Univ Of Arkansas For Med Scis

NIH Research Projects · FY 2026 · 2026-06

Project Summary/Abstract Macroautophagy, here referred to as autophagy, is a recycling process that facilitates lysosomal degradation of cytoplasmic content, including protein aggregates and damaged organelles. In previous work, we showed that autophagy deficiency reduces osteoblast number and bone formation. In work leading to this proposal, we created a novel mouse model in which we stimulate autophagy by increasing expression of endogenous transcription factor EB (Tfeb) using CRISPR activation. This maneuver increased bone formation in cancellous and cortical compartments, leading to high bone mass and increased bone strength. These studies establish that autophagy in osteoblast lineage cells promotes bone formation. However, the mechanisms underpinning this effect are unknown. To fill this gap in knowledge, we used single-cell RNA sequencing (scRNA-seq) of bone cells from autophagy-deficient mice. This analysis revealed that autophagy deficiency increases senescence in osteoblast lineage cells. Moreover, we provide evidence that the autophagy insufficiency in two skeletal diseases, namely aging and Osteogenesis imperfecta (OI), is associated with reduced bone formation and elevated senescence. Specifically, we used scRNA-seq to compare skeletal aging and autophagy deficiency and show that many biological processes altered by aging are similarly changed by autophagy deficiency, including senescence. OI is another condition where insufficient autophagy may lead to osteoblast senescence and reduced bone formation. Misfolded procollagen aggregates are cleared by autophagy, and mutations in collagen or collagen processing enzymes exaggerate collagen misfolding to levels beyond osteoblasts' clearance capacity, leading to intercellular collagen aggregation. We found that insufficiency of autophagy in clearing procollagen aggregates in OI is associated with increased senescence markers in mouse models of OI. Importantly, we found that stimulation of autophagy in a model of OI increased bone mineral density. Together, our results reveal an association between autophagy insufficiency, increased senescence, and reduced bone formation in aging and OI. Therefore, we hypothesize that autophagy promotes bone formation by inhibiting cellular senescence in osteoblasts, and insufficiency of autophagy in aging and OI contributes to the loss of bone mass in these conditions. To test this hypothesis, we propose the following aims. Aim 1 will examine if autophagy promotes bone formation by preventing cellular senescence. Aims 2 and 3 will determine if there is a cause- effect relationship between autophagy insufficiency, senescence, and bone formation in aging and OI.

NIH Research Projects · FY 2026 · 2026-05

Project Summary/Abstract Glioblastoma and pancreatic cancers are among the most aggressive and drug-resistant cancers with poor prognosis and low survival rates. As current therapeutic interventions, which consist of surgical resection followed by radiation and chemotherapy, rely on DNA damage effects, there is an urgent need for new therapeutic strategies to improve outcomes for these patients. A key mechanism contributing to drug resistance in cancer is replication gap suppression (RGS), which helps maintain genomic stability by controlling single-stranded DNA (ssDNA) gaps that affect cell fitness during replication stress. Translesion synthesis (TLS), a process involving specialized DNA polymerases that bypass DNA lesions, plays a central role in RGS, allowing cancer cells to continue proliferating despite DNA damage. However, the mechanism remains unknown. The premise of this study is supported by published and preliminary data that shows: 1) a TLS polymerase kappa (Pol κ) is overexpressed in glioblastoma. 2) early doctoral findings show that Pol κ regulates RGS and fork speed in glioblastoma, processes essential for cancer cell survival. 3) my doctoral research has identified two novel roles of Pol κ: a) Pol κ prevents the accumulation of ssDNA gaps in glioma cells by preventing repriming by Primase DNA polymerase (PrimPol). b) Pol κ slows replication fork speed by promoting the fork reversal repair pathway. This research aims to test the central hypothesis that TLS polymerases enable tumor survival by facilitating the continuation of DNA replication without generating ssDNA gaps that limit cell fitness. Inhibiting TLS promotes ssDNA gap formation and enhances the sensitivity of cancers to standard therapeutics that generate extensive DNA damage that blocks the normal replicative polymerases. During the F99 phase, Aim 1a. will investigate whether Pol κ reduces ssDNA gaps produced from PrimPol by filling these gaps. In this approach, I first use polymerase extension assay to determine the role of Pol κ in extending synthetic substrates with ssDNA gaps. Aim1b. will determine the Pol κ’s mechanism in fork reversal by using enzymatic activity assays to measure changes in the specificity constant (kcat/KM) for Pol κ-mediated fork reversal. Aim 1c. will determine Pol κ interacting proteins during DNA replication using quantitative proteomics approaches TAP-MS and iPOND-MS. During the K00 phase, I will shift my focus to characterizing the architecture of ssDNA gaps and assessing TLS polymerase activity in pancreatic cancer cells. I will involve nanopore sequencing to determine the positions, numbers, and size of the ssDNA gaps in the context of TLS polymerase inhibition to enhance cancer cell sensitivity to DNA-damaging agents. To complete these aims, I have assembled a mentoring team of leaders in cancer research and drug resistance with expertise in enzymology, proteomics, and genomics approaches. These new approaches, combined with my already strong background in genetics, cell biology, molecular biology, and biochemistry, will allow me to address the most challenging issues facing standard therapeutics in challenging cancers and prepare me to pursue a career as an independent academic investigator.

NIH Research Projects · FY 2026 · 2026-05

PROJECT SUMMARY Fetal alcohol spectrum disorders (FASD) occur in almost 5% of children in the U.S. Neurologic deficits associated with FASD are life-long and there is no cure for FASD. The overarching goal of our research is to define the mechanisms by which ethanol causes pathology of the developing central nervous system in order to generate therapeutics to prevent and treat FASD. The focused goal of the proposed studies is to define the roles of oligodendrocyte-lineage cells and myelination in ethanol-induced dysfunction in the developing brain. Studies in rodent models of FASD reveal ethanol exposure produces cerebellar Purkinje neuron loss and behavioral deficits consistent with prominent cerebellar dysfunction in human FASD. Studies by us and others revealed ethanol decreased expression of transcripts associated with oligodendrocyte lineage cells including oligodendrocyte progenitor cells (OPCs) and mature myelinating oligodendrocytes in the developing cerebellum. This suggests that ethanol could contribute to the dysfunction of oligodendrocyte-lineage cells leading to altered network function through aberrant OPC-synapse interactions and changes in myelination. Hypothesis: Alcohol exposure in the developing brain elicits altered myelination through effects on oligodendrocyte lineage cells, and altered OPC-neuron interactions resulting in neuropathology associated with FASD. Model: We will use our well- established neonatal mouse model of FASD with ethanol treatment on postnatal days 4-9; this is equivalent to human in utero, third-trimester fetal alcohol exposure. This period of development is characterized by extensive neurogenesis, robust myelination, and complex glia–neuron interactions critical to normal brain development. In Aim 1 we will determine the effects of developmental ethanol exposure on oligodendrocyte linage cells. (SubAim A) We will examine the effects of ethanol on the number and distribution of oligodendrocyte-lineage cells ranging from OPCs to mature myelinating oligodendrocytes using immunohistochemistry and lineage fate mapping techniques. (SubAim B) We will determine the effects of ethanol on oligodendrocyte lineage phenotypes by RNA sequencing of isolated cells. In Aim 2, we will determine the effects of developmental ethanol exposure on OPC motility and OPC-neuron interactions. (SubAim A) Physical interactions between OPCs and neurons will be determined at the light microscopy level. (SubAim B) OPC motility and dynamic interactions between OPCs and neurons will be determined by two-photon imaging. (SubAim C) The effects of ethanol on OPC function will be evaluated. In Aim 3. We will determine if agents that promote myelination protect against ethanol induced demyelination, neuropathology, and long term behavioral deficits in a mouse model of FASD. The proposed highly innovative studies will address critical knowledge gaps and advance our understanding of FASD.

NIH Research Projects · FY 2026 · 2026-05

Summary Head and neck squamous cell carcinoma (HNSCC) is a major global health challenge, with a high rate of recurrence and metastasis leading to a median survival of only 10-12 months for patients with advanced disease. While immune checkpoint blockade (ICB) has revolutionized treatment, its effectiveness remains limited, with a response rate of only 11-18% at six months. This proposal seeks to address the critical issue of T cell exhaustion (TEX), which hampers the efficacy of immunotherapies like ICB and adoptive cell transfer (ACT). Our preliminary data indicate that TEX is associated with the accumulation of DNA double-strand breaks (DSBs), resulted from the inhibition of the 53BP1-dependent DNA repair activity by glycogen synthase kinase 3β (GSK3β)-mediated phosphorylation. We have developed a knock-in mouse model that expresses a mutant 53BP1 which prevents GSK3β-mediated phosphorylation and inhibition. Using our model, we discovered that blocking this GSK3β- 53BP1 interaction in mouse models significantly enhanced T cell survival following ironing radiation-induced DSBs, infiltration into tumors, and immunotherapy responses in pre-clinical models HNSCC. We hypothesize that inhibition of the GSK3B-53BP1 axis in T cells will enhance DNA repair, promote survival from DNA damage, limit TEX, and increase immune effector function in HNSCC. Aim 1 focuses on understanding how GSK3β inhibits 53BP1 in DNA repair and T cell survival following radiation, hypothesizing that this interaction is crucial for controlling TEX. Aim 2 will investigate the effects of disrupting the GSK3β-53BP1 axis on tumor-infiltrating lymphocyte (TIL) function and the response to ICB alone, or in combination with radiation. Aim 3 tests the therapeutic potential of using 53BP1 mutant T cells in ACT for HNSCC. This study will be the first to explore the GSK3β-53BP1 axis in cancer immunity, aiming to enhance DNA repair, reduce TEX, and improve the efficacy of immunotherapies for HNSCC and other solid tumors.

NIH Research Projects · FY 2026 · 2026-04

PROJECT SUMMARY Epstein-Barr virus (EBV) is a human DNA tumor virus that is present in nearly all cases of the endemic form of Burkitt lymphoma (eBL). In addition to the presence of an oncogenic gammaherpesvirus (GHV), eBL is characterized by translocations between the immunoglobulin locus and c-Myc proto-oncogene. Interestingly, this cancer occurs primarily in areas of the world where infections with the human malaria parasite Plasmodium falciparum (P. falciparum) are common. The epidemiology of these diseases supports the hypothesis that coinfections with EBV and P. falciparum cooperate to promote eBL development, but direct evidence to support this hypothesis is lacking. Since neither EBV nor P. falciparum readily infect mice, we coinfected mice with two well-established model pathogens, murine gammaherpesvirus 68 (MHV68) and P. yoelii, in an effort to better understand mechanisms by which GHVs and Plasmodium species might synergize to promote oncogenic mutations. MHV68 is a murine gammaherpesvirus that is genetically related to EBV and exhibits similar pathogenic phenotypes, especially coopting germinal center (GC) B cell reactions to establish long-term chronic infections in B lymphocytes. Like P. falciparum, P. yoelii stimulates polyclonal B cell activation and achieves high percentages of parasitemia prior to immune-mediated clearance. Using a newly developed PCR-based assay, we evaluated B cells following coinfections and detected the presence of Igh/Myc translocations that were only present in mice infected with both MHV68 and P. yoelii. This indicates that the defining eBL chromosomal abnormality can be generated through coinfecting mice with a GHV and Plasmodium parasite. Moreover, we found that ~90% of cells infected with MHV68 have expressed the GC mutagenic enzyme activation-induced cytidine deaminase (AID). These findings support our major hypothesis that MHV68 and P. yoelii interactions in GC B cells promote oncogenic Igh/Myc mutations. Experiments proposed in this application seek to understand how coinfection with P. yoelii impacts MHV68 latency, reactivation and transcription to promote translocations. We will identify viral gene products required and define the capacity of P. yoelii to stimulate B cell activation that leads to genomic instability. We will determine how GC B cell enzyme AID and coinfection-induced transcription synergize to facilitate non-immunoglobulin locus mutations, and we will define the oncogenic potential of coinfections over time. Results of this work will provide a more complete understanding of how altered infection dynamics due to GHV and Plasmodium species coinfections promote mutations such as those that define eBL.

NIH Research Projects · FY 2026 · 2026-02

PROJECT SUMMARY / ABSTRACT Metabolic syndrome persists as a leading cause of morbidity and mortality among adults in the United States. Specifically, the co-existence of diabetes and hypertension, hallmark components of metabolic syndrome, stand as primary contributors to cardiovascular disease and subsequent mortality. Thus, it is important to identify the pathogenic connection between diabetes and hypertension. Recent research has shed light on the involvement of immune cells, particularly T cells, in the pathogenesis of diabetes and hypertension, suggesting a shared underlying mechanism. However, the precise mechanisms by which immune dysregulation associated with diabetes contributes to hypertension are not fully understood. Here, we delve into the immune-metabolic crosstalk underlying the progression from diabetes to hypertension, employing a high-fat diet-induced type 2 diabetes mouse model. Central to our investigation is the role of T cells, specifically CD8 T cells, in the crosstalk between two diseases. We focus on two key components of diabetes implicated in T-cell activation: ATP and insulin. Elevated ATP levels, acting through the P2X7 receptor, stimulate CD8 T cell activation and cytokine production, promoting the development of hypertension. Moreover, hyperinsulinemia induces ATP release from T cells through the insulin receptor pathway, potentially sustaining chronic diabetic T cell activation. Our research aims are structured around three key objectives: 1) to examine the impact of ATP-P2X7 signaling on diabetes- induced CD8 T cell activation and hypertension using both global and CD8 T cell-specific P2X7 knockout mice; 2) to investigate the role of insulin-InsR-Panx1 signaling in chronic T cell activation during the progression of diabetes and its contribution to hypertension, employing T cell-specific Panx1 knockout and insulin receptor knockout mice; and 3) to understand the formation of kidney-resident CD8 T cells in type 2 diabetes and their involvement in hypertension, utilizing T cell-specific TGFβ receptor knockout mice. Through this multidisciplinary approach encompassing immunology, metabolism, and cardiovascular physiology, our study aims to uncover the mechanisms driving the continuum between diabetes and hypertension. By elucidating these immune- metabolic pathways, we hope to identify new therapeutic targets to decouple diabetes and hypertension, thus mitigating the burden of metabolic syndrome and its complications.

NIH Research Projects · FY 2025 · 2026-02

Obesity is associated with a 35% to 40% increased risk of breast cancer recurrence and poor survival outcomes. One feature of obese adipose tissue is the excess extracellular matrix (ECM) deposition/remodeling in the form of fibrosis. However, function and regulation of obesity-related ECM deposition/remodeling in cancer progression largely remain to be determined. We recently identified Hsp47, a chaperone protein facilitating collagen secretion, as a hub of the ECM transcription network. Our new data showed that Hsp47 was highly expressed in adipose tissue. Importantly, increased Hsp47 expression in human and mouse adipose tissues was significantly associated with obesity development. We found that adipocyte-specific deletion of Hsp47 was sufficient to suppress high fat diet (HFD)-induced obese and mammary tumor growth, which is accompanied by reduced collagen deposition/alignment and macrophage infiltration in adipose tissue. The overall objective of this proposal is to define the mechanism by which adipocyte Hsp47 promotes obese-related fibrosis and breast cancer progression and to explore the value of Hsp47 as a potential target to suppress obesity- associated cancer progression. Using unbiased proteomics analysis, we identified asporin as a new target of Hsp47 in adipocytes. Based on these data, the central hypothesis of this proposal is that Hsp47 induces obesity-related fibrosis by facilitating asporin secretion in adipocytes, and subsequently enhances adipocyte plasticity and breast cancer progression. Following aims are proposed to test our hypothesis: Aim 1. Elucidate the molecular mechanism by which adipocyte Hsp47 induces obesity- and cancer-associated ECM remodeling; Aim 2. Determine how Hsp47 regulates obesity-associated and cancer-induced adipocyte plasticity; Aim 3. Define the potential of targeting Hsp47 to suppress obesity- associate fibrosis, inflammation, and breast cancer progression/metastasis.

NIH Research Projects · FY 2025 · 2025-12

The interaction between cancer cells and platelets plays important roles in regulating cancer cell function. Understanding how platelets communicate with cancer cells to modulate cancer cell colonization at distant organs may identify novel strategies to halt cancer spreading. We recently showed that recruitment of platelet to cancer cells is essential for the colonization of circulating tumor cells (CTCs) at the secondary organs. However, the molecular mechanism by which platelets modulate cancer cell function to promote cancer cell colonization remains to be determined. By analyzing RNA-seq data from CTCs and primary tumors, we found that platelet- specific mRNA was significantly enriched in CTCs. RNAscope and Translating Ribosome Affinity Purification (TRAP) analyses showed the delivery of platelet mRNA and translation of platelet-derived mRNA in cancer cells. In vivo functional screening identified multiple platelet-derived mRNAs contribute to colonization of breast cancer cell at distant organs. These results reveal the new role of platelet mRNA in mediating intercellular communication and in promoting cancer cell spreading. The overall objective of this proposal is to define the molecular mechanism by which platelet mRNA is delivered into breast cancer cells and determine roles of platelet mRNA as the signaling molecular in promoting cancer cell colonization at distant organs. We showed that CD9 expression in CTCs correlated with the accumulation of platelet-specific mRNA. Silencing CD9 in breast cancer cells significantly reduced platelet mRNA transferring and colonization of cancer cells. Platelet factor 4 (PF4) is a small cytokine belonging to the CXC chemokine family that is highly expressed in platelets. We showed that the transfer of PF4 mRNA from platelets to breast cancer cells enhanced stemness and colonization of cancer cells. Based on these results, the central hypothesis of this proposal is that the CD9-dependent mRNA transfer mediates the platelet-cancer cell communication and promotes cancer cell stemness. We propose the following two aims to test this hypothesis and achieve our objective. Aim 1. Elucidate the mechanism by which platelet mRNA is transferred into cancer cells. Aim 2. Determine how the transfer of platelet PF4 mRNA in cancer cells promotes cancer metastasis.

NIH Research Projects · FY 2025 · 2025-09

Under the Health Information Technology for Economic and Clinical Health Act (HITECH) Act, home health agencies (HHAs) and hospices did not receive the health information technology (IT) incentives provided to other healthcare organizations. Leveraging IT with constrained resources presents higher challenges and risks of success among these providers. Therefore, HHAs and hospices must effectively and efficiently leverage IT to meet their pressing priorities. Health IT use among caregivers and patients has also been limited due to cognitive and health limitations, privacy concerns, and perceived complexity and lack of usefulness. Research into developing, testing, and implementing IT-based health innovations is urgently needed to support leveraging IT effectively and efficiently in home healthcare and hospice settings, which share unique characteristics and challenges due to their off-site, intermittent, and interdisciplinary nature. The priority areas include care coordination, decision support, and patient-centeredness. Artificial intelligence (AI), interoperability, telehealth, and security technologies deserve special attention in addressing the priority areas. Leveraging quality big data through the appropriate use of data analytics and AI constitutes an important area of study, and various moral, ethical, and legal issues in this context should be studied. Research is also needed to strengthen the use of health IT among patients and caregivers. There is currently a shortage of research contributing to an evidence base to support better leveraging health IT in home healthcare and hospice. There is insufficient communication among home healthcare and hospice stakeholders, e.g., providers, IT vendors, and government agencies, to align their goals for research collaboration. To bridge these gaps, the principal investigator (PI) and other Senior/Key personnel will organize an innovative interdisciplinary research conference, H3IT: Home Healthcare, Hospice, and Information Technology Conference, with two specific aims: (i) Strengthen the evidence base for leveraging health IT in home healthcare and hospice through facilitating interdisciplinary research, and (ii) Provide a forum to disseminate research results to multiple stakeholders and foster an interprofessional dialogue among them to strengthen IT adoption in home healthcare and hospice. We will partner with the National Alliance for Care at Home (NACH) and co-locate H3IT with NACH’s Annual Meeting to bring all stakeholders together in one meeting. Aligning with the National Institute on Aging’s research goals, H3IT addresses crucial public health problems, including but not limited to the burden of Alzheimer’s Disease (AD) and AD-Related Dementia (AD/ADRD) because patients living with AD/ADRD constitute about a third of patients served at home.

NIH Research Projects · FY 2025 · 2025-09

The underutilization of Pre-Exposure Prophylaxis (PrEP)1–5 in the US stems from a perfect storm of social, health, political, and economic factors contributing to low uptake and retention.6–14 A variety of pharmacist-led PrEP models have demonstrated feasibility and success.15–22 However, most states limit the pharmacists’ scope of practice.23 This project will prove a theory-based, multi-level, longitudinal analysis of expanding the scope of practice of pharmacists implemented to promote PrEP uptake with attention to their longer-term impacts on retention to care and their economic impact. This complex dynamic will be examined through a multi-source, national analysis of datasets. The project’s cutting-edge methods include causal inference techniques of staggered difference-in-differences24,25 and agent-based modeling26, to gauge the evolution of PrEP use vis-à-vis pharmacists’ scope of practice laws. The project proposes three aims: Aim 1 will integrate existing policy, census, survey, and medical claims data to assess the longitudinal impacts of the scope of practice laws on PrEP initiation, abandonment, retention, and new HIV diagnoses among the US population. Aim 2 will assess the economic impact of expanding the scope of practice of pharmacists as well as under what conditions (e.g., training requirements, limits on quantities of PrEP supply, or reimbursement rules) they might become most economic. Aim 3 will produce modeling innovations and an automated decision support system that will enable health departments and public health professionals involved in changing policies to analyze how expanding the scope of practice of pharmacists might promote PrEP access and outcomes. The project will gather existing, dispersed, often untapped sources of data from individuals, communities, and states (e.g., policies), thus producing new synergies and maximizing the use of research resources. This innovative application responds to RFA-MH-25-185 (Advancing HIV service delivery through pharmacies and pharmacists) and will leverage ongoing efforts by an outstanding interdisciplinary, multi-regional team of scholars with expertise in economics, computational methods, pharmaceutical sciences, psychology, communication, public health, law, and public policy in a world-class institutional environment. A policy network with representatives from 9 states across the nation (AZ, CO, IL, MN, NY, PA, TX, VA, and UT) will inform the project and use the recommendation tools. If successful, the project could inform future policy decisions to improve public health outcomes related to HIV prevention.

NIH Research Projects · FY 2025 · 2025-09

PROJECT SUMMARY New psychoactive substances (NPS) are a structurally and functionally diverse group of psychotropic molecules being sold worldwide as legal substitutes for controlled drugs. Over the past decade, NPS production and use has reached worldwide epidemic levels due to high potency, low manufacturing costs, and ambiguous legal status. By the end of 2023, synthetic cannabinoid receptor agonists (SCRA) comprised the majority of first reported NPSs and were the second most detected NPS. Use of NPSs causes hepatotoxicity, respiratory depression, cardiotoxicity, fertility issues, and psychiatric effects posing significant health and economic burdens on society. Effective responses are hampered by the rapid evolution of NPSs that introduce unknown toxic risks and avoid the identification and assessment of the scope of the problem. A common drug development strategy involves halogenation to improve pharmacodynamic and pharmacokinetic properties and is widespread among all NPS classes, i.e. sedatives, dissociatives, hallucinogens, stimulants, cannabinoids, and synthetic opioids. Favorable drug properties due to halogens are undone by metabolism. Cytochromes P450 (CYPs) account for ~75% of drug reactions including dehalogenations. For alkyl halides, CYP oxidations generate an alcohol that is oxidized into a carboxylic acid. These collective metabolic transformations decrease NPS binding to targeted biological receptors and greatly facilitate elimination. Thus, the initial dehalogenation step initiates a major detoxification pathway for NPSs. CYPs are not alone in this role. Based on research by us and others, SCRAs AM2201 and 5F-APINACA undergo novel hydrolytic dehalogenations that are mechanistically distinct from CYP- mediated metabolism. SCRAs are an ideal NPSs to study this pathway given precedence for hydrolysis, accessibility to structurally diverse SCRAs, and dominance as an NPS of concern. Our central hypothesis is that alkyl halide hydrolysis is a significant unstudied SCRA metabolic pathway for detoxification. This hypothesis will be tested by two Aims. Aim 1 will investigate how SCRA head and tail groups impact alkyl halide hydrolyses and how those properties vary across humans and animal models for drugs of abuse. Aim 2 will determine the relative significance of CYPs and the hydrolase in SCRA dehalogenations. Completion of the studies will generate critical new knowledge to advance the field. NPS development outpaces the ability to use traditional approaches accessible to marketed drug workflows, and clinical studies are not ethical for drugs of abuse. Consequently, NPS surveillance and risk assessments rely heavily on indirect methodologies. Results from this study will validate and characterize novel dehalogenation pathways to improve the accuracy and quality of information gained from microsomal studies for inferring and extrapolating human health risks from SCRAs. Further, the hydrolase specificities likely include other NSPs, natural products, and pollutants so that these findings could induce a paradigm shift in our understanding of the metabolism of biologically active molecules.

NIH Research Projects · FY 2025 · 2025-09

The United States (U.S.) has a higher maternal mortality ratio than most other high-income nations. Severe maternal mortality (SMM) and maternal mortality rates are elevated in rural counties compared to national averages. Births covered by Medicaid, of which there is a higher percentage in southern states (and Arkansas specifically), are more likely to experience postpartum SMM and maternal mortality. Individuals in rural, resource-limited counties are more likely to experience SMM and maternal mortality. Arkansas, the location for this study, is largely rural (41% of Arkansans vs 14% U.S.), has higher poverty rates (16.3% in Arkansas vs 11.5% U.S.), has more births covered by Medicaid (54% in Arkansas vs 42% U.S.), and is ranked second worst for the health of women and children among U.S. states. The maternal mortality ratio for Arkansas from 2018-2021 (the most recent data) was 43.5 deaths per 100,000 live births, nearly double the national ratio of 23.5 for the same time period. An estimated 75% of SMM and 76% of postpartum deaths occur within 6 weeks of delivery, with the vast majority (68%) within the first 3 weeks. Multiple studies demonstrate that the majority of postpartum ED visits could be addressed through outpatient care. The standard for postpartum care is a comprehensive visit scheduled approximately 6 weeks postpartum. Given that most postpartum SMM and maternal mortality happens before 6 weeks, one or more early postpartum visit(s) in the first 3 weeks is recommended as part of the American College of Obstetricians and Gynecologists’ (ACOG) 2018 guidelines. However, this early check-in has not been widely implemented. CARE PATH includes three weekly telehealth visits from a perinatal CHW to ensure timely identification and treatment of complications following ACOG guidelines; it is a fully powered RCT conducted among 500 rural postpartum individuals from a range of geographic and economic backgrounds, designed to compare: A) CARE PATH and B) usual care on postpartum visit completion, early detection of postpartum complications, postpartum hospital readmission and ED visits, and reproductive life planning/contraceptive counseling. CARE PATH has potential to reduce SMM and maternal mortality because it is conducted among rural postpartum individuals who experience the most pressing maternal health access challenges and are less often reached by existing health system innovations. CARE PATH directly addresses gaps in current scientific knowledge identified by systematic reviews and is expected to inform policy and practice, while meeting the needs and preferences of individuals residing in areas with limited healthcare infrastructure in Arkansas.

NIH Research Projects · FY 2025 · 2025-09

The University of Arkansas for Medical Sciences (UAMS) proposes the Cancer and Developing Entrepreneurial Technologies (CADET) accredited certificate program for up to 13 graduate and post graduate trainees per year to address the gap between oncological discoveries and the commercialization of technologies that can improve patient outcomes. CADET proposes a value-added educational experience that integrates scientific research with entrepreneurial training to support the commercialization of cancer-based technologies. CADET programming will be primarily team based, led by seasoned instructors and entrepreneurship mentors with a range of relevant subject matter expertise, and focused on practical avenues to translate oncological discoveries into viable businesses. CADET’s investment in trainees includes the invaluable opportunity to travel to the Biotechnology Innovation Organization convention to share abstracts of their cancer-related technologies and chart next steps in their career journey alongside prominent experts and leaders. CADET objectives will be realized by three specific aims: Aim 1: Provide trainee researchers with an accredited certificate program to present principles of entrepreneurship alongside the cancer product development path in context of pressing needs in the oncology field. Trainees will be guided through the process of aligning cancer research with customer needs, interests, and specifications. Aim 2: Assign trainee teams to cancer-related technologies with IP potential and provide the option to request licensing rights. Teams will prepare competitive applications for the largest business plan competition in Arkansas and use their learnings to advance to the next steps for translating cancer-related technologies through integrated learning experiences. Trainees will travel to and either observe or participate in state-level startup competitions. Aim 3: Determine CADET outcomes through rigorous evaluation and iterate future programs in this project accordingly. Evaluation will encompass trainee experiences, program progress, and knowledge retention of business principles and translating cancer-based technologies. Trainee outcomes will be tracked to verify CADET’s effectiveness and alignment to deliver health and social benefits. Guided by a team of instructors, mentors, and cancer experts, CADET participants will have the unique opportunity for concentrated learning and career growth while accelerating the development and commercialization of new cancer technologies.

NIH Research Projects · FY 2025 · 2025-08

Abstract This research project focuses on investigating potential radiomitigating strategies for gastrointestinal (GI) acute radiation syndrome (GI-ARS), a severe condition resulting from high-dose ionizing radiation exposure to the GI tract. GI-ARS is characterized by impaired cell division in intestinal crypts, inflammation, loss of intestinal barrier integrity, and ultimately sepsis. Our study proposes two novel approaches to mitigate the effects of radiation exposure on the GI tract. The first approach centers on methionine restriction (MR). Methionine, an essential amino acid, plays a crucial role in normal tissue and tumor metabolic activity. It serves as a precursor for S-adenosylmethionine, a key methyl donor in various cellular processes. Previous data suggest that reducing dietary methionine improves intestinal barrier function and decreases inflammation. Preliminary studies have shown that MR preserves crypt depth and villous height in the jejunum following acute abdominal irradiation, indicating its potential as an intestinal radioprotector when initiated prior to irradiation. Aim 1 of the project seeks to assess the mitigating effects of dietary MR on GI-ARS following radiation exposure. We will use an animal model, employing total body irradiation, as well as partial body irradiation with 5% hindlimb protection. Twenty-four hours post-irradiation, animals will either continue on a control diet or transition to a diet with significantly reduced methionine content. We will evaluate survival rates after total and partial body irradiation, as well as examine various tissue markers at 3.5 and 7 days post-irradiation. These markers include crypt depth and villous height in the proximal jejunum, crypt survival, plasma citrulline levels, bacterial 16S RNA in the liver, and the expression of inflammation and tight junction genes in the proximal jejunum. The second approach, outlined in Aim 2, investigates the potential of 3-Deazaneplanocin A (DZNep), an inhibitor of methyltransferases, in mitigating GI-ARS. DZNep inhibits the enzyme S-adenosylhomocysteine hydrolase, resulting in reduced methyltransferase activity, similar to the effect of MR. Previous studies have shown that DZNep can decrease fibrosis, inflammation, and sepsis in animal models. Additionally, both MR and DZNep activate the amino acid stress response pathway (ATF4) and decrease the methylation ratio in normal human fibroblasts, suggesting a common mechanism of action. We will assess the mitigating effect of DZNep administration starting 24 hours after irradiation, using the same experimental setup and endpoints as in Aim 1. By exploring these two related but independent approaches, our project aims to identify effective strategies for mitigating the severe effects of GI-ARS. The findings from this study could potentially lead to the development of novel therapeutic interventions for radiation exposure, with implications for radiation emergency scenarios.

NIH Research Projects · FY 2025 · 2025-08

Hearing loss affects a staggering 1.6 billion people worldwide, and 80% of affected individuals live in rural and underserved communities. Access to hearing care is extremely limited in these areas and is a major contributor to poor outcomes. Addressing a challenge of this magnitude requires a research workforce well-versed in the breadth of cross-cutting disciplines needed for real impact: epidemiology, trial design, technology innovation, community engagement, implementation science, cost-effectiveness analyses, and advocacy for policy change. Over the past 8 years, I have developed a robust research infrastructure to comprehensively address hearing health access in rural and underserved populations in the US and globally, and I founded and direct the University of Arkansas for Medical Sciences (UAMS) Center for Hearing Health Access, the only research center of its type in the world. I have a strong track record of mentoring trainees at all levels and purposefully incorporate trainees into all projects at the Center. I am now seeking a K24 award to enhance my mentoring skills and leverage my research program to uniquely train the next generation of clinician-scientists to advance access to hearing health. I have developed three specific strategies to advance my mentoring skills. First, I will be guided by a Mentorship Advisory Board of senior researchers who will formally evaluate my mentoring progress. Second, I will develop INSIGHT (IDeA Network Supporting Investigator Growth to Help Trainees), a novel network to connect mid- career mentors in rural states. Third, I will participate in advanced mentor training through the Center for the Improvement in Mentored Experiences in Research at the University of Wisconsin-Madison. Additionally, I will pursue advanced training in implementation science through the University of Washington Implementation Science in Global Health Summer Institute. I will facilitate my mentoring plan by pursuing two Specific Aims that incorporate the breadth of the Center for Hearing Health Access research program and support the training and career advancement of my mentees. In Aim 1, I will mentor trainees in patient-oriented research (POR) to improve identification and outcomes for hearing loss through two projects: 1) tympanometry to identify middle ear pathology in screening programs; 2) impact of the STAR intervention on longitudinal academic outcomes. In Aim 2, I will mentor trainees in POR to develop and implement new models of healthcare delivery for hearing loss through two projects: 3) identification of treatment needs following school hearing screening; 4) identification of barriers and facilitators to inform a generalizable roadmap to scale STAR. All four projects are new, will be directly supported by the K24, and will occur in the US. I have developed a unique research program that directly facilitates trainee participation in all aspects of the research process across the breadth of disciplines in hearing health access. Facilitated by a K24, I will combine the resources of the Center for Hearing Health Access research portfolio with meaningful involvement of trainees to push the boundaries of POR to achieve hearing health access, both locally and globally.

NIH Research Projects · FY 2025 · 2025-08

Arkansas is ranked worst for maternal mortality and fourth worst for maternal health outcomes. Arkansas is a rural state, and rural women have a higher rate of maternal mortality compared to urban counterparts. The goal of Maternal and Reproductive Community Health Excellence (MaRCH) Center of Biomedical Research Excellence (COBRE) Phase 1 is to build the infrastructure to nurture and develop new investigators, thereby creating the critical mass of researchers needed to truly make a difference in maternal and reproductive health for rural communities in Arkansas and other IDeA states. Our specific aims are: Aim 1: Build the Infrastructure for MaRCH COBRE. MaRCH COBRE will be comprised of an Administrative Core and 2 research cores—a Digital Health Core and a Stakeholder/Community Engagement and Dissemination (SUCCEED) Core. We will build upon two areas where we have established a strong foundation and leverage those strengths to develop and support a critical mass of investigators to conduct research focused on addressing maternal and reproductive health. The SUCCEED Core will focus on stakeholder engagement and dissemination, and the Digital Health Core will harness digital resources to support research in rural communities. Aim 2: Implement a Rigorous Mentoring and Faculty Development Program for Junior Faculty (Primarily Early-Stage Investigators) Focused on Maternal and Reproductive Health. The mentoring and faculty development program will include: 1) grants to Research Project Leaders and Pilot Project Investigators; 2) a formal mentoring program; 3) a training program; and 4) biostatistical and research methods navigation and support. MaRCH COBRE will support well-designed, high-impact research in maternal and reproductive health that is responsive to the needs and context of rural areas with the goal of ensuring that junior investigators transition to independent investigators, as evidenced by securing R01 or equivalent funding.

NIH Research Projects · FY 2025 · 2025-08

Overall – Project Summary/Abstract The overall goal of the Center for Studies of Host Response to Cancer Therapy at the University of Arkansas for Medical Sciences (UAMS) is to become a self-sustaining multidisciplinary center for research excellence that contributes to our understanding of mechanisms for side effects of cancer therapy, identifies methods for early detection, and develops strategies to prevent or treat such side effects. The Center accomplishes this overall goal by assisting junior investigators with research programs in this common theme establish themselves as independent scientists, providing opportunities for established investigators to collaborate and expand their capacities in this area, and strengthening the research infrastructure for all at UAMS. Achieving these goals will create a vibrant, multidisciplinary, yet synergistic research environment. To our knowledge, few research centers focus on cancer survivorship, and none take the paradigm-shifting approach of proactively addressing treatment- related toxicities to improve overall cancer treatment outcomes. During Phases 1 and 2, the Center has grown significantly in critical mass and is spanning the full translational spectrum from basic to clinical research that is funded by a number of federal and private sources. Several research core facilities provide services that enhance the research of Center members. In Phase 3, the Center will strengthen its research portfolio by bringing in new investigators and supporting team collaborations (Specific Aim 1); advance the Center’s technical cores to being self-sustaining by ensuring that they are run by expert personnel, adjusting core services in response to institutional needs assessments, and continuing to advertise the services to grow the user base (Specific Aim 2); and ensure that the Center becomes self-sustaining (Specific Aim 3). The Center will consist of an Administrative Core (Core A) that will continue to oversee the Center’s pilot project program, and 2 technical cores: the Bioanalytical Core (Core B) and Radiation and Imaging Core (Core C). Strengthening our interactions with the 6 other COBRE Centers and additional NIH-supported programs that enhance biomedical research in Arkansas will also contribute to establishing the Center as a self-sustaining research program that is well- integrated in the institution. The Center’s progress will be guided by a comprehensive evaluation plan and a highly qualified Advisory Committee. Strong institutional support combined with active interest from funding agencies in improving uncomplicated cancer cure rates and the quality of life of cancer survivors ensures a high likelihood of lasting success for the Center for Studies of Host Response to Cancer Therapy.

NIH Research Projects · FY 2025 · 2025-08

PROJECT SUMMARY Adoptive T-cell therapies (ACT) have emerged as a transformative approach in cancer immunotherapy, demonstrating remarkable success in hematological malignancies. However, their application in solid tumors is significantly limited by T-cell exhaustion (TEX), a dysfunctional state driven by chronic antigen stimulation and exacerbated by the environmental stresses of the tumor microenvironment (TME). TEX is marked by impaired proliferation, diminished effector function, and the upregulation of inhibitory receptors, ultimately curtailing the therapeutic potential of ACT. To overcome this barrier, innovative strategies are needed to engineer T-cells capable of maintaining their function and persistence within the challenging TME. E3 ubiquitin ligases (E3s) are critical regulators of protein stability and cellular adaptation under stress, yet their roles in TEX remain largely underexplored. Preliminary proteomic studies revealed significant global changes in protein turnover during TEX including the destabilization and loss of the T-cell receptor (TCR) complex, stabilization of inhibitory receptors, and the destabilization of costimulatory receptors. This discrepancy is partially attributed to the accumulation of unfolded proteins and the resulting compensatory increase in proteasomal activity. Through additional proteomic analysis modeling of TEX, I have revealed multiple E3s important to T-cell function. To determine which E3 has the greatest impact on T-cell function, I conducted an overexpression screen of multiple E3s in primary murine tumor-specific CD8+ T-cells. T-cells overexpressing each E3 were evaluated using serial in vitro cytotoxicity assays to assess their ability to control cancer growth. I identified the E3 ubiquitin ligase Ring Finger Protein 166 (RNF166) to enhance T-cell persistence, prolonging the cytotoxic function of the T-cells by 8 days. Further, elevated transcript levels of RNF166 in tumor infiltrating lymphocytes was found to correlate with responsiveness to immune checkpoint blockade (ICB) in metastatic melanoma. Additionally, I demonstrate that RNF166 overexpression reduces the expression of inhibitory receptors PD1, CTLA4, and LAG3 following chronic stimulation in primary human CD8+ T-cells. This proposal aims to elucidate the mechanisms by which RNF166 regulates T-cell function and explore its therapeutic potential to enhance ACT for solid tumors. Aim 1 will define the molecular targets of RNF166 using innovative proteomics approaches to investigate its impact on global proteome turnover and determine its targets for proteasomal degradation. Aim 2 will evaluate the efficacy of RNF166 overexpression in enhancing ACT using preclinical models, including murine syngeneic OT-1 T-cell and human CAR T-cell systems. This research represents the first comprehensive study of RNF166 in T-cell biology, providing critical insights into its role in TEX and its potential as a therapeutic target. By leveraging state-of-the- art mass spectrometry, bioinformatics, and in vivo modeling, this work aims to develop novel immunotherapeutic strategies to enhance ACT for solid tumors. This research proposal represents a unique training opportunity combining high-level mass spectrometry training, bioinformatics, systems biology, and cell engineering.

NIH Research Projects · FY 2025 · 2025-08

Kaposi’s Sarcoma-associated Herpesvirus (KSHV) is the etiologic agent of several human cancers, including Kaposi’s Sarcoma (KS) and Primary Effusion Lymphoma (PEL), which preferentially arise in immunocompromised patients (e.g., HIV+ personnel or organ transplant recipients) and lack of effective therapeutic options. Despite the reduced incidence of KS in the era of combined Antiretroviral Therapy (cART) for HIV infection, KS especially oral KS still remains one of the most common AIDS-associated tumors and a leading cause of morbidity and mortality in this setting. PEL is a rapidly progressing malignancy with a median survival time of approximately 6 months, even under the combinational chemotherapy. Macrophage migration inhibitory factor (MIF) signaling activation have been found closely related to many cancer cell malignant behaviors, however, its role in virus-associated cancers or how oncogenic viruses may regulate MIF signaling activities remain largely unknown. We recently found high levels of MIF signaling activities during KSHV infection or KSHV+ tumor cells in vitro and in vivo. Thus, we hypothesize that MIF signaling activation has important role in KSHV pathogenesis and oncogenesis, which may represent a promising direction to develop anticancer treatments for KSHV-related malignancies. To address this hypothesis, we propose the following Specific Aims: 1) To determine the underlying mechanisms of MIF signaling activation within KSHV+ tumor cells. 2) To develop MIF-targeted therapies against KSHV-related malignancies. Through these efforts, we hope to determine the roles of MIF signaling activation in KHSV pathogenesis and induced oncogenesis, and develop MIF signaling targeted therapies for improving the outcome of KSHV-related malignancies in high-risk immunocompromised patients.

NIH Research Projects · FY 2025 · 2025-08

PROJECT SUMMARY/ABSTRACT Lung macrophages serve as primary host cells for Mycobacterium tuberculosis (Mtb) during infection and are recognized as one of the most crucial cell types in determining the outcome of Mtb infection. We have previously reported that two types of lung macrophages, namely embryonic-derived alveolar macrophages (AMs) and monocyte-derived interstitial macrophages (IMs), display different permissiveness to Mtb at the early stages of infection in C57BL/6 mice. Such distinct permissiveness of macrophages to Mtb infection is determined by their unique metabolic status. However, most of the studies performed to date on the interaction between lung macrophages and Mtb have utilized in vitro models and/or primarily focused on the early stage of in vivo infection. The widely used “resistant” C57BL/6 mice do not form caseous necrotic granulomas (lesions) that are a hallmark of human tuberculosis (TB) disease, which additionally hinders the translation of our knowledge from the mouse model to human disease. Further, while significant work has been put into understanding the immune drivers of lesion formation, the role of immune cells in maintaining lesion structure and control of Mtb growth after lesions have formed remains poorly understood. To this end, how different lung macrophage subsets differ in their capacity to control or promote localized growth of Mtb, and how Mtb responds to the local environment in the context of necrotic lesions during the later stages of infection, is almost completely unknown. Utilizing the C3HeB/FeJ mouse Mtb infection model that forms the hallmark caseous necrotic lesions observed in human TB, we have revealed that manipulation of different lung macrophage subsets after lesion formation has distinct influence on Mtb growth in the necrotic lesions during the later stages of infection, depending on lesion sublocation. We thus hypothesize that the function of lung macrophage subsets is spatially distinct and contributes to the heterogeneity in local environment experienced by Mtb, and consequently bacterial physiological status, within the lesions. We will test this hypothesis with two complementary aims. In Aim 1, we will utilize novel metabolic analysis approaches together with spatial transcriptomics on the host side to elucidate the role of AMs versus IMs in Mtb lesion biology in spatiotemporal context. In Aim 2, we will delineate the relationship between macrophage subsets and local Mtb environment and activity at the single bacterium level, adapting methods to visualize Mtb transcripts in situ. With both Aims, depletion of macrophage subsets, including IMs, will enable elucidation of how macrophages act in the maintenance of lesion structure and local Mtb growth control. Together, this work will provide a conceptual framework for understanding how permissiveness of lung macrophage subsets relates to their spatial distribution within granulomas, and how this spatiotemporal relationship impacts on local Mtb environment and growth.

NIH Research Projects · FY 2025 · 2025-07

PROJECT SUMMARY Kaposi’s sarcoma-associated herpesvirus (KSHV) causes several AIDS-defining malignancies including Kaposi’s sarcoma (KS), the most common oral cancer affecting people with HIV. Persistence of KSHV cancers is rooted in the ability of the virus to establish life-long latency, a dormancy-like phase where no virions are produced, and gene transcription is restricted to the latency genes to drive tumor cell survival and proliferation. In latency, KSHV represses lytic genes that are typically used for viral replication and propagation to evade immune surveillance. Majority of primary tumor cells are latently infected with only <5% of cells supporting lytic replication which is necessary for dissemination. Thus, the balance of latency and lytic transcriptional programs is crucial to KSHV malignancies. Our long-term goal is to understand mechanisms underlying the control of the latency and lytic transcriptional programs. We and others have shown that the latency-lytic balance is coordinated by the organization of the viral genome. However, it remains unknown how these higher order structures are initially formed or how they are maintained after latency is established. Using a CRISPR/CasRx screen tiling the KSHV genome, we recently discovered that a novel long non-coding RNA (lncRNA) from the origin of lytic replication (OriLytL) is critical for viral latency (OriLytL-lat RNA). This was surprising because the OriLytL is only known to function during lytic replication and not during latency. Based on our preliminary data and strategic positioning of this latent lncRNA at the origin of lytic replication, the central hypothesis of this proposal is the OriLytL-lat RNA mediates the latent-lytic balance by driving chromatin remodeling and genome localization. Specifically, we will study how this lncRNA organizes the viral chromatin structure before and after establishing latency. In addition, we will investigate how this directs the spatial localization of the latent chromatin which has now emerged to be a major factor of gene regulation. Together, these Aims will define mechanisms of latency establishment and maintenance which are key to KSHV malignancies.

NIH Research Projects · FY 2025 · 2025-06

PROJECT SUMMARY The human gammaherpesvirus (GHV) Kaposi sarcoma-associated herpesvirus (KSHV) establishes lifelong latency to cause several AIDS-associated malignancies including Kaposi sarcoma (KS) and primary effusion lymphoma (PEL). Because the virus is predominantly latent in these tumors, the prevailing model for KSHV transformation is that latency genes are the primary drivers of these viral cancers. However, published case reports in KS patients together with our preliminary data indicate that lytic gene expression may also be required for KSHV cancers. Whether lytic replication and reactivation influence tumor development and maintenance has not been directly tested. Our over-all objective is to test the hypothesis that lytic genes are drivers of GHV cancers. In this proposal, we will study how lytic gene expression is involved in the two distinct stages of GHV cancers (development and maintenance) using in vivo models. Specifically, we will inactivate the master regulators of the GHV lytic transcriptional program, ORF50 and ORF57, to prevent lytic gene expression. In Aim 1, we will test if lytic gene expression and reactivation is required for tumor initiation using conditional knockouts of ORF50 or ORF57 in the GHV murine gammaherpesvirus 68 (MHV68) in a newly developed B cell lymphomagenesis mouse model. MHV68 is a natural rodent virus that is genetically related to KSHV and provides a well-established, extensively studied, and tractable small-animal model for defining basic viral mechanisms of GHV pathogenesis. In Aim 2, we will test if lytic gene expression is required for the maintenance of KSHV lymphoma in a PEL xenograft mouse model. Using an inducible RNA-targeting CRISPR/CasRx system, we will target ORF50 or ORF57 RNA for knockdown in PEL cell lines after implantation in NOD scid gamma (NSG) mice. In addition, we will perform high-throughput targeting of the KSHV transcriptome using our newly designed CasRx tiling library in this well-established xenograft model to identify in vivo lytic drivers of PEL maintenance in an unbiased manner. Together, these complementary Aims will directly address the hypothesis that lytic gene expression is required for the development (Aim 1) and maintenance (Aim 2) of GHV cancers in vivo. We anticipate that our work will challenge the current latency-centric paradigm of GHV oncogenesis, and shed new light on roles for viral genes in pathogenesis.

NIH Research Projects · FY 2025 · 2025-06

Summary Current chemotherapeutic agents have improved multiple myeloma (MM) patient survival. However, MM remains incurable due to high rate of disease relapse that originate from dormant MM clones resistant to therapy. Further, anti-MM therapies have minor effects on repairing MM-induced bone disease, a leading cause of morbidity and mortality in MM patients. Thus, disease relapse and bone disease remain major unmet medical needs that require innovative approaches to effectively treat MM. The overall goal of this proposal is to evaluate the efficacy of novel bone-targeted therapies blocking key interactions between MM cells and cells of the tumor niche to stop the progression of MM in bone. We will focus on Notch and Wnt signaling, two major signaling pathways mediating tumor-host microenvironment communication. In studies leading to this application, we generated a bone-targeted Notch inhibitor (BT-GSI) that selectively decreases Notch signaling in bone. Inhibition of Notch communication in the tumor niche with BT-GSI reduced MM growth and decreased osteoclast number and bone destruction. Importantly, BT-GSI circumvented the gut toxicity that limits the use of Notch inhibitors in the clinic. Further, we found that interactions between MM cells and osteocytes increase the expression of Sclerostin, a local Wnt signaling antagonist that inhibits osteoblast bone forming function. Blockade of Sclerostin using neutralizing antibodies (Scl-Ab) prevented MM-induced bone disease by increasing osteoblasts and stimulating new bone formation. Importantly, our work leading to this application showed that interactions between MM cells and osteoblasts maintain MM cells in a dormant state, while interactions with osteoclasts promote their reactivation into proliferating MM cells. Based on these preliminary findings, we propose that combined bone- directed therapies inhibiting Notch and activating Wnt signaling will 1) decrease MM growth, 2) prevent reactivation of MM dormant cells, and 3) repair damaged bone, while reducing systemic toxic effects. This hypothesis will be advanced by pursuing specific aims that employ established mouse models of MM-induced bone disease and MM dormancy and new pharmacologic tools targeted to the tumor niche. Two aims are proposed. Aim 1 will determine the pharmacokinetic, pharmacodynamic, and safety profiles of our bone-targeted Notch inhibitor BT-GSI. Aim 2 will examine the effects of combined bone-targeted inhibition of Notch signaling (BT-GSI) and activation of the Wnt pathway (Scl-Ab) on tumor growth, bone repair, and MM cell dormancy.

NIH Research Projects · FY 2026 · 2025-05

There are very few receptive language assessments which are appropriate for autistic children who are minimally verbal/non-speaking.2,7 Because practitioners use outcomes from these assessments to create intervention plans, identify appropriate augmentative and alternative communication (AAC) systems, and inform vocabulary selection for AAC systems, receptive language measures are a vital component of assessment and intervention for autistic children. Eye-tracking methods show promise as an alternative assessment method for this population because they do not require verbal skills, social interaction, or an overt motor response.10,11 The purpose of the proposed study is to examine the feasibility of using eye-tracking technology as a measure of implicit word comprehension for autistic children who are minimally verbal/non- speaking. The specific aims include (1) evaluating the feasibility of using eye-tracking technology, with pictures and object-stimuli, as an implicit measure of word understanding in autistic children who are minimally verbal/non-speaking, and (2) examining eye-movement variables which can be indices of word-understanding in this population. This study will include 35 autistic children who are minimally verbal/non-speaking. Participants will complete two experimental word-understanding eye-tracking assessments: a) an assessment that uses objects as stimuli, and b) an assessment that uses picture stimuli. Aim 1 will evaluate percent unusable data and percent completion of the two experimental eye-tracking tasks to add to the limited available information regarding feasibility of eye-tracking with this population. Behavioral coding will be used to describe participant behavior during unusable trials (i.e., trials with data loss) and during calibration failure. Unusable data may be a result of attentional difficulties, excess movement, or noncompliance. Results from behavioral coding will provide nuanced information about participant behavior during unusable trials which has not been reported in prior studies. This information is important for understanding how to mitigate the occurrence of unusable trials in future studies. Aim 2 will collect preliminary data on eye-movement variables which may be indices of word-understanding in minimally verbal autistic children. Due to the heterogeneity of this population and the systematic exclusion of children with minimal verbal skills from previous research on eye-tracking in autism, there is very little empirical evidence on eye-movement variables which may indicate word understanding for autistic children with minimal verbal skills. This research will address a need identified by NIH to develop and evaluate assessments of receptive understanding for autistic children who are minimally verbal/non-speaking (NOT-DC-23-009).

NIH Research Projects · FY 2026 · 2025-05

Project Summary/Abstract The recent global spread of monkeypox (Mpox) virus and the subsequent declaration of a public health emergency by the World Health Organization highlighted the continuous threat of re-emerging infectious agents. With the possible establishment of new animal reservoirs in non-endemic countries, selection of variants for transmissibility, and potential continued spread in humans, there is an urgent need to be able to predict Mpox evolution. Analysis of viral genomes, by our group and others, from the recent Mpox outbreak showed recent acquisition of C>T mutations at TC hotspots, which is consistent with host APOBEC3-driven mutagenesis. This highlighted the gap in knowledge surrounding the mechanisms by which poxviruses undergo genome remodeling, gene mutation, and acquisition of new genes. AID/APOBEC enzymes, specifically the APOBEC3 branch cause mutations in the viral genome with 2 seemingly opposing consequences: viral restriction and enhanced evasion of host immunity. APOBECs mutate C to U in single-stranded DNA (ssDNA), preferentially in di- or tri-nucleotide “hotspot” sequence motifs that are unique to each APOBEC family member. Human APOBEC3A, for example, preferentially mutates at TC hot spots in ssDNA, whereas APOBEC3G prefers CCC in addition to TC. The role of APOBECs as viral restriction factors has been established through many studies on retroviruses, notably HIV. APOBECs are also implicated as a major source of mutagenesis across many non-retroviruses. Viral genes targeted by APOBEC3s have been shown to have an “APOBEC co-evolutionary footprint” either by having fewer APOBEC3 hotspots, or by being enriched for hotspots in positions where APOBEC3-directed mutagenesis favors the generation of immune- or drug-escape variants. Thus, although APOBEC3s are classically viewed as viral restriction factors, they also have pro-viral effects (e.g., mutating viral cytotoxic T-cell epitopes to drive immune escape). Recent observation of Mpox evolution suggests that the Mpox genome will undergo further APOBEC3-mediated diversification as the virus spreads in the human population. Thus, our long-term goal is to be able to predict the potential variation of Mpox. Toward this goal, we will use an experimental evolution model system in human cells to investigate how and which APOBEC3s affect poxviruses. We propose to conduct out study in 2 stages: (1) examine in vitro biochemical activities of APOBEC3s toward Mpox targets and (2) understand the impact of APOBEC3s on C>T mutagenesis and non-homologous recombination in orthopoxviruses such as vaccinia virus as a surrogate to Mpox using an experimental evolution system. Through this comprehensive investigation of the direct impact of APOBEC3s on poxvirus evolution, we will contribute knowledge that can be used for prediction of virus evolution trajectories and therefore reforming policies to protect public health.