Arizona State University-Tempe Campus

NIH Research Projects · FY 2025 · 2025-09

PROJECT SUMMARY The goal of my research program is to investigate the mechanisms of mammal-microbial coevolution and its implications for host health, with a focus on codiversification—the parallel evolutionary history of host and microbial lineages. The microbiome has emerged as a key therapeutic target, and disruptions in these coevolved relationships are linked to adverse health outcomes, including immune, metabolic, and behavioral changes. However, the mechanisms underlying codiversification and the health impacts of losing vertically transmitted microbes in mammals remain unclear. As human migration and translocation increase, populations are exposed to novel microbes, making it crucial to predict host-microbial interactions in changing environments. Over the next five years, we will utilize Peromyscus spp. (deer mice) in the Arizona Sky Islands—an isolated system where mouse populations diverged similarly to major human populations—to disentangle the mechanisms of codiversification across various temporal and spatial scales. This natural experiment, combined with laboratory experiments, provides a unique model to assess how codiversification influences host phenotypes. The research will address three major knowledge gaps: (1) Identify codiversified microbial taxa and traits across body sites (skin, vaginal tract, small intestine, and feces), populations, and species; (2) Investigate mechanisms driving codiversification, specifically whether host filtering or dispersal limitation governs microbiome assembly; and (3) Assess how disruptions in codiversification affect host health by measuring changes in immune response, metabolic function, and behavior. We will generate whole-genome and metagenomic sequencing data to construct phylogenies for both host and microbial lineages and identify key microbial taxa and traits that are passed across generations. A key challenge will be distinguishing host filtering from dispersal limitations in shaping evolutionarily stable host-microbial associations. However, our comprehensive sampling design, manipulative laboratory experiments, and new bioinformatic tools provide a rigorous framework to tackle this issue. Fecal transplant experiments will offer the first description of mammalian phenotypes in response to host population- and species-level differences in microbiomes, addressing critical knowledge gaps and motivating future research. These findings have significant implications for the development of microbiome-based therapeutics tailored to specific host genotypes and ancestries, supporting a precision medicine approach.

NIH Research Projects · FY 2025 · 2025-08

Project Summary / Abstract: USDA‘s Fresh Fruit and Vegetable Program (FFVP) targets low-income schools, providing fresh fruit and vegetable (FV) snacks to elementary school children. Evidence shows that students who participate in the FFVP develop greater preferences for and consume more FV. Students also request more FV at home and at the store compared to their peers who attend non-participating schools, influencing parent/caregiver purchases and benefiting other members of the household. Promoting FFVP items in stores can capitalize on these healthy requests, prompting parents to act on them and purchase more FV. We have documented the eagerness of grocery stores, FFVP schools, and USDA’s Supplemental Nutrition Assistance Program- Education (SNAP-Ed) to form partnerships to promote FFVP items in stores. While FFVP’s current operations, confined to school settings and primarily focused on the student, limit its ability to have broader impacts, the program’s success demonstrates its potential to serve as a foundation for broader, multisectoral initiatives. By integrating efforts across education, public health, and food retail sectors, we can leverage the FFVP to reduce health disparities in FV consumption. To test this multisectoral approach, we propose to develop and test a novel Public-Private Partnership (PPP) consisting of three sectors -- Arizona’s FFVP, Bashas’ Food City stores (a regional grocery store chain), and SNAP-Ed. The PPP will coordinate efforts of the schools offering FV snacks through FFVP while also promoting these items in grocery stores. We hypothesize that our multisectoral approach can expand and amplify positive health impacts on underserved students and their families beyond what can be achieved in school settings alone. We will test the PPP in a cluster-randomized trial, randomly assigning 16 schools selected for FFVP by the Arizona Department of Education (ADE) to FFVP+ (intervention, 8 schools) or FFVP-only (active control, 8 schools) conditions, with a third observational non-FFVP (passive control group) group sampled randomly from similar schools that were not selected for FFVP (8 schools). Conducted across two phases, we will first test the feasibility of implementing a PPP and then use a confirmatory cluster-randomized trial design to evaluate the effectiveness of the intervention on students and their caregivers’ consumption as well as establish the sustainability of the PPP by estimating the cost-benefit to grocery stores. Evidence of the effectiveness of a PPP could support a scalable model for amplifying the positive impact of the FFVP program on schools, families, communities and grocery stores.

NIH Research Projects · FY 2025 · 2025-08

Summary Barrett’s esophagus (BE) is the only known precursor to esophageal adenocarcinoma (EA), a highly lethal cancer, the incidence of which has been rapidly increasing in the US. Currently, we over-treat the vast majority of patients with BE who will never progress to EA, and under-diagnose those that will progress. However, the ecological constraints and pressures driving phenotypic changes in BE, and the evolution of EA, are currently poorly understood. Our goals are to interrogate the BE tissue ecosystem to map the cellular, microenvironmental, and phenotypic diversity, and to compare the ecological microenvironment in BE patients that progress to EA to those in which BE remains stable over long periods of time. In Aim 1 we will develop a computational method to test if the spatial structure of different cell types in BE biopsies predicts progression to cancer. Aim 2 develops computational methods to detect abnormal cell proliferation at the top of Barrett’s glands which predict progression to EA. Aim 3 develops deep learning methods and tests if they can detect DNA content abnormalities (increased 4N fractions and aneuploidy) which predict progression to EA. These aims are biologically interconnected, profiling the BE tissue ecosystem, yet are technologically independent. We will use state-of-the-art computer vision machine learning tools to automate quantitative analyses of the spatial distribution of key cell types in the BE ecology. Machine learning, both self-supervised and trained by expert pathologist annotations in conventional H&E images, will unambiguously identify multiple specific cell types and quantify spatial patterns of unique cell habitats on biopsy sections. We will test if these BE tissue ecology measures, in combination and separately from abnormal cell proliferation and genomic abnormalities, distinguish those who progress to cancer from those who remain cancer free during follow-up, to improve clinical care of individuals with Barrett’s esophagus. We will leverage our unique cohort of longitudinally collected BE tissue biopsies, analyzing 5,760 digital tissue section images (split evenly into training and test sets) from patients in the Seattle Cohort to develop spatio-temporal tissue maps at cellular resolution in BE as it progresses to EA. We will validate all our results in an independent cohort from UCSF. The Project brings together expertise in machine learning, computer vision, and digital pathology (Yuan), Barrett’s pathology (Stachler), statistical landscape ecology (Brown), Barrett’s esophagus (Grady, Paulson), BE clinical care (Grady), computational biology and the evolution of BE (Maley) to develop computational pathology systems to quantify the ecology, phenotypic heterogeneity, and genomic abnormality within the BE microenvironment. Our pipeline for calculating landscape ecology statistics to measure tumor microenvironments can be used on any tissue for which we have cell locations and classifications. Digital datasets and computational tools will be made publicly available, providing a rich resource for the early detection of cancer and cancer prevention communities, as well as clinical tools for BE patient care.

NIH Research Projects · FY 2025 · 2025-08

PROJECT SUMMARY/ ABSTRACT Healthcare spending will account for 20% of the US GDP in 2028 (>$6 trillion), and the healthcare sector now employs 11% of the US workforce. Regenerative medicine and biomaterials will play an important role in revolutionizing therapeutic intervention strategies to address chronic and genetic health conditions. This challenge will require research and engineering scholars with diverse expertise, knowledge, and perspectives to come together to identify unique solutions. However, with very few formal graduate research training mechanisms in place, the US is falling behind in the development of young scientists who are pursuing postgraduate degrees and employment in these important research areas in the regenerative medicine industry. Moreover, the few opportunities that exist for graduate researchers only provide exposure to a single dimension of stem cell biology and regenerative medicine and have limited industry-focused training and entrepreneurship opportunities. To bridge this gap, the Regenerative Engineering, Science, and Technology Education Program (RESTEP) in Arizona will: (i) enable trainees to build advanced experimental laboratory research skills in regenerative medicine-focused areas while simultaneously facilitating trainees in developing quantitative and critical skills for hypothesis formulation and testing, experimental design, and statistical data analysis and interpretation, (ii) motivate students to develop cross-disciplinary skills, such as oral and written scientific communication as well as responsible innovation and conduct in research, and (iii) provide trainees with opportunities to engage and participate in multiple aspects of the stem cell biology and regenerative medicine industry that span laboratory to market. RESTEP will recruit and support cohorts of 7 predoctoral students each year who will be paired with faculty mentors. Over a two year period, trainees will receive individual instruction in their thesis laboratory, learn from core technical training bootcamp short courses, and take equipment-specific training workshops to improve their technical skills. Additionally, they will receive guidance regarding scientific communications, responsible innovation, and responsible conduct in research. Finally, trainees will complete entrepreneurial training, work on relationship-building with biotechnology industry partners, and experience a formal internship. Through this training program, we seek to develop a new generation of scientists and engineers who will drive the advancement of regenerative engineering and its application to improve human health.

NIH Research Projects · FY 2025 · 2025-08

PROJECT SUMMARY Maternal obesity is epidemiologically linked to offspring's risk of colorectal cancer (CRC), the third most prevalent cancer worldwide. In the United States, nearly half the women of childbearing age are obese or overweight with the trend likely to continue to rise. Along with alarming levels of obesity is the increasing incidence and mortality rate of CRC in younger populations, suggesting very early exposure may result in later development and progression of tumorigenesis. To develop meaningful preventative interventions, the underlying molecular details impacting offspring's risk need to be addressed. Our goal is to determine the impact of maternal obesity on the transformative risk in offspring by directly assessing the developmental programming of intestinal stem cells (ISCs), the cell-of-origin for many intestinal cancers, during pre and postnatal growth. Our aims are predicated on our previous studies from adult mice maintained on a pro-obesity high-fat Western diet (HFD) in which we determined an increases stem cell numbers, proliferation, regenerative capacity, and ability to accelerate tumorigenesis. These features are governed by PPAR-delta or PPAR-alpha, two nuclear receptors orchestrating multiple aspects of lipid metabolism. We established that the metabolic-transcriptional PPAR axis is necessary to enhance stemness and tumorigenic potential, and also stabilize the enhanced HFD-induced ISC chromatin state by epigenetic adaptations. We anticipate a similar program occurs in ISCs from mice exposed to maternal obesity. We posit that naïve exposure to an obesogenic maternal environment establishes a pro-tumorigenic ground state in offspring's intestinal stem cells. Using genetically engineered mouse and organoid models, our objective is to distinguish ISC developmental programming and determine both early intrinsic adaptations and extrinsic environmental interactions that promote establishment of a stable pre-pathological ISC ground state. Our aims are to: (1) interrogate the effects and durability of a pro-obesity maternal diet on offspring's colonic stem cell state; (2) test the requirement and sufficiency of intrinsic lipid mediators in ISC homeostasis and risk of later tumorigenesis; (3) test the contribution of external inflammatory signaling during ISC developmental programming and persistent tumor risk. Elucidating offspring's tumorigenic risk distinctly in ISCs established during maternal dependence is necessary to ascertain how the ISC environment contributes to intestinal homeostasis and long-term disease risk. This proposal will advance our nascent understanding of the developmental programming in early life that leads to health and disease disparities in later life.

NIH Research Projects · FY 2025 · 2025-08

PROJECT SUMMARY Postoperative abdominal adhesions are a major economic and medical burden and remains a significant clinical issue due to the lack of effective treatments. Estimates suggest more than 25% of laparotomy patients are re- hospitalized due to formation of abdominal adhesions within 5 years of the initiating event, leading to annual healthcare costs in the US upwards of $2.3 billion. Despite attention to this issue and the development of a variety of commercially available treatments made from a variety of materials, these products are generally considered only partially effective and there remains an unmet need for effective approaches to limit and prevent postoperative adhesions. We have developed Serograft, a novel bio-inspired and bio-derived membrane to reduce / eliminate formation of post-surgical abdominal adhesions. Serograft is a decellularized, regenerated membrane derived from intestinal serosa and is thus composed of the same lubricating constituents found in endogenous serosa – the native lubricating layer on visceral organs. Ex vivo testing indicates a significant reduction in adhesion measured by shear test and a pilot study in induced abdominal adhesions in rats demonstrated that Serograft outperforms both commercially available cellulose-based membranes and fibrin patches on blinded scoring of degree of adhesion formation at 7 days post-op. This proposal will focus on the further engineering of Serograft in a Janus format to achieve two overall goals: enhancement of anti-adhesive properties on the peritoneal cavity-facing side of the material, and increased tissue adhesivity on the target organ-facing side of the material. Aim 1 will focus on the development of porcine- and bovine- serosa-derived variants of Serograft with conjugation to different forms and densities of poly(ethylene glycol) (PEG), to enhance the anti-adhesive properties of the membrane. Aim 2 will focus on the Janus format of Serograft by incorporated a chitosan methacrylate layer on one side of the material which will impart increased tissue adhesivity to the target tissue in a wet environment. Both aims will employ ex vivo, in vitro, and in vivo studies to systematically characterize the properties, performance, and biocompatibility of the materials. The success of the research is supported by a strong, diverse team with complementary scientific expertise in biomaterials, inflammation and tissue responses, and animal models with additional support from expert colorectal surgeons with extensive clinical experience in the real-word relevance of the proposed application. Using the design-build-test biomaterials development principles and well-established bioengineering methods, this proposal will leverage the innovative and scientifically robust environment at Arizona State University and neighboring institutions to develop a novel therapeutic intervention for abdominal adhesion prevention, with a strong path to clinical translation.

NIH Research Projects · FY 2025 · 2025-08

Project Summary The use of bone morphogenetic proteins (BMPs) shows promise as therapeutics for improving bone repair; however, high supraphysiological concentrations required for the desired osteoinductive effect, costs, and patient variability have prevented the full advantages of BMP-based therapeutics from being realized. Thus, there is a clinical need to develop new bone tissue engineering approaches that promote osteogenesis at lower BMP doses and prevent adverse side effects. In the native extracellular matrix (ECM), BMP is tightly bound by proteins and glycosaminoglycans with its presentation regulated in time to enhance bioactivity. Furthermore, researchers have shown significant synergies with other signaling molecules, such as cell-matrix or cell-cell adhesion ligands. To mimic these interactions, a number of elegant approaches based on photopatterning and orthogonal chemistries have been developed for presenting biomolecules. However, these approaches rely on highly customized chemical reactions (which may be difficult to implement with full length proteins) and are generally restricted to 1-2 biomolecules. They are also often based on photocleavage reactions for temporal control, which precludes their reversibility over multiple cycles. Given the complexity of the extracellular environment (e.g., the stem cell “niche”) in controlling the fate of cells, a general platform that can control three or more proteins with user-defined, temporal control over protein immobilization would be invaluable for teasing apart the factors that control behavior like cell proliferation, migration, differentiation, and new tissue formation, especially in the context of BMP-induced bone repair. With this in mind, the proposed studies will 1) provide new insight into the temporal role of cell adhesion and growth factor binding during BMP- induced osteogenesis and 2) identify key biomaterial design parameters for promoting bone repair.

NIH Research Projects · FY 2025 · 2025-08

We have recently shown that mpox/monkeypox virus (MPXV) is unique amongst the orthopoxviruses in being at least partially sensitive to the anti-viral effects of type I interferon (IFN). IFN-sensitivity of MPXV is dependent on the host IFN-inducible Z-nucleic acid sensor ZBP1, acting through RIPK3 and MLKL. VACV contains an IFN-resistance protein, E3, that contains an N-terminal Z-NA binding domain that competes with ZBP1 for binding virus-induced Z-RNA, and thus inhibits sensing of virus infection by ZBP1. This domain is truncated in the MPXV homologue of E3 (the MPXV F3L gene), likely leading to the IFN sensitivity of MPXV. Since both current vaccines for protection against MPXV contain full-length E3L genes, both of the current vaccines could potentially repair the F3L truncation in MPXV-infected individuals who are then vaccinated. In this grant we will establish a MPXV skin CAST/EiJ mouse model. We will use this model to evaluate virulence of multiple strains of MPXV, including clade 1, clade IIA and clade IIB MPXV. We will then use this model to evaluate efficacy as a vaccine, of a novel highly attenuated, replication-competent strain of vaccinia virus that cannot repair the truncation of the MPXV F3L gene.

NIH Research Projects · FY 2025 · 2025-07

Project Summary: Chromera velia is a photosynthetic, free-living algae that is closely related to apicomplexans, which are a phylum of intracellular parasites responsible for many devastating diseases, including malaria, cryptosporidiosis, and toxoplasmosis. With molecular and cellular landmarks that are clearly related to but distinguishable from those found in apicomplexan parasites, Chromera provides a fantastic opportunity to investigate the evolutionary origin of structures and processes integral to intracellular parasitism. However, tools for defining localization and functions of gene products do not exist for Chromera, which creates a major bottleneck for exploring its biology. We propose to overcome these hurdles. Specifically, we will establish a molecular map of the subcellular structures in Chromera, focusing on identifying structures related to those known to be important for apicomplexan infection of host cells (Aim 1). In parallel, we will develop transformation tools that will enable function analysis in Chromera (Aim 2). Our work will yield fundamental insights into the evolution of aspects of cellular physiology essential for the intracellular parasitic life-style of the apicomplexans. It will also develop for the community molecular genetic and cell biology tools that will synergize evolutionary cell biology research for apicomplexans.

NIH Research Projects · FY 2025 · 2025-07

SUMMARY Psoriasis vulgaris (or plaque psoriasis) is a chronic skin disease affecting 2-3% of the worldwide population and the most common manifestation of psoriasis. Though psoriasis has a low mortality rate, it is strongly associated with several potentially deadly comorbidities, including several cancers, and psoriasis patients experience significantly elevated levels of depression, anxiety, and completed suicide. There is a recognized unmet need for new treatments against moderate-to-severe psoriasis due to the development of treatment inefficacy and high costs for more effective, second-line treatments. Despite substantial progress in characterizing the molecular mechanisms of psoriasis, the molecular events stimulating the initiation and pathogenesis of plaque psoriasis remain unknown. While inflammation, particularly Th17-driven, has gained attention, there is significant ongoing debate about the role of both immune dysregulation and keratinocyte dysfunction in the onset and progression of psoriatic disease, and investigation of druggable factors from keratinocytes is warranted. SerpinB3 is a keratinocyte-expressed serine protease inhibitor with substantial evidence for a potential mechanistic role in psoriasis. SerpinB3 is highly upregulated in the skin of patients with psoriasis and the misprocessed form of SerpinB3, Pso p27, is the dominant autoantigen found in the protein mass of psoriatic plaque scales. However, despite robust and suggestive evidence no studies investigating SerpinB3 as the initiating, etiological agent in the pathogenesis of psoriasis have been reported. This proposal will explore the hypothesis that misprocessing of SerpinB3 is the initiating agent of psoriasis in three aims. Aim 1 will focus on mechanistic investigation of SerpinB3 dysregulation in vitro using cell-based studies to understand how SerpinB3 may traffic from keratinocytes to mast cells, which evidences suggests produce Pso p27 despite do not endogenously expressing SerpinB3, as well as a role for Pso p27 in Th17-driven inflammation. Aim 2 will evaluate the role of mouse ortholog Serpinb3a in the pathogenesis of psoriasis with the imiquimod-induced psoriasis model in wildtype, Serpinb3a-deficient, and mast cell-deficient mice. Further, an investigation of whether Pso p27 is the etiological agent of psoriasis will be undertaken by direct delivery of immune complexes into the skin of wildtype, mast cell-deficient, and IL-17-deficient mice with no other stimulus. Aim 3 will explore whether SerpinB3 is a druggable target for the treatment of psoriasis at the transcriptional, translational, and post- translational levels in both human explanted culture models and mouse models. The success of the research is supported by a strong, diverse team with complementary scientific expertise in serpin biology, drug delivery, dermatology, and pathology. This proposal, a new direction for an early-stage investigator PI with established expertise in serpin biology and relevant techniques, will leverage the innovative and scientifically robust environment at Arizona State University and neighboring institutions to develop a paradigm-shifting molecular mechanism of disease in psoriasis with potential for therapeutic targeting with a solid path to clinical translation.

NIH Research Projects · FY 2025 · 2025-07

Digital health technologies and artificial intelligence (AI) are rapidly expanding how the behavioral and social sciences (BSSR) can advance chronic disease prevention and management. However, future BSSR leaders need mastery of contemporary methods for intervention development and advanced data analytics to harness these opportunities. We propose the Comprehensive Health Analytics Training for Behavior Change Technologies (ChatBCT) career development program – in the College of Health Solutions (CHS) at Arizona State University (ASU) - to support predoctoral trainees in acquiring advanced training in digital health analytics and personalized behavior change. Our approach is comprehensive and focuses on four core competencies: (a) digital health technology design for health behavior change, to ground scholars in theory-driven and user-centered approaches to technology development; (b) emerging adaptive and optimization methods and designs, to speed progress and foster innovation in intervention personalization; (c) data integration and curation techniques, to leverage the unique challenges and opportunities of digital health data (e.g., wearables, smartphones, time-intensive self-reports, and other pervasive sensing platforms); and (d) advanced data analytics, to equip scholars with skills in advanced regression, deep learning, digital twin, generative AI, transfer learning, and explainable AI. BSSR participating faculty have expertise in digital health and other behavioral interventions in a range of behavioral domains including physical activity, nutrition, substance use, cancer prevention and control, sleep, and more. Data science participating faculty have expertise in applied statistics, AI/machine learning (ML), and algorithm design. ChatBCT will support three annual cohorts of three new predoctoral scholars (N total = 9). Six will be funded by this program, and an additional three will be funded internally at ASU to sustain the program. Scholars will be co-mentored by a multidisciplinary pair of BSSR and data scientists. The ChatBCT curriculum and activities will include foundational courses in research methods and statistics; flagship courses in digital health design and integrated advanced research methods and data analytics; laboratory rotations and internships; problem-based models of inquiry through case studies; journal clubs; and professional development seminars. Importantly, ChatBCT scholars will engage in these activities alongside data science scholars in biomedical informatics, biostatistics, computer science, and engineering to foster team science. We are committed to recruiting a highly qualified pool of scholars. ChatBCT is poised to produce next-generation BSSR scientists capable of developing more effective and precise digitally-delivered behavioral interventions for chronic disease prevention and management.

NIH Research Projects · FY 2026 · 2025-06

Project Summary This new RO1 application entitled “Understanding the Role of Mechanical Load in Endogenous and Induced Mammalian Digit Regeneration” is focused on determining how mechanical load regulates various aspects of mammalian appendage regeneration. In the US, one in 190 people is living with limb loss, and that number is projected to double by the year 2050. Present treatments for limb amputation include replantation of amputated parts, revision amputations to accommodate prosthesis fitting, transferring tissue from other locations (e.g. toe-to-thumb transfer), or hand transplantation. These treatments are not without risks and the restoration of normal function is rarely realized. An alternative approach is to utilize the mouse digit, which possesses amputation-level-dependent regeneration capabilities, to inform the development of targeted therapies for inducing multi-tissue regenerative responses at otherwise non-regenerative digit amputation wounds, with the ultimate goal of scaling those therapeutic strategies up to the amputated limb. This approach has led to the discovery that BMP2 induces patterned bone regeneration at otherwise non-regenerative digit amputation wounds, and remarkably, BMP2 induces patterned tibia and fibula regeneration at limb amputation wounds. These findings are a proof-of-concept that induced-regeneration outcomes in the digit can be scaled up to the amputated limb. We have recently reported that mouse digit tip regeneration is mechanical load dependent, and that hindlimb unloading mice during digit tip regeneration inhibits regeneration at the earliest stages. In our preliminary studies, we have identified the mechanosensitive ion channel, Piezo1, is expressed throughout the regenerating digit. Moreover, injecting a Piezo1-agonist rescues the catabolic stage of digit tip regeneration when mice are hindlimb unloaded. Studies in Aim 1 will determine if the Piezo1-agonist is capable of rescuing the anabolic component of digit tip regeneration, as well as determine if Piezo1 expression in monocytes and osteoprogenitor cells is required for successful regeneration. In Aim 2, we will determine the mechanical properties of the unamputated and regenerating digit tip. These studies will use compression based microcomputed tomography scanning and atomic force microscopy combined with fluorescent imaging various to quantify the mechanical properties of the regenerating bone. These data will subsequently be incorporated into a finite element model which we will use to predict various components of digit tip regeneration. In Aim 3, we will determine if mechanical load is required for BMP2-induced regeneration following non-regenerative digit amputation, as well as determine if increased mechanical load, either with treadmill running exercise or a Piezo1-agonist, can enhance BMP2-induced regeneration. The successful completion of these studies will determine the specific role of Piezo1 during endogenous digit tip regeneration, as well as elucidate if mechanical load is required for non-regenerative appendage injuries.

NIH Research Projects · FY 2026 · 2025-04

Project Summary: The apicomplexans are unicellular parasites that infect a wide variety of vertebrates and invertebrates, and are the causative agents for many diseases (e.g., malaria, toxoplasmosis, and cryptosporidiosis) that impact the global population. Although differing greatly in host range and specificity, these parasites share similar major features in their cellular architectures, with species-specific modifications. For example, they all have an array of cortical (subpellicular) microtubules rooted in a ring-like structure (the apical polar ring), but the number of cortical microtubules varies widely (e.g., two to four in P. falciparum asexual blood-stage parasites vs. 22 in T. gondii). Chemical inhibition of microtubule polymerization results in ill-formed daughter cortex and inviable progeny, indicating that the construction of the cortical microtubules is required for guiding the growth of the parasite cortex and proper packaging the daughter organelles. Although their importance to parasite replication has long been appreciated, the basic mechanism of patterning and development of the cortical microtubules remains unexplored. In the last few years, we discovered that the structure and activities for both the apical polar ring and the cortical microtubules are distinct in the mature vs. growing daughter parasites and can be separated genetically. We will take advantage of this unique launch pad and combine it with molecular genetic, microscopy, and comparative proteomics to explore the initiation of patterning (Aim 1), growth and maturation (Aim 2) of the microtubule array. This project will open new avenues for discovering new druggable, parasite- specific targets for treating toxoplasmosis, generate novel molecular and structural insights into the mechanism through which complex cytoskeletal frameworks are assembled, and enable comparative studies of the biogenesis of mcrotubule arrays in other apicomplexan parasites. When integrated with the naturally occurring variations among these relatives, this will help to reveal the molecular basis for divergence of apicomplexan cytoskeletal structures, an important part of the evolution of this group of parasites.

NIH Research Projects · FY 2026 · 2025-04

Abstract Sepsis is a life-threatening condition that occurs when the body's response to an infection damages its tissues and organs. It can quickly progress to septic shock, leading to multiple organ failure (heart, lung, kidney) and death. Sepsis is often difficult to recognize in emergency departments and intensive care units because it is a milieu of nonspecific symptoms, and a rapid diagnosis enabling earlier intervention could save many lives and preserve heart and lung function as myocardial depression occurs in 50% of patients with sepsis. The current diagnosis of sepsis requires a complex evaluation of signs and symptoms, identification of the infection source, and laboratory tests to assess systemic inflammation and organ dysfunction. The team has performed sepsis- animal studies and probed the diagnostic accuracy of sepsis through urine biomarkers of hypoxia. Other biomarkers in blood, such as arterial blood gas pH and lactate, can be used to monitor a patient's sepsis response to treatment. However, due to the invasive nature of blood sampling and associated safety requirements, sepsis diagnosis typically occurs in hospital laboratories. Urine analysis is a non-invasive method for diagnosing various diseases and is suitable for sepsis detection. A timely sepsis diagnosis without a blood test would represent a significant breakthrough in the medical field. Due to the invasive nature of blood analysis, arterial blood gas pH or lactate clearance is typically assessed over hours to a day rather than minutes. Continuously monitoring of urine sepsis biomarkers enables the patient's sepsis early diagnosis within minutes (less than 200 minutes), not several hours to a day. The team will develop a continuous, real-time, automated Smart Catheter Analyzer for early identification of sepsis through urine biomarkers to enable clinicians to respond quickly to support heart and lung function. It is envisioned that the device will be used by minimally trained personnel in emergency departments, urgent care, rural emergency services, intensive care units, and out-of-hospital settings. The team, comprised of sensors, engineering, computer science, medical and clinical research, and medical device industry/manufacturing expertise, will work to design and develop the Smart Catheter Analyzer for sepsis-related urine biomarkers in a 2-year R61 (Phase I) and to further develop and refine the Smart Catheter’s Algorithm for Sepsis in a 1-year R33 (Phase II). The device prototype developed in Phase I at Arizona State University will be used in a study during Phase II at Mayo Clinic Arizona, comparing noninvasive biomarker patterns in septic and non-septic cases. Industrial partner, Sequitur Health Corp., will contribute to the acceleration of the technology towards practice. This project will enhance medical personnel's technical capabilities for the diagnosis and treatment of sepsis and enable gains of scientific knowledge for heart and lung-related functions.

NIH Research Projects · FY 2025 · 2025-03

PROJECT ABSTRACT Severe maternal morbidity (SMM) is defined as an unexpected adverse outcome during pregnancy or postpartum (PP) with significant short- or long-term negative consequences to a woman’s health. Rates of SMM have risen substantially in the past decades and are >50% higher for non-Hispanic Black women than non-Hispanic White women. Leading causes of SMM and associated deaths are preventable and result, in part, from a systems-level failure to recognize and manage the co-occurring physical, mental, and social risk factors that women experience across the perinatal, intrapartum, and PP periods. Adequate prenatal care and appropriate management of chronic conditions during pregnancy may mitigate rising maternal risk. However, important knowledge gaps limit efforts to improve and optimize care. First, clinicians and health systems are limited in predicting patients who will be most likely to have complications such as SMM. Second, social determinants of health (SDOH), defined as, conditions in the places where people live, learn, work, and play that affect a wide range of health and quality-of life-risks and outcomes, may be an important determinant of outcome disparities and inadequate prenatal care. However, SDOH may be sub-optimally captured by using routine screening questions during patient encounters and population-level exposures. We propose addressing these critical knowledge gaps by leveraging highly granular, longitudinal clinical data linked with SDOH data derived from the Patient-Centered Outcomes Research Institute (PCORI)-funded INSIGHT Clinical Research Network (Co-PI Pathak) on >365,000 women across New York City (NYC). In Aim 1, we will link longitudinal electronic health records (EHRs) and claims data and characterize the study cohort. We will also ascertain community- and individual-level measures of SDOH by linking population-level SDOH data for the study cohort using natural language processing (NLP) and machine learning (ML) methods from clinical note narratives. In Aim 2, we will predict the risk of SMM, as well as assess fairness and bias through ML models. Our rich multi- level data, measurement, and analytical approach will apply ML models to analyze EHRs and community/neighborhood- and individual-level SDOH data, and ascertain key drivers and predictors of SMM risk. In Aim 3, we will collaborate with the recently established NICHD U54 center to study the clinical interpretability and actionability of ML-based risk models for SMM. Findings from this aim will provide actionable recommendations in future risk score implementation efforts using point-of-care clinical decision support tools.

NIH Research Projects · FY 2026 · 2025-03

7. Project Summary/Abstract Residents of rural areas often exhibit lower rates of physical activity (PA), correlating to elevated cancer incidence and mortality rates compared to urban dwellers. The lack of PA resources significantly contributes to the lower rates of PA observed among racially and ethnically diverse and lower-income rural populations. A major obstacle to addressing urban-rural PA and cancer disparities is an insufficient understanding of the neighborhood environment—specifically, the pedestrian environment features that inhibit or promote PA— which can be cost-effectively modified. Existing, publicly available pedestrian environment measures assess macroscale walkability features (e.g., land use mix, street intersection density) that are costly and infeasible to improve in rural areas. While smaller-scale research has identified more affordable, microscale Pedestrian Environment Features (PEFs) (e.g., sidewalks, crosswalks, lighting), person-led, microscale audits of PEFs show limited feasibility across expansive rural geographies. Machine learning algorithms have been developed using data from urban and suburban areas to audit microscale PEFs, but these can introduce bias when scaled up for use across expansive rural areas to study their relationship with PA. Addressing urban-rural cancer disparities necessitates assessing the association between microscale PEFs and PA in both urban and rural areas of the US. Therefore, we propose three specific aims: 1) further validate existing machine learning algorithms to assess 9 microscale PEFs (sidewalks, sidewalk buffers, curb ramps, zebra and line crosswalks, walk signals, bike symbols, benches, and lighting) for rural areas, 2) test the relationship between rural microscale PEFs and middle to older age adult PA, and 3) identify disparities in microscale PEFs by income levels, racial and ethnic composition, & geographic location across the US. We will retrain and leverage existing deep learning classifiers developed as part of preliminary work funded by the National Cancer Institute to assess urban and suburban microscale PEFs, to create classifiers that generalize and perform well in rural areas. We will validate these microscale PEF classifiers with human virtual audits and examine their relationship with PA among middle and older age adults, given this age group is at high risk for physical inactivity. We hypothesize that greater rural PEFs will be associated with greater minutes per week of total PA and walking, as measured by the International Physical Activity Questionnaire, after adjusting for covariates. Finally, we will explore income, racial, ethnic, and regional disparities in rural microscale PEFs across the US where policy or environmental intervention may be necessary. This project aims to validate a new scalable tool for identifying rural PEFs and uncovering potential environmental and health-related disparities in diverse rural locales across the US. Results will inform larger-scale research that uses AI-measured PEF assessments to address physical inactivity and cancer-related health disparities. In turn, existing cancer prevention and PA promotion initiatives can intervene on lower-cost and modifiable neighborhood environment features.

NIH Research Projects · FY 2025 · 2025-01

PROJECT SUMMARY Funds are requested to provide partial support for the 69th Annual Conference of Coccidioidomycosis Study Group (CSG) to be held on April 5-6, 2025, hosted by the Arizona State University Health Futures Center in Phoenix, Arizona. CSG prides itself on bringing the largest group of coccidioidomycosis researchers together to share the latest clinical and basic laboratory findings, provide opportunities for collaboration, and especially to promote the development of junior trainees. Researchers, physicians, veterinarians, other healthcare providers, epidemiologists, and various trainees (students/residents/fellows/postdocs) from over 30 laboratories have attended annually. The CSG typically rotates between Arizona and California, but the 68th CSG was in San Antonio which is at the edge of the endemic region. A growing number of medical mycologists have attended this meeting, leading to its longevity and significance over the past 68 years. Although the meeting format has evolved over the years, the current format focuses on oral and poster presentations by trainees regarding their most exciting and impactful research data. The small group setting provides a welcoming environment that successfully promotes discussion and constructive feedback for trainees. The program includes seven scientific sessions with 38-40 slots for trainees’ oral presentations, a poster session, a keynote speaker, a business meeting hour, and a sponsor-funded banquet. The small group setting in the planned program and attendance by PIs and trainees is excellent for networking and promoting trainee development Dr. Thuy Le, a renowned medical mycologist from Duke University in the area of talaromycosis has accepted our invitation to be the 2025 keynote speaker. We request 10 travel awards ($750 each) for trainees to present in-person and to encourage more early career scientists to attend the meeting. Travel award recipients will be selected on the basis of their application for (i) need of travel support and (ii) quality and merit of their research. Aligning with DEI requirements, we will also assign a higher priority for women and minority trainees as well as anyone challenged with a physical disability.

NIH Research Projects · FY 2026 · 2025-01

Project Summary Uncovering the mechanisms enabling the cross-species jumps of viruses that happen in nature is essential for our understanding of viral spillovers, most notably those that can result in severe disease outbreaks, for example, the coronavirus SARS-CoV-2 pandemic and Mpox (monkeypox) epidemic. Therefore, studying the evolution of viruses that cause species jumps is essential. Myxoma virus (MYXV), a leporipoxvirus, is nonpathogenic in its evolutionary host (Sylvilagus sp.) but was highly lethal (causing myxomatosis) immediately after it leaped into European rabbits (Oryctolagus cuniculus) in the late 19th century. The introduction of MYXV to control feral European rabbit populations in Australia and Europe in the early 1950s presents the best-documented field example of host-virus co-evolution. In 2018, a new natural MYXV variant was identified in Iberian hares (Lepus granatensis) in Spain, causing a myxomatosis-like disease in hares and wild European rabbits. Between 2018 and 2020, the disease became endemic, with an estimated mean mortality rate of 55% in hares. This newly emerged MYXV variant, named MYXV Toledo (MYXV-Tol) or hare MYXV (ha-MYXV), has acquired a novel insertion of four viral genes “cassette” of ~ 2,800 bp within the M009L gene. The MYXV-Tol genome also includes three disrupted genes (M009L, M152R, and M036L). We recently reported that the C7-like host range gene M159-Tol present in the MYXV-Tol recombination cassette is essential for infection and replication in hare cells, suggesting that M159-Tol may be required for the extreme pathogenicity in hares. Since MYXV-Tol is also isolated from wild European rabbits, we studied the pathogenicity of MYXV-Tol in European rabbits and compared it with MYXV-Lau and the C7-like host range mutant vMyxTol-M159KO. Our results, for the first time, demonstrate that the natural MYXV variant MYXV-Tol has adapted to cause a uniquely different lethal disease and pathogenicity in European rabbits compared to typical myxomatosis caused by MYXV-Lau. Surprisingly, the deletion of M159-Tol had minimal or no effect on the disease progression and pathogenicity of MYXV-Tol in rabbits. Thus, M159-Tol may have adapted hare-specific host tropism functions, and we hypothesize that the additional newly acquired viral genes or the disruptions in some of the ORFs have enabled MYXV-Tol to cause a novel lethal disease in Iberian hares and European rabbits. In this application, we propose investigating the biological mechanisms and genetic changes in the MYXV-Tol that facilitate species leaping and cause novel pathogenicity and disease in European rabbits. Aim 1: Elucidate the biological mechanisms of how MYXV-Tol is causing a novel lethal disease in European rabbits. Aim 2: Define the genetic changes in MYXV causing the novel disease in European rabbits. This information will be essential for future identification of the unique cellular targets for MYXV-Tol. This R21 proposal will enable us to understand how natural genetic changes in poxviruses allow species leaping and sometimes cause a new lethal disease in a new host.

NIH Research Projects · FY 2026 · 2025-01

Title: Sustainability via Active Garden Education (SAGE): Scaling up evidence-based, policy-guided physical activity and nutrition education for preschoolers Sustainability via Active Garden Education (SAGE) is an evidence-based physical activity and nutrition program that has been delivered in low-income serving, early care and education (ECE; preschool) sites in Maricopa County, AZ. Gardens in ECE sites improve interest in and consumption of fruit and vegetables among young children; teach important science, social, and motor development skills; engage families and communities; and offer important outdoor learning opportunities. The overall objective of this project is to compare how three different SAGE implementation strategies impact measures of implementation (primary), sustainability (secondary), cost and child health outcomes (secondary). Strategies we will compare include (1) SAGE (garden + online curriculum + materials box) vs. SAGE plus e-support implementation package (text messages + newsletters + hotline), (2) SAGE with no in person support and training vs. SAGE with in person support and training, and (3) SAGE usual activities vs. SAGE with a ECE virtual learning collaborative to share SAGE implementation experiences and strategies with other ECE sites and community partners. We will (Aim 1) apply the Consolidated Framework for Implementation Research (CFIR) to identify inner and outer setting characteristics that hinder or facilitate SAGE implementation to tailor support strategies for local context; (Aim 2) use the Multiphase Optimization Strategy (MOST) framework to analyze SAGE implementation strategy components to determine the most efficient and effective combination of strategies across contexts; and (Aim 3) investigate the potential for sustainability, costs and cost effectiveness outcomes that may influence implementation strategies and their effect on locomotor skills and nutrition effectiveness outcomes. In Aim 1 (MOST screening), we will measure ECE site and teacher characteristics via an in person visual assessment and a teacher and director survey (inner setting). We will also complete a social network analysis of ECE personnel. With this information we will use an implementation mapping process to collaboratively develop and finalize implementation strategies. In Aim 2 (MOST refine), 32 existing SAGE ECE sites will be pair matched by degree of individual implementation and site characteristics (size, enrollment) assessed in aim 1, and assigned to one of eight implementation strategy combinations to a full factorial model. Sites will be assessed at the beginning and ending of the academic year with site audits, parent and teacher surveys, and non-invasive child fitness, physical activity, veggiemeter and eating in the absence of hunger measures. For Aim 3, (MOST refine) the potential for sustainability, costs and cost effectiveness ratio for each of the strategies will be calculated from a payer and societal perspective to determine which implementation strategy or combination of strategies may be most scalable. Results will help inform decisions about garden and curriculum implementation strategies that can be scaled for ECE sites in underserved communities.

NIH Research Projects · FY 2026 · 2025-01

PROJECT SUMMARY My research program has the goal of identifying predictive rules of cross-species viral transmission (or ‘spillover’) from wild mammals to humans. To do so, we study processes at both global and local scales. This work comes at a pivotal time for human health globally, with recent outbreaks of Ebola, monkeypox, MERS, and SARS- related CoVs all originating in wild mammals. Societal decisions increasingly hinge upon the ability to identify and mitigate risks of spillover. However, which types of species interactions carry the greatest zoonotic risks? The answer is not straightforward. Not only are complex ecological dynamics involved, but also the complex histories of biologists studying the involved species. Taxonomic classifications of wild mammals and their viruses are at center stage, not least because the flood of genomes is changing views of evolutionary relationships. Quelling the unfolding drama of emerging wildlife viruses will require attention to both the quality of public data that informs global models and the quantity of data available for local models of mammal-virus dynamics. Over the next five years, my research group will develop projects to address gaps in mammal-virus knowledge in the following areas. (1) Decay in the quality of public genetic and phylogenetic data through time requires systems to update the taxonomy of species names used to label and aggregate data. With 45% more mammal and 500% more virus species now recognized than 30 years ago, global mammal phylogenies and spillover risk models are quickly becoming outdated. In response, we will build automated tools for curating mammal and virus genetic data, including a pipeline for regularly re-inferring the Mammalia species-level molecular phylogeny from curated data. (2) Most models of spillover risk offer coarse-grain predictions due to data imprecision. But categories of all bats or all rodents hide the tremendous eco-physiological and immune variation among species. In response, we will apply the taxonomically updated data curated by our tools to test the sensitivity of species-level spillover risk models globally. (3) Lack of local knowledge of how viruses are shared among hosts requires a renaissance of field-based surveys coupled with genomic tools. We will sample forest-dwelling rodents in isolated montane habitats of Arizona’s Madrean sky islands to investigate the extent to which rates of gene flow predict viral sharing. If gene flow can proxy viral sharing, at least for certain taxa, then public DNA data can be leveraged to predict viral interactions without needing to describe the entire mammal virome, of which only ~3% is globally known. My research program will generate mechanistic models of viral spillover risk while contextualizing those results within mammal-virus evolutionary history. By unifying perspectives across scales, this research advances hypothesis-driven ecological studies of how and why viral spillover occurs while building tools for the global- scale curation of biomedically relevant data. Jointly, these synergistic projects will spur nonlinear outcomes.

NIH Research Projects · FY 2026 · 2025-01

Project Summary/Abstract Autistic adults have a 2.6 times higher risk for Alzheimer’s disease compared to those without autism, and less than 0.001% of autism research publications include older autistic adults. Previously, in both cross- sectional and longitudinal designs, we published that middle-aged and older (MA+) autistic adults experience accelerated cognitive and brain aging compared to neurotypical adults. Thousands of risk alleles have been identified in autism spectrum disorder, and it is not known whether they impact cognitive aging risk. Instead of assessing each risk allele separately, polygenic risk scores (PRS) enable the computation of a “genomic dosage” unique to each individual. This project assesses the central hypothesis that autism PRS scores contribute to accelerated age-related: Aim 1) memory decline; Aim 2) temporal lobe aging; and Exploratory Aim 3) sex differences in cognitive and brain aging in MA+ autistic adults. The proposed research will significantly impact biological understanding of cognitive and brain aging and sex differences in autism by incorporating both molecular and systems-level approaches. We will use powered multilevel mixed models to evaluate age by autism PRS interactions in predicting Aim 1) verbal and visual short-term and long-term memory and Aim 2) cortical thickness and hippocampal volume in MA+ autistic adults. Exploratory Aim 3 will identify the contribution of autism risk genes on autism-related sex differences in these measures. Ms. Harker is determined to become a tenure-track professor at an R1 university and an expert in the neurogenomics of autism and aging. Her long-term goal is to direct a cross-disciplinary clinical laboratory that emphasizes inclusion and diversity in autism research by understanding the relationship between brain aging and genetic risk in autistic individuals across the lifespan, especially women. Ms. Harker’s past training and experiences of 1) being autistic, 2) writing autism advocacy articles, 3) being an autistic research participant, and 4) doctoral coursework have prepared her to assume the role of a doctoral candidate and attain her academic and professional career goals in autism research. In her current laboratories, she has gained foundational knowledge in neuroimaging statistics/neuropsychology, genomics, autism ethics, and professional development. Through this proposal, she can translate these developing skills into expertise to discover and compare aging differences for neurotypical and autistic adults. Training will occur primarily at Arizona State University (ASU). ASU is a well-regarded R1 institution with collaborations at Barrow Neurological Institute’s top- notch neuroimaging facilities. This is an optimal, supportive training environment for Ms. Harker to hone her skills in interdisciplinary neuroscience. In addition to the proposed goals, training will focus on professional development and dissemination of findings to the broader autism community and will be empowered by Ms. Harker’s unique perspective as an openly autistic adult.

NIH Research Projects · FY 2025 · 2024-12

PROJECT SUMMARY Sex chromosomes have long been excluded in genetic and genomic research of human diseases, partially due to the technical challenges of analyzing the data from large-scale molecular profiling methods, such as next- generation sequencing (NGS). Yet their contributions are significantly implicated in the sex dimorphism of Alzheimer’s disease (AD). In this project, the team will apply a sex-chromosome-completement aware alignment approach to re-align large amounts of NGS data from large clinical cohorts of AD, for systematically investigating the genetic contributions of sex chromosomes to AD. Variants will be called based on the realignments, and both X and Y chromosomes will be specifically investigated for the variants’ associations with AD phenotypes. The team will also consider the contributions of the homologous X-Y gene pairs to gene expression and perform gene network analysis to evaluate how the expressions affect sex differences in AD. The reprocessed data will be disseminated to the public for broad use to benefit the scientific community. Taken together, the work will lay the foundation for determining the genetic components of sex chromosomes to AD and pave the way for future in-depth study of these genomic features and their implication in sexual dimorphism in AD.

NIH Research Projects · FY 2026 · 2024-12

PROJECT SUMMARY The goal of this work is to detect and differentiate with MRI the invasive NEU and GPM high-grade glioma subtypes based on their divergent microstructure, glycolytic metabolism, and glutaminergic synapse profiles. High grade glioma (HGG) brain tumors rank among the most lethal of all human cancers, with a median survival of ~17 months. Current therapies for HGG, like surgery and chemoradiation, rely on contrast-enhanced (CE) MRI to demarcate treatment targets based on tumor-associated blood brain barrier (BBB) disruption. CE-MRI is a powerful tool to detect these so-called “enhancing” lesions. However, infiltrating tumor cells extend well beyond the boundaries of BBB disruption and these “non-enhancing” tumoral regions remain invisible on CE-MRI. This failure of standard-of-care CE-MRI to detect infiltrating tumor leads to undertreatment of HGG and greater incidence of recurrence. Recently, four HGG subtypes have been identified based on developmental and metabolic features, including the proliferative/progenitor (PPR), neuronal (NEU), mitochondrial (MTC), and glycolytic/plurimetabolic (GPM) phenotypic subtypes and confers clinical implications. Expanding on this and using 313 image localized biopsy tissue samples across 68 HGG patients, recent work has shown that the majority of non-enhancing (invasive) tumor cells are of NEU or GPM subtype, and that they cluster spatially. The NEU subtype uniquely forms unmyelinated neurite-like microtubes and glutamatergic synapses with neighboring HGG and host cells, while the GPM subtype has a uniquely high glycolytic activity involving interaction with astrocytes, other glial cells, and infiltrating immune cells. The predominance of one subtype over the other influences biological behavior and therapeutic susceptibilities. For this reason, non-invasive methods to spatially resolve clusters of these invasive HGG subtypes would be a major advance in the diagnosis and treatment of HGG. To spatially resolve clusters of invasive NEU and GPM HGG subtypes, we will leverage well-established advancements in quantitative diffusion MRI (dMRI)-based unmyelinated neurite microstructure mapping and deuterium (2H) MRI-based mapping of glycolysis and neurotransmitter (glutamate) synthesis. We hypothesize that: 1. The GPM subtype will be made MRI-detectable based on low neurite-like microtube density, high glycolytic metabolism, and low glutamate synthesis, and 2. The NEU subtype will be made MRI-detectable based on high neurite-like microtube density, low glycolytic metabolism, and high glutamate synthesis. The Specific Aims of this work are: Aim 1. Establish and validate quantitative dMRI microstructural signatures of NEU and GPM HGG subtypes based on their known differential expression of neurite-like microtubes; Aim 2. Establish and validate quantitative metabolic 2H MRI signatures of NEU and GPM HGG subtypes based on their known divergent glycolytic and glutaminergic synapse phenotypes.

NIH Research Projects · FY 2026 · 2024-11

PROJECT SUMMARY (See instructions): 15-20% of the US population 65+ is predicted to be cognitively impaired. Age serves as the strongest risk factor for Alzheimer's Disease (AD) with 38% of cognitively impaired older adults predicted to develop AD within 5 years. Therefore, our ability to understand and identify mechanisms underlying age and AD-related cognitive decline that inform discovery of effective treatments for improving cognitive function is of utmost importance. The long-term goal of this research proposal is determine whether ACVR1 C functions as a self-regulating mechanism underlying age and ADrelated impairments in cognitive function where, downstream regulation becomes impaired with age and AD, and is maintained through self-directed aberrant epigenetic transcriptional repression in the female and male brain. The proposed experiments will test the central hypothesis that ACVR1 C represents a key novel mechanism that is disrupted with age and AD and contributes to age and AD-related cognitive decline. In the K99 phase of this award, I found that a member of the TGFr.. signaling family Acvr1c, serves as a bidirectional regulator of long-lasting forms of synaptic plasticity and long-term memory which becomes impaired with increasing age and in AD. Overriding this impairment through overexpression of Acvr1c in the dorsal hippocampus ameliorates impairments in long term memory and synaptic plasticity identified in aging and 5xFAD mice In the ROD phase, I will continue to investigate the role of Acvr1c in age and AD-related memory function. I will determine whether ACVR1 C functions as a self-regulating epigenetic mechanism mediating gene expression and memory in the adult, aging and AD female and male brain. To better understand how downstream ACVR1 C signaling may be contributing to impairments in age and AD-related memory formation we will first characterize how SMAD2 (phosphorylated by ACVR1C and forms a complex with SMAD4 to regulate gene expression) changes after learning in the adult, aging, and AD brain. We will determine whether enhancing ACVR1C function rectifies impairments in downstream SMAD signaling that occurs with aging and AD. Next, I will characterize epigenetic regulation of Acvr1c and the impact of enhancing Acvr1c function. I will identify how ACVR1C regulates gene expression and chromatin accessibility by performing snRNA-Seq and snATAC Seq following viral manipulations which enhance or repress Acvr1c function. These findings will 1) identify ACVR1 C as a novel self-regulating mechanism responsible for maintaining epigenetic dysfunction and repression associated with aging and AD-related cognitive dysfunction and 2) identify novel gene targets regulated by this mechanism which provide insight for therapeutic intervention.

NIH Research Projects · FY 2025 · 2024-09

Project Abstract Injection drug use is expanding and may compromise progress in achieving the 95-95-95 goals in South Africa, an already high HIV burden setting. At this time, there is 11.4-58.4% HIV prevalence range for people who inject drugs (PLWHID) with less than half adherent to antiretroviral therapy (ART) and virally suppressed. Despite established clinical guidelines for ART and opioid substitution therapy (OST) and harm reduction strategies, retention in treatment remains low. Our current ART-OST program provides free access to both treatments with recruitment and referral being led by peer navigators at Yeoville Clinic in the City of Johannesburg, South Africa. A clinic is located high population density setting and serves a low-income community with overlapping vulnerabilities like trauma and drug use. Over the last four years, 3021 PLWHIDs were initiated on ART, OST, or ART-OST, but the 12-month retention was low at 26%, 30%, and 31% respectively. Process evaluation outcomes showed that peer navigation alone may not be enough to support treatment outcomes, but PLHWID preferences for additional family engagement may address a support gap. Building upon our established ART- OST program infrastructure in Johannesburg, South Africa, we will assemble evidence-based practices for family-engaged interventions and enhanced training for peer navigators to deliver the intervention for ART and OST support, and then assess its preliminary impact in improving ART adherence and OST continuation. The intervention is called Project Vuselela (PV), meaning Restore in isiZulu. Our intervention will be guided by Social Action Theory and Information-Motivation-Behavior model. In Aim 1, we will develop PV guided by the Intervention Mapping model. We will assemble evidence-based practices for peer navigation and family engagement; interview PLWHIDs, family members and service providers to identify preferences for intervention content and delivery; and then establish implementation protocols and measures for fidelity and behavior change. Intervention development will be guided by a community advisory board. In Aim 2, we will pilot-test PV using randomized controlled trial design. PLWHIDs will be recruited who are newly engaged in ART and OST services. We will assess ART adherence and OST continuation (primary outcomes) at 3- and 6-months. If PV shows trending effectiveness, we will conduct an efficacy trial of the intervention that may be scaled to improve PLHWID HIV and OST outcomes in similar settings where injection drug use is expanding.