critical components of the spread of asyn and asyn-related pathology. In Aim 1, the PI will examine the role of Rab27b in promoting the lysosomal clearance of asyn using in vitro and in vivo asyn models. In Aim 2, she will examine the impact of Rab27a in mediating asyn endocytosis in in vitro and in vivo asyn models. The long-term goals are to advance our understanding of asyn pathology and to identify new therapeutic targets for potential disease-modifying therapies for PD, PDD, and DLB. The proposed training plan for Kacie is sponsored by her project sponsor, Dr. Talene Yacoubian. The overall goal is to provide her with a solid foundation for a successful career in academic science. The training plan includes experiences that will help Kacie develop skills in rigorous neuroscience research in synucleinopathies including training in the responsible conduct of research, critical research techniques, data analysis, and the available literature. It will also expose her to invaluable career and professional development opportunities in areas including scientific communication, translational research skills, and grant and manuscript writing. This proposal will drive the development of the skills needed to conduct rigorous scientific research in synuclein disorders and provide an invaluable foundation for the PI’s future career as an academic scientist focused on neurodegenerative diseases, such as PD, PDD, and DLB.

NIH Research Projects · FY 2024 · 2024-09

Abstract Disparities in lung disease and other chronic conditions between poor, mostly Black residents of public housing communities and the general population are profound, leading to an extraordinary human and economic burden. Rooted in structural inequalities, these disparities are exacerbated by the conditions of daily life, including housing and neighborhood physical (built) and social environment. Together, adverse housing and neighborhood conditions increase disease risk through multiple pathways, including behavioral and biological. Despite compelling evidence of the health effects of neighborhoods, few interventions have examined the extent to which specific modifications of housing and neighborhood conditions improve health outcomes. The proposed study, Housing, Environment, And Living Conditions for Transformed Health (HEALTHe Birmingham), aims to fill this research gap. Taking advantage of a major investment by federal and local government, businesses, and organizations, we will evaluate, in a natural experiment, the health effects of a comprehensive intervention that addresses multiple social determinants of health (SDoH): public housing quality and features of the neighborhood built and social environments (Aim 1). Recognizing that major community revitalization efforts are not always possible, to generate solutions that are potentially more feasible and have wider reach, we also will conduct a prospective trial to determine whether less-expensive improvements, such as indoor air purification, can positively impact lung health in public housing sites not undergoing housing renovation, comparing a site exposed to industrial pollution vs one less contaminated (Aim 2). To bolster the public health and policy implications of this research, we will conduct cost-effectiveness analyses from economic and societal perspectives and use implementation science to prioritize intervention strategies, recommend scale-up efforts across communities and contexts, and inform policy on federal and local levels. We also will assess the extent to which specific components impact health equity between intervention and control communities (Aim 3). Study findings will facilitate translation of SDoH interventions into practice, inform public policy across locations and contexts, and contribute to the evidence base of reducing health inequity through action on SDoH.

NIH Research Projects · FY 2024 · 2024-09

PROJECT SUMMARY Oxidative stress (OxS) is a biochemical process that leads to damage of cellular lipids when endogenous redox homeostasis is disrupted. OxS is mechanistically linked with the physiology of aging and age-related diseases, such as cardiovascular disease, neurodegeneration, cancer, frailty, diabetes, and SARS-CoV-2. The identification of biomarkers to measure OxS is thus of significant public health revelance in order to better understand disease mechanisms and target potential therapies. F2-Isoprostanes (F2-IsoPs) are formed from the oxidation of the cellular lipid arachidonic acid and considered to be excellent biomarkers of OxS. Currently, F2-IsoPs are being used as outcome measures in more than 80 active clinical trials worldwide. Further, the NIA-sponsored Interventions Testing Program (ITP) has identified nine agents that significantly increase lifespan, and four of those agents are known to decrease F2-IsoPs. While F2-IsoPs have proven to be useful biomarkers of OxS, our laboratory has obtained evidence to support the hypothesis that metabolites of F2-IsoPs more accurately reflect endogenous OxS than unmetabolized F2-IsoPs in certain biological settings. Yet, F2-IsoP metabolites are rarely quantified in clinical studies. F2-IsoP-like molecules (F-isoprostanoids) are made from the oxidation of other polyunsaturated fatty acids (PUFA), including adrenic, eicosapentaenoic (EPA), and docosahexaenoic acids. These compounds are proving to be useful biomarkers in neurodegenerative conditions and age-related macular degeneration, but their metabolism has never been studied. The central hypothesis of this proposal is that understanding the metabolism of F-isoprostanoids is critical for the accurate and complete quantitation of these urinary biomarkers in aging and OxS-related diseases. In Specific Aim 1, we will use human liver microsomes to identify metabolites of several F-isoprosatnoid isomers generated from the free radical oxidation of PUFA. Metabolites will be identified using mass spectrometry (MS). In Specific Aim 2, we will establish and validate a robust LC/MS method for the quantification of F-isoprostanoid metabolites, from Specific Aim 1, in human urine. For this purpose, we will utilize urine samples from The Fatty Acid Desaturase Activity, Fish Oil, and Colorectal Cancer Prevention Study (FnADAFO), a randomized clinical trial that was completed in 2018 at Vanderbilt. Subjects recruited in this study were supplemented with olive oil or marine fish oil for six months, so these urine samples are ideal for validation of this metabolite quantification. We anticipate that the completion of this application will redefine our understanding F2-IsoP metabolism and, for the first time, define a strategy to comprehensively assess this important biomarker of lipid peroxidation. Overall, these studies will change how the field evaluates endogenous OxS and lipid peroxidation, thus setting the stage for future applications examining the role of isoprostanoids in human physiology and the pathogenesis of disease.

NIH Research Projects · FY 2025 · 2024-09

PROJECT SUMMARY/ABSTRACT The objectives of this proposal are to (1) obtain the experimental skills and career training necessary to develop a translational research program investigating mechanisms underlying skeletal muscle wasting and (2) generate the data necessary to determine the feasibility of targeting senescent cells to restore muscle size and function. Sarcopenia is a debilitating age-related skeletal muscle wasting syndrome associated with poor quality of life and high health care utilization. The etiology of sarcopenia is not fully understood, and there are currently no effective treatments. Identifying the processes mediating sarcopenia is critical for developing pharmacologic therapies. Senescent cells accumulate with age and at the anatomical sites of disease. Thus, they are regarded as a logical therapeutic target. Indeed, in mice, the targeted elimination of senescent cells improves function and parameters of health in multiple tissues. Our preliminary data show (1) senescent post- mitotic muscle fibers accumulate in sarcopenic mice, (2) the cyclin-dependent kinase inhibitor p21 is a critical regulator of muscle fiber senescence, and (3) a subset of myonuclei within multi-nucleated muscle fibers are uniquely vulnerable to senescence induction. I will use mouse models that allow for muscle fiber-specific labeling and modulation of p21 to advance our understanding for muscle fiber senescence and examine the direct contribution of senescence to muscle dysfunction. In Aim 1, I will overexpress p21 in muscle fibers in vivo and apply well-validated markers of senescence together with transcriptome-wide analyses to determine the core properties of muscle fiber senescence and identify regulatory processes that may serve as therapeutic targets. In Aim 2, I will use gain-of-function and loss-of-function p21 models and assess measures of muscle health, function, and size to determine the clinical relevance of senescent cell burden in skeletal muscle. In Aim 3, I will use myonuclear identification and isolation techniques together multiomic profiling to examine differences between senescent and non-senescent subsets of myonuclei to gain new insight into the factors regulating myonuclear senescence. The K99 phase will be conducted at Mayo Clinic and will focus on obtaining mentored training in methods required to complete the proposed aims. The R00 phase will be conducted in my independent lab and will focus on analyzing mouse tissues and data, publishing findings, and developing an R01 application based on these results. This proposal synergizes new skills in advanced senescent cell identification, imaging, bioinformatics, and drug target discovery techniques to create a research trajectory that is distinct from my mentors’ foci. This work will produce a robust foundation for an independent research career elucidating cellular mechanisms of skeletal muscle dysfunction with the aim of translating these findings into therapies to improve human health and well-being.

NIH Research Projects · FY 2025 · 2024-09

Oropharyngeal cancer (OPC) is a type of head and neck cancer and ~70% cases of OPC are associated with high-risk (hr) human papillomaviruses (HPV) infection. OPC cancers are increasing in prevalence especially in persons living with HIV (PWH) and this group also has higher rates on HPV associated OPC. Reasons for these findings are not well understood. While antiretroviral treatment (ART) does diminish HIV replication and immune activation, in a large majority of PWH it is generally started in chronic infection, when HIV reservoirs have already been established and uncontrolled HIV replication has resulted in significant immune dysfunction. Based on our preliminary data and what is known in the literature, we hypothesize that ongoing HIV replication and the resultant production of its proteins upregulates oncogenic HPV proteins (E6 and E7) thereby enhancing the probability of OPC development. HIV replication also results in exhaustion of CD8 T cells which is further exacerbated by increased HPV replication making HPV-specific CD8 T cells especially prone to overstimulation and exhaustion. These dysfunctional CD8 T cells thus make it even more likely for OPC to occur in PWH. Furthermore, both HIV protein production and immune activation continue after potent ART is started. As such, production of HIV proteins from previously latently infected CD4 T cells continues to drive HPV oncogenic protein production as well as CD8 T cell exhaustion and OPC continues to occur at higher rates in these PWH. Solidifying this overall hypothesis as proposed in our 3 aims would provide comprehensive insights into the mechanisms of OPC in PWH leading to improved prevention and therapies. Our overall study hypothesis is that chronic inflammation despite ART in PWH favors both persistence and proliferation of hrHPV16 infected oropharyngeal epithelial cells and contributes to impaired anti-HPV specific T cell immunity leading to initiation of OPC. We will test this hypothesis in the following three aims: In aim 1, we will determine the HPV types present in OPC from PWH and how T cell mediated anti-tumor immunity is impaired. We will examine whether multiple HPV subtypes persist. In addition, we will determine whether tumor and CD8 are spatially distant and whether the intra-tumoral CD8 are exhausted. Our aim 2 will determine how an HIV infection influences HPV infection, its gene expression and DNA replication to facilitate oncogenic transformation of oropharyngeal epithelial cells. Using 3D based models, we will show that HIV infection via its specific proteins (Tat and/or envelope gp120) modulates HPV pathogenesis by interfering at one or more steps in its life cycle. In aim 3, we will determine the mechanisms of HPV specific CD8 T cell dysfunction in PWH with OPC and whether tumor specific immunity can be restored. Our successfully completed studies will show how chronic, albeit low grade inflammation in PWH on ART is beneficial to the initiation of HPV associated OPC via increased susceptibility of epithelial cells to HPV infection, increased oncogene expression which when coupled with an inability of CD8 T cells to kill HPV infected cells tips the balance of an HPV infected cells towards OPC initiation.

NIH Research Projects · FY 2025 · 2024-09

Gout is the most common inflammatory arthritis, but beyond the well described role of the NLRP3 inflammasome, the molecular genetic causes of gout flares is least well known among the arthropathies. Published and preliminary results from our group have implicated genes associated with inflammation in gout which do (e.g., TMEM176B) or may not (e.g, FADS2) relate directly to inflammasome activation. A powerful approach for understanding the mechanistic basis of gout flares is through transcriptomic profiling of mononuclear cells from the target organ of inflammation, the synovial fluid, but these studies have not been rigorously carried out. We have designed a first of its kind, time-sensitive ancillary study, through the parent clinical trial, Treat-to-Target vs Treat-to-Avoid-Symptoms (TRUST), which will allow novel comparisons of candidate gene expression in mononuclear cells of synovial fluid to peripheral blood cells prior to and during active gout flares. These studies will require consenting TRUST participants for arthrocentesis during active flares. This additional, fresh biospecimen collection, facilitated by the TRUST trial, is highly time-sensitive and crucial for thorough investigation of molecular mechanisms of gout flares. We will use these samples to carry out Aim 1 - differential gene expression analysis of myeloid subsets before and during a flare in peripheral blood and synovial fluid samples during active flare. Flow cytometry on samples from 20 individuals will be used to isolate non-classical and classical monocytes followed by bulk RNA sequencing. Single cell RNAseq will be done on peripheral blood mononuclear cell (PBMC) samples from five of the 20 individuals to infer specific cell-types. In Aim 2, using our existing ex vivo cell culture paradigm we will stimulate PBMCs with LPS and C18.0 fatty acid (FA) in the presence/absence of MSU crystals, followed by scRNAseq 24 hours post stimulation. Cells will be isolated from fresh samples of blood collected from people with gout (intercritical) enrolled at UAB. scRNAseq transcriptomes will be compared between unstimulated, C18.0 FA and LPS stimulated cells. Readouts will allow mechanistic insight into gout flares that are TLR-agonist mediated and related to potential gout flare triggers. Finally, we will knockdown candidate genes, by attenuating their expression and then measure NLRP3 inflammasome activation. Altered expression of secreted IL-1β would confirm their mechanistic role in gout flares. The proposed research is highly innovative by sampling, with never before collections of matched samples of peripheral blood and synovial fluid, by analyses, novel transcriptomic analyses of myeloid cells in samples and in an ex vivo system, and by design, leveraging resources of the TRUST parent clinical design for this time-sensitive ancillary study. Our work will provide new knowledge of genetically-based mechanisms of gout flares and aid in identification of new therapeutic targets.

NIH Research Projects · FY 2025 · 2024-09

Oral anticoagulants (OACs), including warfarin and direct oral anticoagulants (DOACs), form the cornerstone of therapy for thromboembolic conditions. However, individual variability in OAC response can result in lack of efficacy (thromboembolism) or safety (hemorrhage), with OAC-related hemorrhage a serious adverse effect. Ancestry and sex influence OAC response and variable drug levels, therapeutic target levels, and clinical OAC responses have been observed. Differences in pharmacogenomic variant frequencies, gene expression, and metabolite profiles by ancestry and sex may explain variable drug response. However, pharmacogenomic evaluations of DOAC response have been limited in diversity, evaluated candidate genes, and lacked evaluation of sex-related predictors. Furthermore, metabolomics signatures of variable OAC response have not been evaluated. This is a major barrier to establishing therapeutic drug and biomarker levels and personalizing OAC therapy. The NIH recognizes the importance of identifying factors that affect treatment response among diverse patients and the use of pharmacogenomics and metabolomics to identify and develop new therapeutic targets/ biomarkers. With the support of this K23 award, Brittney Davis, PharmD will identify and evaluate ancestry and sex-related pharmacogenomic and metabolomic signatures of variable OAC response, including pharmacokinetics (PK), pharmacodynamics (PD), and clinical outcomes (hemorrhage). This will be achieved through integrated research and training aims that build on her prior clinical and research background. Specifically, she will evaluate pharmacogenomic predictors of DOAC PK (drug levels) and PD (anti-Xa levels), and integrate pathway and functional effects to characterize drug response pathways (Aim 1). To evaluate clinical outcomes, she will identify pharmacogenomic predictors of OAC-related hemorrhage employing a DOAC-specific approach and a combined drug class approach (warfarin + DOAC), and replicate findings in an independent cohort identified using electronic medical record (EMR)-based phenotyping (Aim 2). Finally, she will conduct metabolomics analysis and characterize signatures of anti-Xa and OAC-related hemorrhage to determine if metabolite profiles can be serve as OAC response biomarkers. This project provides a highly significant opportunity to employ strategies to identify and target DOAC and anti-Xa threshold concentrations, which could help maximize efficacy and safety, elucidate biologic pathways and metabolomic signatures of variable response, and lay the foundation for personalized strategies. To achieve her research and career goals, Dr. Davis has constructed a multidisciplinary mentoring team with extensive expertise in areas relevant to her career development, including 1) bioinformatics/statistical genetics 2) metabolomics and pathway analysis 3) electronic medical record (EMR)-based phenotyping and 4) clinical research. This mentored training experience at the University of Alabama at Birmingham will lay the foundation for an independent career focused on integrative pharmacogenomics and metabolomics approaches to personalize OAC therapy.

NSF Awards · FY 2024 · 2024-09

The National Science Foundation (NSF) Graduate Research Fellowship Program (GRFP) is a highly competitive, federal fellowship program. GRFP helps ensure the vitality and diversity of the scientific and engineering workforce of the United States. The program recognizes and supports outstanding graduate students who are pursuing research-based master's and doctoral degrees in science, technology, engineering, and mathematics (STEM) and in STEM education. The GRFP provides three years of financial support for the graduate education of individuals who have demonstrated their potential for significant research achievements in STEM and STEM education. This award supports the NSF Graduate Fellows pursuing graduate education at this GRFP institution. This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.

NSF Awards · FY 2024 · 2024-09

Everything in biology is connected. Our job as life scientists is to reveal important biological properties in the most impactful, efficient, and economical way. To do so we look for model organisms that are particularly tractable for studying complex biological processes and then apply what we learn to better understand other organisms. For more than a century, sea urchins have provided a valuable research model that has contributed significantly to our understanding of many fundamental biological processes such as fertilization, embryonic development, and cell division. Sea urchins have proven to be a valuable model due to their close genetic relationship to vertebrate animals and many features that make experimentation easier. The goal of this proposal is to create the next generation of tools to enhance the utility of sea urchins as research models that will enable new areas of research and to make these tools widely available to the scientific community. Areas of biological research to be enhanced by the tools created from this proposal include a better understanding of how eggs and sperm interact at fertilization, understanding the rules of embryo development, how nerve cells are made, how sex is determined, how animals protect themselves from environmental insults and from infection, and how tissues and organs can regenerate when they are damaged. The outcomes of this proposal will reach far beyond the scientists, to the public, students and teachers and make the sea urchin a highly attractive and impactful research and education tool of the twenty-first century. Sea urchin researchers have long sought to leverage the experimental tractability of the embryo and adult with genetic approaches but, to date, manipulations have been limited largely to dependence on morpholinos or pharmacology. The overarching goal of this EDGE proposal is to build tools that overcome major obstacles to testing gene functionality in echinoderms, opening up a new era of discovery for diverse and integrated studies across all life history stages of this valuable sister group to chordates. This goal will be realized as follows: (1) Simple and efficient protocols for culturing cells from embryos to investigate gene function in vitro; (2) Rapid, scalable DNA transfection of embryos, adult tissues, and cell cultures for conditional, and reversible gene control; (3) Techniques to promote standardization of sea urchin husbandry with open hardware and cryopreservation for sea urchin germplasm and cell lines; (4) Virtual, interactive educational materials to reach secondary school and undergraduate students and investigators learning from and even considering entering this research community. These integrated new technologies with controlled and heritable genetic manipulations and the ability to test gene function and regulation in in vitro cell-based systems will enable new avenues of investigation that fully exploit the important properties of echinoderms as a research organism. The tools developed in this proposal will remove the bottlenecks and provide scalable and sustainable resources for the community of echinoderm researchers. The proposal was funded by the Enabling Discovery through GEnomics (EDGE) program and the Developmental Systems Cluster in the Division of Integrative Organismal Systems. This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.

NIH Research Projects · FY 2025 · 2024-09

There is a fundamental knowledge gap in achieving maternal glycemic control sufficient to reduce maternal and neonatal morbidity and mortality in pregnant individuals with type 2 diabetes mellitus (T2DM). Nearly all pregnant individuals with T2DM experience either maternal or newborn morbidity, with worse outcomes seen in socially disadvantaged groups. The key to reducing these adverse outcomes, especially for the newborn, is achieving maternal glycemic control; and the first step towards this goal is effective glucose monitoring. Current self-monitoring of blood glucose (SMBG) 4 times daily is burdensome and only provides snapshots of glycemic status. Compared to SMBG, continuous glucose monitoring (CGM) was shown to improve maternal glycemic control and reduce the risk of adverse neonatal outcomes in type 1 diabetes (T1DM) pregnancies, but the benefits in T2DM pregnancies are unknown. An additional challenge is that what constitutes adequate glycemic control in T2DM pregnancies is also unknown. While there are established glucose targets for SMBG and CGM, the percentage of glucose values that should meet these targets is not clear. Last, social and structural factors must also be addressed as they create barriers to T2DM management and contribute to up to 60% of differences in outcomes. The overarching goal is to improve short- and long-term maternal and child outcomes among pregnant individuals with T2DM. The research objective of this proposal is to determine the effectiveness of real-time CGM at reducing maternal and neonatal morbidity, define an outcome-based definition for glycemic control and identify social and structural barriers to improving outcomes. The central hypothesis is that real-time CGM provides patients and providers the necessary tool to prevent maternal hyperglycemia and improve neonatal outcomes in T2DM pregnancies. Additionally, we hypothesize that unfavorable social and structural factors interfere with T2DM management and result in differences in outcomes. These hypotheses will be tested by pursuing the following specific aims: 1) Determine the effectiveness of real-time CGM at reducing neonatal morbidity and mortality in pregnant individuals with T2DM, compared to SMBG, 2) Determine the effectiveness of real-time CGM at improving maternal glycemic control and reducing maternal morbidity, compared to SMBG, and 3) Identify the biologic, personal, social and ecological factors associated with morbidity and mortality of neonates born to pregnant individuals with T2DM. Successful completion of the proposed study will determine if real-time CGM, compared to SMBG, improves maternal and neonatal outcomes in pregnant individuals with T2DM and define what SMBG and CGM goals constitute adequate glycemic control. Identification of the key factors associated with differences in outcomes in this historically disadvantaged population will lay the foundation for future intervention studies. This project has the potential to revolutionize management of T2DM in pregnancy and impact the lives of 100,000 pregnant individuals and their children in the U.S. each year.

NIH Research Projects · FY 2025 · 2024-09

PROJECT SUMMARY/ABSTRACT Cilia are complex structures with more than 1,300 proteins involved in their formation and function. During development, disruption of cilia function causes gestational lethality and mild to severe birth defects. Variants in cilia proteins are causally associated with more than 35 ciliopathy syndromes. Ciliopathy patients have a wide range of phenotypes affecting nearly every organ system. Despite the cilium's clinical importance, the functions of the cilium and molecular pathways the cilium regulates are poorly defined. To understand the pathophysiological mechanisms driving ciliopathy birth defects, we are extending and utilizing protocols, expertise, and tools developed within the UAB U54 Center for Precision Animal Modeling (CPAM). We will identify and characterize variants of interest derived from patient and variant repositories from local, regional, and national/international sources. Both variants of unknown significance (VUS) in known ciliopathy genes and predicted deleterious variants of interest identified in novel candidate ciliopathy genes that we prioritize through this application will be selected. Each variant will undergo robust assessment based on known or predicted deleteriousness, pathway and protein interactions, and phenotype and functional associations as compared to known ciliopathies. Prioritized variants will be subjected to a robust wet lab process to test pathogenicity, determine ciliopathy protein cellular localization, and screen rapidly for cilia related phenotypes in zebrafish F0 Crispant mutants. For variants that remain highly prioritized after these steps, we will generate precision engineered mouse models corresponding to the patient variant. These models will undergo phenotype analyses to assess the clinical correlation between the model and the patient. We will analyze the variant's impact on cilia assembly, morphology, formation of specialized cilia sub-compartments, and disruption of cilia protein interaction networks. We will determine the impact of the variant on developmental signaling pathways known to be associated with the cilium as well as identify novel pathways not previously identified as being regulated by the cilium. To accomplish the goals of project, we have assembled a team with a wide range of expertise in medicine, genetics and molecular diagnostics, computational biology, bioinformatics, and data science, biochemistry, cell biology, and animal model generation and phenotyping. Collectively we will confirm the functional impact of variants identified in patients with ciliopathy-like birth defects and patients with variants in genes predicted but not already well known to affect the cilium or its activity. The outcomes from this project will uncover novel cilia protein interactions and subcomplexes involved in cilia formation and maintenance, cilia protein transport, and cilia sensory and signaling activities. This work will also support definitive diagnoses for patients with cilia associated birth defects and generate data that can be used to predict potential therapeutic strategies. We will also develop and disseminate patient relevant models and bioinformatics tools for the broader community.

NIH Research Projects · FY 2025 · 2024-09

PROJECT SUMMARY The onset of a first episode of psychosis (FEP) in late adolescence or early adulthood often leads to lifelong disability. Timing and precision of treatment are of the essence during this critical developmental period. Unfortunately, FEP patients who do not respond to a conventional first-line antipsychotic (FL-AP) are often delayed in transitioning to clozapine (CLZ) - or never switch at all - despite the clear superiority of CLZ to FL- APs in treatment resistant individuals. However, CLZ treatment involves risks of severe side effects, including agranulocytosis and weight gain. Currently, clinicians and patients currently have no objective, clinically validated tools to guide this complex decision making in FEP. Our collaborative group has recently published work showing that a functional brain scan can help predict which FEP patients might not respond to FL-APs, such as aripiprazole and risperidone. Further, we have shown that a simple genetics test can help predict who is less likely to gain significant weight, and, similarly, who is less likely to develop agranulocytosis. We propose to conduct a multi-center, harmonized, randomized clinical trial with the goal of testing whether the use of biomarkers can lead to better outcomes for FEP patients. The goal of the proposed study is to develop a clozapine decision support tool based on these biomarkers. First, we will characterize 410 people with an FEP using three specific biomarkers: a resting state fMRI scan from which we will derive the striatial connectivity index (SCI) and two genetics tests (one for weight gain and the other for agranulocytosis). Those patients who are predicted to not respond to FL-APs, and who also have low risk of weight gain and agranulocytosis (approximate n=180), will be randomized in a triple-blind controlled study to either clozapine or an FL-AP (either aripiprazole or risperidone) for 12 weeks of treatment. Our main outcomes relate to clinical response, including positive symptoms, suicidal thinking, and days of hospitalization. We will also perform an MRI at study end to determine whether functional patterns in the brain distinguish CLZ responders from non-responders (target engagement). Critically, we are partnering with people with lived experience of psychosis and family members to help guide us during this trial, and to inform the study design and outcomes; information and choice are amongst the strongest elements of a successful therapeutic relationship. Overall, our study will evaluate the efficacy of whether using three biomarkers at the beginning of a first psychotic episode can lead to better patient outcomes for patients at risk for poor response, by rapidly introducing CLZ rather than waiting for multiple failures of FL-APs. Our key deliverable would be a clozapine decision support tool, consisting of the three biomarkers combined with our CLZ dosing strategy for FEP. Such a tool would be a necessary step in the development of precision psychiatry; if this efficacy trial is successful, a future study would then utilize implementation science to optimize strategies for dissemination of the decision support tool.

NIH Research Projects · FY 2025 · 2024-09

Abstract The hydrogen peroxide (H2O2)-producing oral commensal, Streptococcus parasanguinis, plays a major role in maintaining oral homeostasis in a nitrite (NO2)-dependent manner. Specifically, salivary NO2 produced by nitrate- reducing bacteria reacts with H2O2 to produce reactive nitrogen species (RNS), such as peroxynitrite (ONOO-), which is an antimicrobial that targets diverse pathogens, such as Streptococcus mutans, Enterococcus faecalis, and Aggregatibacter actinomycetemcomitans. In S. parasanguinis the production of H2O2 is mediated by the poxL (pyruvate oxidase) gene, which is homologous to the Streptococcus pneumoniae spxB gene. Multiple studies have shown that in S. pneumoniae H2O2 production has an inverse relationship with capsule production. Capsule production in S. pneumoniae is important for biofilm formation and oxidative stress resistance. However, the relationship between capsule production and H2O2 production, oxidative stress tolerance, and biofilm development remains unknown in S. parasanguinis. Additionally, the role of capsule in NO2-mediated nitrosative stress tolerance remains unstudied. S. parasanguinis harbors a capsule biosynthesis (CPS) operon that is homologous to the S. pneumoniae CPS operon, indicating that the roles of capsule may function in a similar manner to S. pneumoniae as it pertains to fitness. CpsE, a galactosyl transferase, is required for initiating the addition of the first monosaccharide in the formation of S. parasanguinis polysaccharide capsule biosynthesis. The goal of this project is to characterize the role of S. parasanguinis CpsE in modulating H2O2 production, NO2- mediated stress tolerance and biofilm formation, and commensal fitness within multispecies biofilms. We hypothesize that capsule production plays a critically important role in S. parasanguinis biofilm formation, stress response, and polymicrobial interactions. The specific aims of this project are to: 1) Determine the role of capsule production on S. parasanguinis biofilm development and stress tolerance, and 2) Determine the role of capsule production on S. parasanguinis’ microbial competition. Ultimately, the completion of the proposed aims will provide new knowledge about the role of capsule in oral commensal fitness, colonization, and ability to antagonize oral pathogens, which has never been studied.

NSF Awards · FY 2024 · 2024-09

This project analyzes the structure and dynamical properties of families of complex polynomials of degree three. Nonlinear mappings arise in mathematical models across a host of scientific and applied fields, and a key issue is to understand how the behavior of such mappings changes as the underlying parameters vary. Among the simplest nonlinear mappings are complex polynomials. The structure and dynamical properties of the space of complex quadratic polynomials has been intensively studied since the early 1980s, culminating in a detailed understanding of the celebrated Mandelbrot set. Analyzing the structure of spaces of complex cubic polynomials is at the heart of this project. The project also provides research opportunities for graduate students and contributes to the training and mentoring of undergraduate students. In addition, the principal investigator continues to serve as director of an outreach program aimed at Alabama high school students. The project develops the dynamical and structural theory of moduli spaces of complex polynomials of degree three from several perspectives. A first line of inquiry concerns the construction of locally connected models of the cubic connectedness locus. By analogy with classical combinatorial models for the Mandelbrot set, the project also studies a combinatorial model in the cubic case based upon critical portraits. This work relies on recent laminational results recently developed by the PI and collaborators. A further approach to be investigated involves analytic tools. Estimates for the moduli of annuli will be used to show that Julia sets of polynomials of degree three are generated by rational cuts and admit a description in terms of rational laminations. If successful, this line of inquiry will validate conjectural laminational models of such Julia sets as well as certain subsets of the cubic connectedness locus. This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.

NIH Research Projects · FY 2024 · 2024-09

Abstract Alzheimer’s disease (AD) affects millions of people worldwide, and its prevalence is expected to increase dramatically in the coming years. Although some people are resilient to AD pathology with normal cognition despite tau and amyloid deposits, understanding the factors that drive such resilience will be critical for identifying treatments for those at the highest risk of impairment. In the research proposed here, we will use cognitive neuroscience methods to develop a systems-level understanding of the mechanisms that underlie early-stage AD. We will examine tau deposition and functional network health in a sample of participants with normal cognition to understand the etiology of AD and individual differences in cognitive resilience. Recent results have shown that tau is present in different parts of the brain in different people. Thus, we hypothesize that tau deposits in a particular brain network disrupt functional network health, and patients who appear cognitively normal despite pathology have tau deposits in locations that have a minimal impact on functional networks. To test this hypothesis, we will use tau positron emission tomography (PET) to quantify the spatial distribution of tau pathology. We will also determine the role of brain network connectivity and atrophy in the health of a cohort of participants enriched for individuals at risk for AD. In Aim 1, we will use data from the publicly available Alzheimer's Disease Neuroimaging Initiative dataset to test our hypotheses by determining how tau deposits affect the health of pre-defined brain networks. We will measure functional network health based on network segregation, neural dynamics, and cortical atrophy. In Aim 2, we will determine how segregation, dynamics, atrophy, and tau deposits affect network flexibility. We will recruit 150 cognitively normal participants aged 55 or older from populations enriched in participants with blood markers indicating tau and, thus, at high risk for developing AD. They will undergo tau PET and resting-state functional magnetic resonance imaging (fMRI) as part of a University of Alabama at Birmingham Alzheimer's Disease Center study and will undergo fMRI during an auditory/visual attention task. In Aim 3, we will determine how these variables interact to affect cognitive and sensory performance and whether they predict longitudinal cognitive decline. Successful completion of this work will result in a better understanding of how tau deposits affect the normal patterns of brain activity and patterns of brain atrophy. These studies will provide new information on the mechanisms through which tau results in a system-wide decline and the conditions that lead to resilience. This knowledge may suggest treatments for patients with AD and patient-specific training or behavior modification strategies that, applied early in the course of AD, could mitigate its long-term effects.

NIH Research Projects · FY 2025 · 2024-09

PROJECT SUMMARY Of the 150,000 individuals diagnosed with colorectal cancer (CRC) each year, 15% will carry a hereditary pathogenic germline variant (PGV) including some associated with syndromes (such as Lynch Syndrome and Familial Adenomatous Polyposis) that are associated with a 35-100% lifetime risk of cancer. Identification of these PGVs through germline genetic testing informs treatment, screening, and familial cascade testing to reduce cancer incidence, morbidity, and mortality. In 2022, national guidelines expanded indications to consider genetic testing in all patients with CRC, yet only 5.6% of CRC patients undergo genetic testing in the US. Conventional pathways for genetic testing require non-genetic healthcare provider (NGHCP) referral to genetic counselors, leading to several gaps where patients may fail to complete testing. Mainstream genetic testing (MGT) has emerged as an effective pathway to increase rates of genetic testing in which NGHCPs perform pre-test counseling and coordinate genetic testing. However, the national uptake of MGT has been limited. The goal of this project is to increase the use of MGT in CRC by characterizing barriers to implementing MGT for CRC and piloting a multi-level implementation strategy tailored to these barriers. We will assess barriers among NGHCPs (i.e. surgeons, medical oncologists, and radiation oncologists) and institutional stakeholders (i.e. clinic nurses, clinic managers, genetic counselors) through semi-structured qualitative interviews. Patient perceptions of MGT will be assessed using a sequential explanatory mixed methods approach. CRC patients will be surveyed regarding perceptions of MGT and semi-structured qualitative interviews will explore these preferences. Identified barriers/needs will be used to tailor a multi-level implementation strategy consisting of provider education, technical assistance by genetic counselors, and provision of patient education materials. The multi-level implementation strategy for MGT will be pilot tested at two institutions in Alabama to determine patient level reach (clinical outcome) and provider perception of acceptability, appropriateness, and feasibility (survey data). This mentored research and a structured training plan to gain expertise in implementation science and exposure to mixed methods will facilitate my career development plan. My long-term goal is to use implementation science to improve outcomes in hereditary colorectal cancer patients. The findings of this proposal will inform a hybrid effectiveness-implementation trial (R01 proposal) for implementing MGT in CRC patients and provide me a direct pathway to becoming an independent investigator.

NSF Awards · FY 2024 · 2024-09

The frequency of different extreme environmental events poses a significant threat to the health of people, livestock, and agriculture by causing economic disruption that affects local communities. For instance, heat and drought are expected to reduce soybean yields by 40%, and these effects are predicted to be particularly severe in most Southern US soybean-growing areas. To address this challenge, this project brings together a team of scientists, educators, social and economic researchers, extension specialists, and outreach professionals. They will assess the impact of changes in the environment on soybean yields, from the cellular level to the whole plant, as well as on associated microbial communities, utilizing advanced technologies and artificial intelligence. The team will also develop solutions to boost soybean yields. The impacts of this project will be evaluated by social and economic scientists. The project also focuses on education and workforce development. An important goal of this project is to train and support students, teachers, and early-career researchers. The project provides training for teachers and students and will reach thousands of K-12 students annually. The results of the project will also benefit other crops and improve food security both in the US and globally. By integrating innovative research with education and community outreach, the team will build a sustainable future for agriculture and positively impact affected communities. To combat the decline of soybean yield, this initiative conducts extensive research from "single cell to field-based phenomics." The team includes 11 STEM experts, social and economic scientists, extension specialists, and outreach professionals. The project aims to enhance soybean resilience to heat and drought through five key strategies by generating single-cell level data, using advanced sensing to collect detailed morphological and physiological data, evaluating soil chemistry, root structures, and microbial communities, utilizing network science and Artificial Intelligence to find novel RNA markers and beneficial microbes, and testing selected markers and microbes in field conditions. The project aims to enhance sustainable soybean production by understanding stress responses from cellular to field levels. It integrates data from diverse scientific disciplines to develop precision agriculture solutions and assess their impacts. Moreover, the project employs a comprehensive, multipronged approach with eight programs to train a STEM workforce. Overall, the project aims to advance knowledge from single-cell -omics to phenomics, develop strategies that integrate data from various scientific fields and technologies, provide precision agriculture solutions using cultured microbes in field conditions, and assess the impact on a range of communities. Moreover, it will broaden the pipeline for individuals to enter STEM research careers. This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.