Wake Forest University Health Sciences

NIH Research Projects · FY 2025 · 2025-09

The US Deep South bears the highest burden of HIV, and the South is lagging behind in achieving Ending the HIV Epidemic (EHE) goals. People who use drugs (PWUD) like cocaine, meth, heroin, and fentanyl, are more likely to fall out at each step of the HIV care cascade. Contextual factors contribute to poorer HIV and substance use outcomes, neuroimmune dysfunction, and related chronic illness. The overarching goal of CASCADE (Carolina Addiction Science Coalition for Accelerating Discovery and Engagement) is to investigate the impacts of established and emerging drug use patterns and addiction treatment on the HIV prevention/care cascade in the South. As a community-academic-health system partnership, this proposal is a collaboration between Wake Forest University Health Sciences in Winston-Salem and Charlotte and multiple community organizations throughout Central and Western North Carolina. Leveraging the robust infrastructure of Atrium Health, one of the largest nonprofit health systems in the South, along with HIV and substance use service programs, we will enroll a status-neutral cohort of 1,000 persons who use stimulant and/or opioid drugs – 500 people with HIV (PWH) and 500 people at risk for HIV. Using an observational-implementation hybrid approach, our aims are to: (1) Recruit and retain the CASCADE Cohort to collect multilevel data harmonized with other NIDA-funded HIV cohorts for emerging and high-priority research; (2) Using a social-ecological framework, examine the effects of individual, community, and contextual factors on status-neutral HIV and substance use outcomes over time, investigate the neuroimmune mechanisms through which psychosocial stress affects neuropsychiatric outcomes, and identify structural modifiers (e.g., rural/urban setting) and potential resiliency factors (e.g., coping); and (3) Conduct mixed-methods assessments using implementation mapping to identify structural factors, organizational practices, and other contextual factors that influence the uptake of evidence-based HIV and substance use treatments in healthcare settings, and co-create and disseminate a set of multilevel strategies informed by user-centered design to improve service delivery. Through our application of cutting-edge biostatistics and data science methodologies, our findings will yield novel insights to accelerate scientific discoveries while also enhancing translation to clinical care and facilitating rapid dissemination. As the first NIDA HIV Cohort in the South, we will partner with our Community and Scientific Advisory Board, consisting of members from community organizations, health system administrators, public health officials, scientific leaders, and persons with lived experiences, to inform guidelines and practices in the Carolinas and beyond. CASCADE aligns with national priorities by addressing the growing burden of chronic illness and substance use through a pragmatic, science-based approach.

NIH Research Projects · FY 2025 · 2025-09

While vascular dementia is recognized as the second most common form of dementia and the leading nondegenerative cause of dementia, vascular contributions to cognitive impairment and dementia (VCID) have not been thoroughly studied among residents in the Stroke Belt. Vascular disease may be present in the majority of dementia cases in varying degrees, including in Alzheimer’s disease, accounting for 60-80% of dementia cases. Individuals in the Stroke Belt experience a higher prevalence of risk factors for stroke (e.g. smoking and obesity) as well as chronic disease associated with stroke (e.g. hypertension, diabetes, and coronary heart disease) compared to individuals in other US regions, placing this population at risk of cerebrovascular pathologies that may lead to cognitive impairment or dementia. In addition, lifestyle and non-medical drivers of health factors put this population at an increased risk of cardiovascular disease (CVD) and dementia. Without increased participation in VCID clinical trials to thoroughly understand VCID, gaps in understanding the safety and effectiveness of therapies in this population will persist. Clinical trial readiness—encompassing factors that influence participation and the ability to engage in clinical trials—is a critical area of research to improve VCID clinical trial participation. Examining factors influencing readiness and developing tailored, innovative strategies to improve participation in VCID clinical trials has the potential to reduce gaps in adverse health outcomes. Inspiring Healthy Engagement and Learning for Vascular Dementia (I-HEAL), submitted in response to RFA-NS-25-013, focuses on addressing gaps in VCID clinical trial participation among Americans, with an emphasis on populations residing in the Stroke Belt, a region in the southeastern United States with a higher incidence of stroke mortality compared to the rest of the United States. We have assembled an I-HEAL learning network of 6 universities, including 3 Alzheimer’s Disease Research Centers located in or near the Stroke Belt to reach varied stakeholders. Our methods leverage upstream and downstream approaches to co-create a VCID clinical trial readiness educational program with dementia and community engagement researchers and members of communities throughout the stroke belt. In this project, we will develop and validate a VCID clinical trial readiness and preparedness measure, PREP (Promoting Readiness, Engagement, and Participation) for VCID Trials Scale (Aim 1). Next, our team will develop and evaluate a customizable, multi-media clinical trial readiness educational program designed to prepare communities for participation in VCID clinical trials. Last, we will build a community-based workforce (I-HEAL Champions) prepared to engage and educate communities in CVD and VCID, VCID risk factors, clinical trial processes, human subject protections, and community engagement at the 6 I-HEAL study sites.

NIH Research Projects · FY 2025 · 2025-09

Project Summary/Abstract Cocaine use disorder (CUD) remains a significant public health problem with no FDA-approved medications. Acknowledging this need, NIDA identified discovery of novel pharmacotherapies as a key component of its current strategic plan. Recent data suggest that drugs that target brain nociceptin/orphanin FQ peptide (NOP) receptors may have potential in treating CUD. For example, rodent studies indicate that NOP receptor agonists can decrease the rewarding/reinforcing effects of cocaine. Moreover, PET imaging and the novel NOP receptor radiotracer [11C]NOP-1A were used to show that NOP receptor binding was higher in individuals with CUD versus controls. While these data are encouraging, there are significant gaps in our knowledge that can be filled by using translationally relevant nonhuman primate (NHP) models of CUD and treatment. This application proposes NHP studies of long-term cocaine self-administration (SA) in combination with PET imaging to provide critical information regarding the relationships between NOP receptors and cocaine reinforcement that will help generate novel CUD treatments. Specific Aim 1 will examine how NOP receptors influence vulnerability to developing CUD. [11C]NOP-1A PET imaging will be used to determine the relationship between drug-naïve monkeys’ NOP receptor binding and sensitivity to cocaine during their initial experience with cocaine SA (acquisition and an initial dose-effect curve). Aim 2 will identify changes in brain NOP receptors with repeated [11C]NOP-1A PET scans during long-term cocaine SA. Aim 3 will assess the ability of NOP- acting drugs to decrease cocaine SA using a highly relevant model of pharmacotherapy evaluation that incorporates aspects of human CUD and treatment. Studies focus on buprenorphine analogs synthesized by Co-I Dr. Stephen Husbands that have agonist activity at mu opioid peptide (MOP) and NOP receptors (“bifunctional agonists”). These drugs lack abuse potential (i.e., they are not self-administered by NHPs) and have shown promise as medications for alcohol and opioid use disorders. Moreover, our preliminary data suggest that the ability of these drugs to decrease cocaine SA in rodent models of CUD extends to NHPs. Initial Aim 3 studies will provide detailed information regarding the pharmacodynamic profile (i.e., MOP vs. NOP receptor affinity and efficacy) for an ideal CUD medication that will be used to select candidates from the library of Dr. Husbands’ compounds for testing during chronic treatment. Throughout the studies female and male NHPs will be compared, generating novel information about potential sex differences in NOP neurobiology and the effects of NOP receptor-acting drugs; such data are nearly non-existent. Taken together, these studies will use a highly translationally relevant NHP model to provide novel information about reciprocal interactions between NOP receptors and behavioral effects of cocaine as well as specific information to aid development of novel CUD pharmacotherapies.

NIH Research Projects · FY 2025 · 2025-09

PROJECT SUMMARY Differences in cost-benefit analyses for goal-directed motivation and behavior characterize many substance use disorders (SUD). An important feature of these cost-benefit analyses and decision-making is effort-based decision making (EBDM) which evaluates the reward magnitude and probability in relation to the effort required to obtain the reward. Dopamine (DA) modulates EBDM indicating that increasing or decreasing DA transmission enhances or diminishes (respectively) the willingness to expend effort for rewards. DA has also been shown to be affected by chronic substance use, more specifically tobacco use and opioid use such that over time the production, transmission, absorption, and sensitivity to DA is altered. In line with this, EBDM has been shown to be altered in tobacco use disorder (TUD) but has not been directly investigated in opioid use disorder. For successful recovery, individuals with SUDs must exert effort for non-drug rewards and value non- drug rewards more than drug rewards. But if the endogenous DA system is dysregulated due to substance use, the value of and motivation for non-drug rewards could be hypothetically compromised. This is why it is critical to understand how EBDM might be differentiated in the ability or inability to successfully quit smoking. It is also critical whether these differences in smoking status are unique to the pharmacology of nicotine and tobacco use, or if they are related more broadly to other SUDs such as opioid use. The primary goal of this fellowship proposal is to investigate the neurocomputational basis of EBDM in individuals with TUD, tobacco and opioid use disorder (TOUD), and controls (Aim 1) and characterize the neurocomputational basis of EBDM in a smoking cessation attempt (Aim 2). In both aims I will computationally model effort-based choice behavior to assess the underlying processes that potentially differ between groups such as the systematic use of reward and effort information and learning from the outcomes of previous actions. In Aim 1, I will set the foundation by understanding how EBDM differs between TUD, TOUD, and controls; this will further the understanding of not only how EBDM in TUD but also how EBDM could differ in polysubstance use (TOUD). In Aim 2, I will then further this work by understanding how EBDM is implicated in a smoking cessation attempt to potentially create new pathways for therapies. This 3-year fellowship will be analyzed by leveraging a previously completed dataset and an existing ongoing study. In all, this fellowship will provide training in contemporary computational modeling methods and experimental design that address fundamental questions in computational neuroscience regarding the neurocomputational basis of EBDM. The central findings of this research will advance our understanding of the principles of EBDM in SUDs and a smoking cessation attempt.

NIH Research Projects · FY 2025 · 2025-09

PROJECT SUMMARY CRISPR-based therapeutics hold tremendous promise for treating genetic diseases, one of the major final frontiers of medicine. Their ability to edit or correct genetic mutations provides the basis for many future gene- targeted drugs. However, their broad clinical utility in patients is handicapped by two significant challenges – targeted and precise delivery to the correct tissues and organs in the body and reduction of off-target editing, which has the potential to cause new diseases like cancer. Approaches to address in vivo delivery of CRISPR-based therapeutics have focused on searching for delivery vehicles like engineered adeno-associated viruses (AAVs) or lipid nanoparticle (LNP) formulations that can exhibit preference for certain tissues. Specificity has been addressed through bioinformatics approaches that can predict guide RNAs and targets with the lowest off-target potential or engineering of CRISPR-Cas proteins with higher specificity. However, no delivery vehicle, currently or expected in the near term, can exhibit pure tissue-specificity and some organs, like the liver, will invariably be exposed during systemic in vivo delivery. Likewise, off-target editing by CRISPR-Cas enzymes like Cas9 will always be present as prediction tools are not perfect due to the intrinsic nature of the enzyme and natural diversity in human genomes. These shortcomings suggest the need for a radical new approach to targeted delivery and safer gene editing. We propose that combining focused ultrasound (FUS), an established and non-invasive method to perform manipulations deep inside the human body with high resolution in space and time, with gene editing would offer a simple but revolutionary approach to safer targeted gene editing in the future. To accomplish such a lofty goal requires inventing a gene editing technology that can respond to FUS. To accomplish this, we propose a proof-of-concept study to establish feasibility. We hypothesize that the industry-standard Cas9 can be fused to an inhibitory anti-CRISPR (Acr) protein, which will keep the enzyme inactive, via a temperature-sensing protein domain tuned to a thermal response window. Our rationale is that protein folding is naturally cooperative, temperature-responsive protein domains are known and can be thermally tuned, Cas9 can be effectively inhibited by Acrs, and FUS combined with magnetic resonance imaging (MRI) is a mature clinical technology that can control temperature very precisely in deep tissues, such as the brain, in the human body. Our first aim rationally builds several thermo-controlled Cas9s (tc-Cas9s) from existing modular parts, computationally refines those designs, builds them, and tests their properties and activity in vitro and in cells. Our second aim creates randomized mutagenesis libraries and uses thermal shifts in cells to perform directed evolution and select tc-Cas9s that perform editing in the desired temperature regimes. Together, these results will test the feasibility of creating gene editing platforms that can be controlled non-invasively with FUS, potentially rethinking delivery and safety for therapeutic gene editing.

NIH Research Projects · FY 2025 · 2025-09

ABSTRACT Calcium homeostasis is essential for cellular signaling and mitochondrial metabolic regulation, which are critical for meeting the metabolic demands of various cell types. Calcium modulates cellular functions by binding to calcium-sensing domains on numerous proteins. Many calcium sensors have multiple calcium binding domains with varying affinities, allowing for diverse and graded signaling. Calcium concentrations vary across cellular compartments, and the localization of calcium sensors facilitates subcellular and organelle-specific signaling. Mitochondrial calcium flux is necessary for cell viability, especially in cells with high energy needs. Dysregulated mitochondrial calcium leads to mitochondrial dysfunction, including ATP depletion, reactive oxygen species production, loss of mitochondrial membrane potential, mitochondrial permeability transition pore opening, and apoptogen release. These disruptions cause metabolic stress, triggering cell death and contributing to pathological conditions. Mitochondrial-induced cell death plays a key role in degenerative diseases and other cell death-related disorders. Understanding the molecular mechanisms behind mitochondrial stress responses may identify new therapeutic targets for conditions linked to mitochondrial dysfunction. Recent studies have shown that mitochondrial calcium uptake protein 1 (MICU1), located in the intermembrane space, regulates the cristae structure through the mitochondrial contact site and cristae organizing system (MICOS) independently of its established role in controlling mitochondrial calcium uniporter (mtCU) channel opening. This finding suggests that calcium sensors may have additional molecular functions beyond mitochondrial calcium uptake. MICU proteins, including MICU1, MICU2, and MICU3, regulate mtCU activity by controlling its open probability in response to calcium. This regulation depends on calcium binding to EF-hand domains, with mtCU remaining closed until cytosolic calcium levels reach a threshold. Knockout models for MICU proteins show abnormalities in mitochondrial ultrastructure not observed in mtCU-specific knockout models, suggesting that MICUs regulate other mitochondrial processes. The current research hypothesis is that MICU proteins influence mitochondrial processes beyond mitochondrial calcium uptake. Over the next five year, our research program will focus on three key questions: 1) do MICU proteins universally affect MICOS and mitochondrial ultrastructure? 2) what is the cell type-specific regulatory role of MICU proteins in mitochondrial ultrastructure? 3) do MICU proteins collaborate in regulating calcium sensing at mtCU and MICOS? By employing genetic, molecular, imaging, and protein biochemistry approaches in cellular and mouse models, this investigation aims to clarify the molecular mechanisms involved in mitochondrial calcium sensing and its effects on cellular physiology. This research addresses critical gaps in understanding mitochondrial physiology, focusing on the interplay between mitochondrial calcium sensing, mitochondrial calcium flux, and mitochondrial ultrastructure. The outcomes may reveal new strategies for treating diseases related to mitochondrial dysfunction.

NIH Research Projects · FY 2025 · 2025-08

Scientific Abstract: Sepsis and septic shock are global healthcare problems associated with mortality rates of up to 40% despite best therapy efforts. Circulating markers of septic shock severity may constitute a clinically relevant approach to individualize therapy and resuscitation for those patients at risk for poor outcomes early in the course of the disease, which may facilitate early and more precise intervention to improve patient outcomes. However, currently used septic shock biomarkers including lactate, may be non-specific, and have variable impacts on prognosis and/or disease management. Activation of the renin-angiotensin-aldosterone system (RAAS) is an early event in septic shock and recent data has shown that elevated renin, is more predictive of worse outcomes in septic shock than lactate, as well as a more relevant biomarker for mortality. However, our preliminary data suggest that activation of the RAAS downstream from renin, particularly the Angiotensin Converting Enzyme (ACE)- Angiotensin II (Ang II)-AT1 receptor axis is blunted, thus contributing to the severity of septic shock through a reduced ability to maintain adequate blood pressure and tissue perfusion, as well as an attenuated immune response. The current project proposes a randomized clinical trial to precisely determine the benefit of exogenous Ang II versus norepinephrine (conventional care) treatment in septic shock patients. Moreover, we will determine whether there are more precise and complete measures of renin and other RAAS components (prorenin, aldosterone, Angiotensinogen (Aogen), DPP3, ACE, ACE2 and Ang II) that provide stronger associations and better predictors of septic shock severity. This approach may inform more appropriate treatment regimens and improve outcomes for these patients. Specifically, Aim 1 proposes a clinical trial to compare the benefits of Ang II treatment and the norepinephrine (NE). Aim 2 will assess protein levels of renin, prorenin, aldosterone, Ang II, Aogen (total and intact), DPP3 and ACE, as well as their ratios in comparison to serum lactate as the strongest predictor of disease severity and outcomes in septic shock patients prior to and following Ang II and NE treatment. Aim 2 also establishes the regulation of Aogen by serum factors from septic shock patients prior to and following Ang II and NE treatment. Aim 3 will assess the response of the immune system regarding monocyte function and cell signaling events associated with the RAAS in the septic shock before and after treatment. Successful accomplishment of our aims will provide the capability to improve endotyping of septic patients by establishing the most precise and robust measurement of renin (and RAAS dysfunction). This work will improve staging and clinical precision and will facilitate the criteria for therapeutic development of targets in septic shock.

NIH Research Projects · FY 2026 · 2025-08

Cocaine use disorder (CUD) continues to be a major public health problem worldwide, with no FDA-approved treatments. An important consideration in evaluating neural and behavioral mechanisms of CUD and potential treatment strategies is the observation that most individuals suffering from CUD also co-use other substances, including tobacco products and alcohol. The goal of this new research project is to extend the study of cocaine misuse to include the co-use of nicotine and/or alcohol in female and male cynomolgus monkeys. When alcohol and cocaine are co-used, there is an active metabolite formed, cocaethylene, which we recently showed had reinforcing effects that were similar in potency and reinforcing strength to cocaine, when studied under a progressive-ratio schedule of reinforcement. Preliminary data using a cocaine vs. food choice paradigm, found that co-use of nicotine not only potentiated the reinforcing effects of cocaine, but it enhanced the reinforcing strength of cocaine. Studies proposed in this application will extend the evaluation of cocaine misuse to determine how nicotine and cocaethylene influence the ability of behavioral and pharmacological interventions to decrease the reinforcing effects of cocaine and pharmacological interventions on the discriminative stimulus effects of cocaine. In Aim 1, we propose to examine several behavioral interventions on drug self-administration. For these studies, monkeys will choose between cocaine (including saline) and food and the following interventions will be examined: delay discounting involving both food and drug (cocaine ± nicotine and cocaethylene ± nicotine) delays; changes in the magnitude of the food reinforcer; and negative punishment, using response-contingent timeouts. The studies in Aim 2 will examine the effects of chronic drug treatments in female and male monkeys self-administering cocaine ± nicotine and cocaethylene ± nicotine in the context of an alternative, non-drug, reinforcer (food-drug choice). We will combine chronic pharmacological treatments with behavioral interventions in an effort to further decrease cocaine choice. The goals of Aim 3 are to examine how nicotine and cocaethylene influence the discriminative stimulus effects of cocaine. Pharmacological treatments examined on self-administration, will also be examined in this model of subjective drug effects. The scientific premise for these studies is that co-use of nicotine and alcohol with cocaine result in different behavioral consequences compared with cocaine alone and are not simply additive drug effects. Thus, co-use of alcohol and/or nicotine with cocaine will require different behavioral and pharmacological treatment strategies than cocaine alone. Results from these studies will aid in the development of personalized medicine strategies for cocaine use disorder that incorporates polysubstance use.

NIH Research Projects · FY 2025 · 2025-08

PROJECT ABSTRACT Radiation therapy for head and neck cancer significantly increases the risk for hyposalivation, dental caries, gingival recession, trismus, tooth loss, and osteoradionecrosis, contributing to a well-documented decline in oral health-related quality of life (OH-QOL) after radiation therapy for head and neck cancer. A major contributor to this decline in oral and dental health and in OH-QOL is the unusually rapid progression of dental caries. Although topical fluoride can reduce caries progression, compliance with homecare and with preventive professional dental care is low in the head and neck cancer population. To address this problem, we propose to test an innovative intervention in a setting with known high compliance, the oncology office. This clinical trial's overall objective is to determine if an Intensive Preventive Dental Program administered in an oncology practice can reduce dental disease in patients with head and neck cancer post-radiation therapy compared to current oncology care practice that occurs post radiation therapy. The feasibility of this prevention program has been established by a pilot study of this intervention and by our completed OraRad study, which enrolled 572 patients with head and neck cancer across our 6 U.S. clinical sites. The Intensive Preventive Dental Program includes 1) application of fluoride varnish by a medical team member during routinely scheduled post-RT oncology follow-up visits and 2) recognition and dental referral for patients with signs and symptoms of dental disease or poor compliance with preventive professional dental care. Our primary hypothesis is that a preventive dental program in oncology offices will improve oral health outcomes and improve oral health follow- up for this high-risk group of patients. We will test this hypothesis by conducting a randomized clinical trial to accomplish these Specific Aims: determine the impact of an Intensive Preventive Dental Program on 1) dental caries progression (decayed, missing and filled surfaces- DMFS, primary outcome); 2) tooth loss and oral health-related quality of life (secondary outcomes); 3) homecare compliance and compliance with receiving preventive professional dental care (secondary outcomes). We hypothesize that participants who receive the Intensive Preventive Dental Program will have lower DMFS scores and tooth loss, higher oral health-related quality of life, and increased compliance with homecare and preventive professional dental care, compared to participants who do not receive the Intensive Preventive Dental Program. If effective, these findings could support translation of this intervention across oncology centers nationwide. Our proposed study thus has the potential for high societal impact by further integrating medical and dental care to improve health outcomes.

NIH Research Projects · FY 2025 · 2025-08

Project Summary In the event of a radiological emergency, the ability to measure acute radiation exposure will be paramount. While several potential direct molecular markers of radiation damage have been identified, there are currently no tools available with the necessary speed and sensitivity to mace their deployable assessment feasible. However, the developments in nanotechnology provide a potential solution to this significant national challenge in the form of solid-state (SS-) nanopores: nanometer-scale holes fabricated in thin, insulating membranes that can facilitate the electrical translocation and measurement of single molecules. SS-nanopore sensors operate on the simple principle of resistive pulse sensing in which key signals are carried via an ionic current that can be measured with simple and readily-miniaturized transimpedance amplifiers and used to determine molecular size. In this proposal, we will wise this unique capacity to probe three related but independent DNA-based biomarkers of radiation exposure. We select DNA as the critical biomarker because it is (1) the most thoroughly characterized biopolymer in nature and (2) has high chemical stability, enabling reliable physical models to be built for determining how ionizing radiation interacts with DNA in vivo. In this project, we propose a panel of DNA biomarkers that will support mass casualty assessment, including direct fragmentation of mitochondrial DNA (Aim 1), shifts in the characteristic length of cell-free DNA (Aim 2), and changes in the abundance of oxidative lesions in genomic DNA (Aim 3). When measured independently and considered jointly, these markers will provide high precision (uncertainty < 0.5 Gy) in determining the exposure range from 0-10 Gy as well as the radiation source modality. The resulting technology will address the catastrophic measurement gaps that currently exist and offer a clear path towards a tool for on-site radiological triage.

NIH Research Projects · FY 2026 · 2025-08

Project Summary/Abstract Heart failure with preserved ejection fraction (HFpEF) affects nearly 50% of heart failure patients and represents a significant unmet medical need due to a lack of effective treatments and incomplete understanding of its molecular mechanisms. Recent studies suggest mitochondrial dysfunction plays a causal role in HFpEF, with mitochondrial calcium (mCa2+) emerging as a crucial regulator of mitochondrial metabolism and function. While genetic manipulation of mCa2+ flux in cardiomyocytes has shown promise in heart failure with reduced ejection fraction (HFrEF), its role in HFpEF remains unexplored. Furthermore, cellular heterogeneity in mCa2+ signaling and functions in HFpEF, along with the potential therapeutic manipulation of mCa2+ in a heart cell-specific manner, remain undetermined. This study aims to address these gaps by investigating heart cell-specific mCa2+ signaling and function in HFpEF. We hypothesize that disrupted cellular heterogeneity in mCa2+ signaling contributes to HFpEF progression, and therapeutic manipulation of cell type-specific (cardiomyocytes, fibroblasts and endothelial) mCa2+ flux may offer novel treatment strategies. Our approach involves characterizing heart cell- specific mCa2+ signaling and functions in HFpEF mouse models (aim1), evaluating the effects of manipulating mCa2+ flux on HFpEF pathogenesis (aim2), and studying the molecular mechanisms of mitochondrial dysfunction in HFpEF (aim3). This proposal is significant and innovative, offering insights into heart cell-specific mechanisms contributing to mitochondrial dysfunction and identifying new therapeutic targets for HFpEF. It shifts the paradigm by proposing cellular heterogeneity in mCa2+ as a key molecular target for HFpEF. Additionally, it enables the PI to transition into a new research direction and involves a strong team of investigators with expertise in HFpEF and cardiovascular studies to ensure project success.

NIH Research Projects · FY 2025 · 2025-08

PROJECT SUMMARY There is a high prevalence of risky drinking in adolescents. This is concerning because alcohol use during adolescence substantially increases risk of eventually developing an alcohol use disorder (AUD). Studies have begun to show that functional neuroimaging data may be useful for predicting drinking vulnerability in adolescents. Further, studies show that drinking history is associated with altered functional brain network architecture in adolescents, particularly in three key subnetworks of the brain (the Default Mode Network [DMN], Central Executive Network [CEN], and Salience Network [SN]) which together comprise the Triple Network model. Outside of the adolescent drinking literature, methods for studying time-varying dynamic functional brain networks (DFNs) have rapidly gained popularity. DFNs depict the second-to-second changes in functional brain connectivity which have now consistently been shown to support cognitive processes. Further, DFNs are excellent tools for predicting behavioral and psychiatric outcomes, suggesting that they are more meaningful models of brain function than regional activation or static functional connectivity. However, DFNs have never been used to study vulnerability to future drinking nor the effects of drinking on the brain in an adolescent population. The proposed study will be the first to apply DFNs to studying these two important topics. I will use a distinct method for analyzing DFNs in each of two aims. In the first aim, I will use sliding window correlation-based DFNs to predict risky drinking onset in 17-year-old participants of the NCANDA study using an approach which our lab has previously used to predict success in a behavioral weight loss intervention with 95% accuracy. In the second aim, I will use Hidden Semi-Markov Models (HSMMs, a novel method for interpreting brain network dynamics) to assess the longitudinal effect of risky drinking on the brains of adolescents. My preliminary analyses using HSMMs have shown that individuals who spend more time in states with strong connectivity between the SN and CEN tend to drink less over the next year of their lives. This result provides proof of concept that 1) patterns of brain network dynamics are related to future drinking vulnerability, and 2) the specific method which will be used in the second aim of the proposed project can successfully identify patterns of brain network dynamics which are relevant to alcohol use. Together, the two aims in the proposed project will yield novel insights on the biological underpinnings of adolescent alcohol use vulnerability as well as the effect that alcohol use has on the adolescent brain. We believe that the knowledge gained from these aims will ultimately help to develop more effective prevention initiatives and provide novel explanations as to how risky drinking during adolescence can put young people on a pernicious path towards eventually developing an AUD.

NIH Research Projects · FY 2025 · 2025-08

The rise in stimulant use is undermining HIV prevention efforts for women who inject drugs (WWID) in the southern U.S., where evidence-based interventions (EBIs) often fail to reach women. Contingency management (CM) is one of the most effective evidence-based interventions (EBI) for reducing stimulant use and preventing HIV among stimulant-using WWID. Incorporating positive affect (PA) strategies—such as activities that enhance feelings of joy, optimism, and gratitude—into CM may further strengthen its impact, making it more likely for WWID to achieve sustained stimulant use reduction and enhanced HIV prevention outcomes. To close the implementation gap for stimulant use EBI, implementation strategies must focus on the end-user, stimulant using WWID—amplifying their personal agency for HIV prevention and stimulant use. Our team of interdisciplinary experts, ideally positioned at the intersection of HIV prevention and stimulant use, implementation science, health outcomes research, and community-partnered research, will 1) use human- centered design to tailor a scalable CM+PA for HIV acquisition risk reduction among stimulant using WWID— SHE CARES; 2) conduct a pilot of SHE CARES and two-wave optimal validation study of objective measures of HIV acquisition risk reduction; and 3) compare the effectiveness and implementation of SHE CARES to an informational+CM-control for reducing HIV acquisition risk among stimulant using WWID. To develop SHE CARES, we will use the Discover/Design/Build/Test (DDBT) process to conduct in-depth interviews and focus group discussions with stimulant-using WWID and key informants to “discover” facilitators and barriers of a PA+CM for reducing HIV acquisition risk and hold stakeholder workshops to iteratively “design” and “build” SHE CARES. To “test” SHE CARES, understand user experiences, and determine revisions for SHE CARES we will conduct a brief, small-scale pilot among 30 WWID. We will also conduct a targeted validation of self- measured HIV acquisition risk among 60 WWID. To compare the effectiveness and implementation of SHE CARES to an informational+CM-control, we will deploy a type I effectiveness-implementation hybrid design, enrolling 350 stimulant-using WWID randomized 1:1 to SHE CARES or the informational+CM-control. Enrolled WWID will complete a 12-week CM program, with the SHE CARES arm also completing 5 PA sessions over the same period. CM and PA programs will be facilitated by trained peers. WWID will be followed for 9 months post-randomized and complete behavioral and biomedical assessments. Effectiveness will be measured as prevention-effective PrEP at 6 months. Guided by the RE-AIM framework, we will assess SHE CARES’ feasibility, cost, and economic value, ensuring it aligns with the needs of WWID while advancing HIV prevention. This project will prioritize the voices of WWID, providing a scalable model with potential for lasting public health impact in Ending the HIV Epidemic (EHE) regions.

NIH Research Projects · FY 2025 · 2025-07

ABSTRACT The main goal of our project is to develop innovative interpretable deep learning models for multi-modality imaging in cancer prognostic assessment. Overall, we aim to improve both the accuracy and the interpretability of prognosis decisions from deep learning models. On the one hand, accurate prognostic assessment plays a key role in personalized treatment. Gastric cancer prognosis has historically been determined based on tumor histopathology (i.e., size, grade, etc.) and TNM staging. However, the current clinical staging system cannot accurately predict the prognosis of gastric cancer, and patients in the same stage would have significant variability in treatment outcomes. Therefore, it is crucial to develop new approaches for accurate prognostic prediction of gastric cancer patients on an individual basis. With the rising of artificial intelligence (AI), deep learning models show enormous potential in cancer prognosis tasks. On the other hand, nevertheless, only limited deep learning models have been adopted in clinical settings, primarily due to their lack of transparency and interpretability, which makes it challenging to gain the trust from doctors as well as patients especially for the high-stake scenarios such as prognosis and treatment decision-making. Existing deep learning models are mostly black-box and fully data-driven in nature, without integrating domain knowledge from physician experts and/or disease pathobiology. Thus, constructing interpretable deep learning models is also of great importance in gastric cancer prognosis, to better enhance the patient's treatment outcomes and life quality. Computed tomography (CT) and hematoxylin & eosin (H&E) stained whole-slide pathological images (WSIs) are commonly used in the clinical examination of gastric cancer patients. Our prior research has demonstrated that both CT and WSI images contain valuable prognostic information for gastric cancer and validated that deep learning approaches are effective for analyzing these types of images. To bridge the research gaps in interpretable prediction with deep learning, distinct from previous work, we will integrate domain knowledge from physician experts with biological insights into the model inference process through prototypical and attentional modeling, which are informed by and designed to capture important aspects of disease pathobiology. We propose three aims specifically: AIM1) Build a knowledge-guided Vision Transformer (ViT) that employs informative visual prototypes for explainable prognosis on CT images; AIM2) Develop a knowledge-guided Graph Neural Network (GNN) that employs contributive subgraph prototypes for interpretable prediction based on singe-cell classification; AIM3) Design a novel attentional multi-modal learning approach to fuse the clinical attribute information together with the complex interactions between WSI and CT in latent spaces for transparent prognosis. If successful, the proposed methods will enhance the accuracy and interpretation of prognosis predictions. Considering that CT and H&E imaging is used as part of routine clinical care, our study could provide new tools to improve treatment decisions, without additional cost.

NIH Research Projects · FY 2026 · 2025-07

ABSTRACT Electronic cigarettes (e-cigs) are being touted as safer alternatives to traditional cigarettes, which have well- known harmful effects on the brain due to combustion-related inflammation and oxidative stress. Some smokers report using e-cigs to help quit smoking and switch to exclusive e-cig use. However, nicotine itself, as well as the other components of e-cig vapor, produce inflammation and oxidative stress, albeit to a lesser extent than traditional cigarettes. The effects of long-term e-cig use on the brain are poorly understood. Smoking cessation is associated with improvements in brain structure and function that correlate with quit duration, suggesting a recovery from the harmful effects of smoking. But whether switching from cigarettes to e-cigs results in comparable brain health is unknown. Most research on the health effects of e-cigs has been on short-term effects and/or use in adolescents and young adults compared to healthy non-users. Adult smokers are now the target of e-cig marketing and are being encouraged to make the switch to e-cigs. Research on the long-term, relative safety of e-cigs in this population is desperately needed. Existing research indicates smoking negatively affects brain measures, including gray matter volume (GMV), white matter integrity (WMI), cerebral blood flow (CBF), and cognitive performance (CP). Evidence from ex-smokers indicates that quitting smoking leads to positive changes in brain measures. Smoking and e-cigs also negatively affect physiological measures, such as autonomic function and inflammation, which in turn affect the brain. The key problem is to what extent abstinence from cigarette smoke, compared to abstinence from chronic nicotine, affects brain and physiological health. An important biomarker of the heaviness and duration of cigarette smoke exposure is DNA methylation of the AHRR CpG site, which we have shown correlates with GMV, WMI, and CP among smokers and ex-smokers. We will investigate the relationship between the objective AHRR biomarker and brain/physiological measures among ex-smokers (Ex-Quit) and ex-smokers who switched to e-cigs (Ex-Ecig) (compared to smokers and never-smokers) to shed light on the relative harm of e-cigs. Smokers are increasingly relying on e-cigs to make a quit attempt; yet research on the long-term health effects of e-cigs (> 1 year of use) on adult ex-smokers is almost nonexistent. This study will expeditiously fill this critical gap in knowledge.

NIH Research Projects · FY 2026 · 2025-07

Project Summary/Abstract Alzheimer’s disease (AD) is a multifactorial neurodegenerative disease with heterogeneous pathologies that affect the cognitive function of the brain, eventually leading to dementia. The heterogeneity of AD is manifested both in terms of diverse neurodegeneration patterns and clinical presentations, which poses challenges in developing effective interventions. Specifically, individual genetic variations might be associated with such disease manifestation variability. It is crucial to unravel the intrinsic heterogeneity within the AD spectrum for achieving personalized diagnosis and precision medicine, and eventually developing effective disease-modifying treatment; however, several obstacles and knowledge gaps remain: currently, the genotype-phenotype association that defines distinctive AD subtypes is poorly understood, and current AD prediction methods preclude the development of strategies for accurate selection of at-risk clinical trial participants and accurate disease onset time estimation. The objective of the proposed study is to establish the connection between AD-related genomic markers and neuroimaging phenotypes and their association with the clinical onset of dementia. We hypothesize that a) genomic factors are associated with diverse AD-related neuropathological and clinical progression patterns; and b) the genotype-phenotype interaction is dynamic along the AD progression trajectory, which in turn regulates the clinical progression of dementia. We plan to develop data-driven computational models using multi-modal imaging-genomics information, to test these hypotheses with the following two Specific Aims: (1) to characterize distinctive subtypes of AD neuropathological patterns by constructing clinically relevant computational neuroimaging-genomic fingerprints, and (2) to achieve accurate prediction of AD progression through subtype-aware artificial intelligence models with novel genomic-neuroimaging integration. Our multi-disciplinary team of experts in AD mechanism and clinical manifestation, neuroimaging, genomics, gerontology, artificial intelligence, and biostatistics will construct and validate generalizable artificial intelligence models by utilizing the available data from the Alzheimer's Disease Sequencing Project (ADSP) and the ADSP Phenotype Harmonization Consortium (ADSP-PHC), which is a multi-institutional effort for harmonizing genomic and phenotypical data of more than 22k participants collected from over 30 AD-related cohorts to produce a large-scale, multi-ancestry, standardized set of clearly defined data. This study will be one of the first to establish a comprehensive picture of AD pathogenesis that (i) connects genomic-level risk factors with neuropathological profiles, and (ii) determines their combined effects on the clinical syndrome that leads to dementia, thereby generating crucial knowledge to inform the development of personalized interventions.

NIH Research Projects · FY 2026 · 2025-07

: Overdose and HIV are among the greatest threats to people who inject drugs (PWID) in the United States (US). Although pre-exposure prophylaxis (PrEP) was approved in 2012, its adoption has been slow, creating obstacles to the US Ending the HIV Epidemic (EHE) goals—an initiative launched in 2019 to reduce new HIV infections by 90% by 2030. Currently, less than 1% of people who use drugs use PrEP. Overdose death rates are rising at alarming rates among people at risk for or living with HIV. People living with HIV are more likely to die from overdose than HIV-related conditions. Pharmacies offer over-the-counter overdose prevention tools, such as naloxone and fentanyl test strips, but ensuring broad access remains a challenge, particularly in rural areas. Pharmacies remain an underutilized healthcare setting for HIV and overdose prevention. State and federal policies have advanced efforts to increase the availability of these services through pharmacies, but implementation has varied widely. North Carolina (NC) and Illinois (IL), both part of the EHE initiative, offer a valuable case study due to their differing approaches: In IL, pharmacists are authorized to initiate PrEP under standing orders from physicians or medical directors, whereas in NC, pharmacists may only dispense but not initiate PrEP. Understanding the real-world accessibility of these services is essential for informing future policy development and public health initiatives. We propose three aims: 1) assess the changes in the availability of HIV and overdose prevention services at all community and retail pharmacies in IL and NC using mystery shopper calls; 2) examine regional (i.e., rural vs. urban) differences associated with integrated HIV and overdose prevention services at community retail pharmacies in IL and NC; 3) conduct a 3-phase mixed- methods assessment, using qualitative interviews and an e-Delphi approach, to develop strategies with pharmacies and end-users address implementation gaps integrated HIV and overdose prevention services. By evaluating the pharmacy-based landscape for HIV and overdose prevention services, this research will generate actionable insights to support ongoing federal and state efforts to expand healthcare access and improve public health infrastructure. The study aligns with national priorities to improve healthcare delivery, increase service availability, and remove challenges to essential prevention. This work contributes to broader efforts to enhance pharmacy-based access to prevention options, ensuring that healthcare services are more widely available to all individuals, regardless of location.

NIH Research Projects · FY 2025 · 2025-07

ABSTRACT Streptococcus pneumoniae is an opportunistic human pathogen that causes pneumococcal pneumonia, an infection of the lower respiratory tract, as well as life-threatening bloodstream infections and meningitis. Despite the availability and widespread administration of pneumococcal vaccines, these infections continue to disproportionately affect people over the age of 65. Due to the diversity in pneumococcal exposures over the lifespan, vaccine responses, and comorbidities observed in elderly patient cohorts, it is difficult to assess the extent to which vaccine responsiveness versus aging-associated changes in the lung contribute to failures in vaccine-elicited protection. This project proposes the use of an aged mouse model to circumvent these confounding factors so that underlying mechanisms that affect vaccine-induced protection against pneumonia in aged individuals can be determined. Our preliminary data show aged male mice mount significantly higher antibody (Ab) responses to Pneumovax23, a non-adjuvanted vaccine consisting of 23 serotypes of pneumococcal capsular polysaccharide (PPS), than younger mice. Consistent with this, aged male mice have significantly increased expansion and activation of PPS-specific innate-like B cells after immunization. Even though these aged male mice make 5 to 10-fold greater antibody responses than their younger counterparts and are highly protected against bacteremia, they have significantly increased lung bacterial burden and lower survival than younger mice in response to respiratory pneumococcal challenge. Therefore, the central hypothesis of this proposal is that increased PPS-specific Ab responses in aged male mice are due to intrinsic differences that occur in B cell populations with aging. Nonetheless, we hypothesize these Abs have little effect on protection against pneumonia due to failed complement-dependent Ab effector mechanisms in the aging lung. In Aim 1, I will test the hypothesis that intrinsic differences in B cell subsets occur as a result of aging and contribute to heightened T cell independent antibody responses. I will also determine the extent to which the aged male environment contributes to increased antibody responses. In Aim 2, I will examine mechanisms contributing to the susceptibility of Pneumovax23-immune aged male mice to pneumococcal lung infection. I will test the primary hypothesis that aging compromises complement-dependent effector functions in the lung. I will examine whether Fc-dependent effector functions are similarly impaired or if they can be leveraged to improve protection. Collectively, this project will reveal basic mechanisms contributing to altered vaccine responses and susceptibility to pneumococcal infections that occur with aging.

NIH Research Projects · FY 2025 · 2025-05

Project Summary / Abstract Ice hockey’s growing popularity includes over one million athletes in the US and Canada with a strong increase in participation among females and adolescents. The sport has relatively high concussion rates compared to others, including football, as it is a fast-paced sport with ice and board surfaces. Subconcussive head impact exposure (HIE) has been associated with short- and long-term neurobehavioral changes. Detailed information about head impact biomechanics and neurobehavioral health in this young and developing population are lacking. Our study leverages multidisciplinary expertise to relate biomechanics-based metrics to athlete and play characteristics and neurobehavioral health. We will implement advanced measurement and analytical approaches characterizing HIE in adolescent boys’ and girls’ ice hockey players. This goal addresses an unmet need to intersect these study elements to inform safety recommendations to improve the sport’s safety. Dr. Joel Stitzel (WFU, MPI) has developed and employed an innovative instrumentation system, and video and data processing strategies and algorithms to adequately contextualize HIE. Dr. Jason Mihalik (UNC, MPI) has strong experience studying youth hockey head impact biomechanics and neurobehavioral outcomes. Combined, our inter-institutional multidisciplinary team has a proven record deploying head impact technologies in the field, working with adolescent athletes, studying neurobehavioral outcomes, and translating key findings into recommendations and policy changes to improve athlete and sport safety. Together, we will address our central hypothesis that biomechanics informs understanding of HIE in the context of athlete and play characteristics, and HIE among adolescent ice hockey players elucidates neurobehavioral health effects (i.e., executive function, impulsivity). This will serve as a paradigm to evaluate key community members’ awareness and receptivity to strategies to improve safety by reducing HIE. This addresses our long-term goal to use head impact biomechanics to improve sport safety more broadly. Our specific aims are to (1) Characterize head impact biomechanics and neurobehavioral health in adolescent boys’ and girls’ ice hockey, (2) Evaluate the relationship between athlete and play characteristics and HIE while controlling for neurobehavioral health, and (3) Determine the awareness and receptivity among key community members to using biomechanical data to improve head impact safety in ice hockey. We will accomplish this by using innovative mouthpiece-based instrumentation and neurobehavioral measures (Aim 1), using time synchronized video to identify head impact biomechanics event context and controlling for neurobehavioral health outcomes (Aim 2), and using a community-engaged approach to assess knowledge, attitudes, and perceptions of hockey HIE and concussions (Aim 3). We will develop a comprehensive understanding of HIE in boys’ and girls’ youth hockey grounded in accurate HIE metrics and their relationship to athlete and play characteristics and neurobehavioral health. This will facilitate discussions of receptivity to strategies to reduce HIE and concussion risk and increase benefits of participation in ice hockey.

NIH Research Projects · FY 2026 · 2025-05

Project Summary Radiotherapy (RT) planning systems are typically inaccessible to providers outside the RT department, making comprehensive sharing of RT targets a challenge. Many radiation oncologists (ROs) and radiologists feel that more collaboration is needed in both the pre-treatment planning and post treatment follow-up setting. Elimination of prevalent systemic barriers that currently limit collaboration between ROs and radiologists represents a low-cost, high-impact opportunity to improve cancer care delivery for the estimated 1 million US patients who receive RT each year. Improved communication could enhance RT target accuracy and reduce avoidable treatment toxicity, while also improving the efficiency and accuracy of post treatment imaging interpretation. Ultimately improved communication between providers has the potential to lead to improved locoregional cancer control, and beneficial impacts on patient stress and anxiety. Our multidisciplinary team of ROs, radiologists, and care delivery researchers developed the novel CORRECT workflow (Collaborative Oncology, between Radiologists and Radiation oncologists for the Evaluation of Contoured Targets) to enable efficient sharing of RT plans with diagnostic radiologists for input on accuracy of RT targets prior to treatment initiation. In our single site pilot trial, CORRECT facilitated communication between ROs and radiologists and led to substantial changes in treatment targets for 46% of reviewed lung cancer cases. Our pilot trial was promising but we need key information to inform a multi-site efficacy trial in collaboration with the Wake Forest NCI Community Oncology Research Program Research Base (WF NCORP RB). Specifically, we need to better understand: 1) feasibility of an updated workflow at community practices with varying usual patterns of RO-radiology collaboration for RT planning, 2) RO and radiology perspectives on barriers and facilitators to participation in the future trial, and 3) stakeholder preferences for key design features of the future trial. Community oncology practices may experience challenges in engaging radiology partners for research, thus it is critical to understand barriers and facilitators of provider engagement in future trials and ensure our promising feasibility and utility findings translate to community settings. To support the planning of a future Phase III multi-site efficacy trial of CORRECT to improve locoregional cancer control, we propose three Specific Aims. In Aim 1, we will determine feasibility and acceptability of CORRECT at 4 NCORP practices with varying RO-radiology collaboration for RT planning. In Aim 2, we will utilize semi structured interviews of ROs and radiologists to evaluate facilitators and barriers to RO-radiology research and clinical collaboration. Informants will include providers who participated in Aim 1 and providers who responded to our pre-grant survey indicating interest but with barriers to participation. For Aim 3, we will work closely with NCORP stakeholders to develop the future multicenter cluster randomized efficacy trial to determine the impact of CORRECT on locoregional cancer control outcomes, informed by data from Aims 1 and 2.

NIH Research Projects · FY 2026 · 2025-04

PROJECT SUMMARY Chronic pain is a debilitating disorder that effects 50.2 million people and is characterized by persistent pain lasting three months or longer and negatively impacts mood, cognition, sleep, health, and quality of life. Sleep disturbances are reported by 50-80% of patients with chronic pain that are not adequately targeted by traditional analgesics. Given the importance of sleep in regulating general brain health and contributing to daily function, developing novel analgesics that improve sleep disruptions represent a critical unmet need. Using electroencephalography (EEG) in rats, we will 1) examine the duration and severity of sleep-disruptions in a rodent model of sub-chronic neuropathic pain (partial sciatic nerve ligation; PSNL); 2) examine how current analgesics oxycodone and gabapentin influence sleep and pain sensitivity in this model; and 3) investigate the effects of Nociceptin/Orphanin Opioid (NOP) receptor agonists on sleep and pain. Similar to MOR agonists, NOP agonists demonstrate analgesic activity, yet in contrast with MOR agonists, demonstrate low abuse liability and improve sleep. I expect that PSNL will produce extensive disruptions in sleep duration and quality, lasting 2-3 weeks. I hypothesize that oxycodone will significantly decrease sleep duration and quality in PSNL rats, and that gabapentin will not impact sleep, both within analgesic dose ranges. Lastly, I hypothesize that NOP agonists will reduce pain sensitivity and increase sleep duration and quality in PSNL rats. Collectively, these studies will reiterate the importance of sleep disruptions associated with pain states, highlight unmet need for novel treatments specifically targeting sleep disruptions, and test the viability of NOP agonists for the treatment of chronic pain.

NIH Research Projects · FY 2026 · 2025-04

Young infants are at high risk for severe disease following influenza virus infection. The current strategy for protecting infants is to increase antibody in the mother that can be transferred across the placenta to the fetus such that infants are born with influenza virus-specific antibodies on board. However, while maternal antibodies can decrease the likelihood that infants develop influenza disease, in many cases this protection is incomplete and infants remain at high risk. Further, maternal antibody will wane in all infants, leaving them more susceptible to infection. The combination of the lack of a vaccine for infants under the age of 6 months, the need for two doses of vaccine to achieve protective levels of antibody, and waning maternal antibody results in a window of vulnerability in infants. Our goal is to effectively vaccinate young infants when maternal antibody is at high levels, such that as maternal antibody is waning, a protective anti-influenza response is rising in the infant. Among the challenges associated with effective vaccination of newborns is the potential for interference by maternal antibody. Currently, there is debate in the field regarding the extent of the impediment posed by maternal antibody in the context of influenza vaccination. A fuller understanding of the potential for maternal antibody-mediated regulation has been hampered by the lack of study using a model that closely resembles humans in maternal antibody transfer and infant immune system development/function. Here, we use the nonhuman primate model to investigate this significant area. NHP are the most reflective pre-clinical model of human maternal antibody transfer and infant immune development/function. Vaccine responses in infants born to influenza virus-immune or naive mothers will be evaluated at the antibody and cellular level. These studies will significantly move forward our mechanistic understanding of the impact of maternal antibody in the context of influenza vaccination and provide insights into the development of more effective vaccines for newborns.

NIH Research Projects · FY 2026 · 2025-04

Two decades of research shows that the psychological well-being of unpaid family caregivers (CGs) is a significant determinant of quality of life for both the person with dementia (PWD) and CGs. One dominant model used to understand CG burden is the Pearlin stress process model, which takes a life course approach. Within this model, identified risk and protective factors include background factors (sex, race, age, socioeconomic status), primary stressors (PWD diagnosis, behavioral symptoms, functional dependency), secondary stressors (job-caregiving conflict, economic burden, altered relationships), social and personal resources (self-efficacy, coping), and outcomes (mental health factors (depression, anxiety), physical well-being, and burden). Based on our team’s clinical work with CGs, we hypothesize that another, previously unrecognized dimension of caregiver burden, Post-Traumatic Stress Symptoms (PTSS), may contribute to CG burden and depression. We hypothesize that exposure to potentially traumatic events and PTSS can contribute to caregiver burden in three ways: 1) exposure to potentially traumatic events prior to caregiving; 2) exposure to potentially traumatic events that occur in the course of caregiving (related to caregiving or not); and 3) the chronic stress of caregiving. This proposal builds on our pilot data from 25 CGs which showed that 40% of the sample had experienced at least one Adverse Childhood Event (ACE), 44% reported lifetime exposures of 4 or more traumatic events, 16% reported that caregiving for their PLWD was the most stressful event of their life, and 36% scored above the PTSD screening threshold for PTSS. PTSS scores were highly predictive of important caregiver outcomes, including self-efficacy, depression, grief, caregiver burden, and social support. We will expand this to a larger sample of 1200 CGs in the state of North Carolina. The aims of this proposal are to 1) determine the prevalence of caregiving-related PTSS and exposure to potentially traumatic events across the lifespan in CGs of PWD and assess the relationship between PTSS and overall exposure to traumatic events and specific exposure to interpersonal violence; 2) assess direct and indirect effects of PTSS on caregiver burden as well as determining relationships between PTSS and well-established risk and protective factors in CGs and PLWD; and 3) examine the impact of contextual factors important for identifying patients for future intervention, including geographic location (urban/suburban/rural), race, and CG relationship (spouse/adult child) on the prevalence of PTSS and associations with CG burden and depression. This foundational knowledge will provide evidence for the implementation of screening for post-traumatic symptoms and adaptation of caregiver support services to address PTSS in CG of PWD by determining 1) whether enough CG are affected to warrant interventions specifically addressing PTSS, 2) which CG are most likely to benefit from additional or targeted supportive services aimed at PTSS, and 3) what aspects of CG and PWD well-being are likely to be addressed by treating PTSS.

NIH Research Projects · FY 2026 · 2025-03

The immune system of young infants exhibits profound alterations compared to that of older children and adults. Notable among these are lower responses to TLR engagement, reduced dendritic cell maturation, reduced Tfh responses, and a strong Th2 bias. While proposed to be beneficial for establishment of the microbiome and preventing untoward inflammatory responses, these alterations hamper the ability to respond to vaccines. As a result, infants are poor at mounting protective antibody responses following vaccination with standard seasonal influenza vaccines. Consequently, these vaccines are not approved for infants under 6 months of age. An ideal vaccine for young infants would require only a single vaccination to elicit high levels of protective antibody. In our efforts to more fully understand the infant immune response and achieve high levels of protective antibody with a primary vaccine regimen, we explored a prolonged antigen delivery approach. We found that this resulted in significantly increased levels of antibody in infant mice following administration of a nanoparticle vaccine containing only the stem region. Infants vaccinated with a bolus dose of this vaccine had barely detectable antibody at 14 days following vaccination. In striking contrast, infants vaccinated with the prolonged approach elicited a strong stem-specific antibody at d14 that was similar in level to that of adult animals. Notably, there was minimal difference in the bolus versus prolonged approach in adult mice. Together, these data form the foundation for the proposed studies, which seek to understand at a mechanistic level how antigen duration and vaccine construct modulate the infant B and T cell response. At the conclusion of these studies, we will have gained novel insights into the regulation of the infant influenza-specific immune response. These findings have important implications for the rational design of novel vaccine approaches that can be used in this at-risk population.

NIH Research Projects · FY 2026 · 2025-03

Food insecurity (FI) affects 20% of the 116 million people in the US with hypertension (HTN). FI is associated with poor adherence to evidence-based HTN treatments, worse blood pressure control, and a higher risk of mortality. Interventions used to address FI in clinical care settings include 1) providing information about community resources, 2) utilizing community health workers, and 3) delivering medically-tailored meals. Although there is evidence for each of these interventions, people differ in the support they need to reduce FI and little is known about which interventions work best, or for whom. Rather than use a single FI intervention, adaptively allocating interventions could be a more effective and efficient approach to improve food security, treatment adherence, and blood pressure for the large, vulnerable population affected by FI and HTN. Our objectives are to 1) determine which initial FI intervention more effectively improves adherence and blood pressure and 2) for those who do not respond to the initial intervention, evaluate how best to provide additional support. We will conduct a Sequential Multiple Assignment Randomized Trial (SMART) in partnership with Atrium Health Wake Forest Baptist, an academic medical center that serves communities in North Carolina with high rates of FI and HTN. In the SMART, patients with uncontrolled HTN and FI will be randomized to 1 of 2 first-stage FI interventions: 1) resource information or 2) community health worker support. Participants who do not have an improvement in blood pressure after 3 months will be re-randomized to 1 of 2 secondstage interventions for an additional 3 months: 1) community health worker support or 2) medically-tailored meals. In Aim 1, we will determine which first-stage FI intervention is more effective in improving adherence and blood pressure. In Aim 2, we will evaluate which FI intervention is the best next step for those who do not respond to the initial intervention. In Aim 3, we will explore how, why, and under what circumstances participants achieved improvements to the first- and second-stage interventions by conducting semi-structured interviews with participants and evaluating for potential predictors of heterogeneity in response to each intervention. The proposed research complements NHLBI’s NOSI (NOT-OD-21-100) to “overcome barriers to adherence to evidence-based guidelines” and “address social determinants that contribute to disparities in adherence.” This will be the first study to evaluate an adaptive intervention to enhance adherence to HTN treatments, by addressing FI. Given the growing interest among health systems in addressing FI as part of clinical care, an efficacious adaptive intervention could be broadly disseminated across healthcare settings. An adaptive FI intervention could reduce the costs and burden to patients and providers by providing no more treatment than is needed for patients who respond to a less intensive approach and redirecting the saved resources to patients who need a more intensive approach. Our team of established investigators has successfully used the methods proposed and has the full support of the health system where the study will occur.