Medical University Of South Carolina

NIH Research Projects · FY 2025 · 2025-07

TITLE: Administrative Supplement to Expand Enhancement of the IMHRD Cohort in EXACT-PLAN ABSTRACT. The NIAMS funded parent project planning award entitled: “Enhancing the IMHRD cohort to support study of the exposome in autoimmune disease” seeks to develop resources and strategies needed to examine the role the exposome plays in the development and progression of autoimmune disease within a highly diverse cohort centered on lupus and scleroderma. Achieving this goal will advance NIH’s EXposome in Autoimmune Disease Collaborating Teams PLANning Awards (EXACT-PLAN) initiative by direct contributions to the collaborations, resources, and methodologies necessary to conduct exposome-wide association studies (ExWAS) that can comprehensively assess the role the environment plays in autoimmune disease. The goal of this administrative supplement is to expand the parent grants infrastructure and resources to include emerging directions and priorities identified through new collaborations with the Network for Exposomics in the United States (NEXUS; U24ES036819), HERCULES Exposome Research Center (P30 ES019776), and the NIH OADR/NLM. It is important to note that these directions are within the scope of the original award and directly align with NOT-OD-23-112. This supplement is necessary to address the unforeseen costs associated with achieving goals in three additional projects. The first includes support to develop workflows and resources necessary to facilitate a multi-site geospatial project focused on establishing geographic resources needed to characterize the external exposome for study populations within EXACT-PLAN. This project includes participation from all EXACT-PLAN sites and incorporates extensions recommended by the Geospatial Sciences Hub in NEXUS. The second project will enhance application of exposomics resources and expertise within EXACT-PLAN by establishing a new collaboration with the HERCULES Exposome Research Center and IMHRD. This includes support to access metabolomic, targeted analyses, and data science resources within HERCULES. This supplemental project will build upon the PI’s HHEAR project by incorporate new directions focused on the internal exposome. This will include targeted analyses of biological samples, assistance with analyses of untargeted metabolomics data, and resources to enhance epigenetic research in IMHRD. The third project seeks to establish the bioinformatics resources necessary for preparation of IMHRD resources to participate in a Federated Data Platform. Successful completion of these supplemental projects has multiple benefits as execution will enhance resources and decision-making tools needed to promote success of a future EXACT Network. Secondly, findings will fill important knowledge gaps related to the burden and health impacts of chemical and geographically determined exposures experienced by populations with autoimmune disease.

NIH Research Projects · FY 2025 · 2025-07

This application requests support of the Medical Scientist Training Program at the Medical University of South Carolina. The major goal is to train the next generation of physician-scientists who will choose a career that will integrate both the basic and clinical sciences to improve human health and treat diseases. Initiated at the Medical University of South Carolina (MUSC) in 1980, our MSTP has graduated 157 students and currently has 64 students in the program in a variety of disciplines. Of these 157 alumni, their positions are: 1 associate dean and endowed chair, 4 endowed/named chairs, 6 professors, 10 associate professor, 47 assistant professor, 6 instructors, 2 VAMC, 9 pharmaceutical/industry, 1 NIH, 40 private practice, 29 residents and fellows, 1 retired, and 1 deceased. Our program in the medical school has incorporated a new preclerkship (FLEX) curriculum in which the first two years are condensed into 18 months, and summer vacation is eliminated. This curriculum has increased flexibility for graduate students to re-enter into medical school at three time points. In addition to rigorous basic science research training and medical school, trainees gain experiences in translational research via the Translational Sciences Clinic, a month in the Clinical and Translational Research Center and the Translational Medicine Seminar series. The objectives for the next phase are to continue: 1) Providing a state-of-the art curriculum that increases critical thinking skills, drives curiosity, and encourages inquiry-based learning in both basic and translational research and clinical investigation; 2) Providing rigorous training in key areas of biomedical research from a highly collaborative core group of faculty with exceptional records of accomplishment in research and mentoring; 3) Providing an interactive training environment that embraces research and entrepreneurial sciences and provides opportunities for professional and leadership development; 4) Providing constructive, ongoing mentoring of each MSTP student using Individualized Development Plans, based on guidelines established by FASEB’s Science Policy Committee; 5) Managing an expanded formal evaluation plan that includes both formative and summative assessments and incorporates quantitative and qualitative data; and 6) Working towards obtaining a degree completion rate of 95% and an average time to degree of 8 years. Due to the strong institutional commitment and leadership of the program, the growth in the quality and quantity of our applicants has increased, supporting the basis for the requested 14 positions per year.

NIH Research Projects · FY 2025 · 2025-07

Findings from rodent models of heroin self-administration (SA) and cue-induced heroin seeking demonstrate that chronic opioid exposure leads to maladaptive cortical plasticity mechanistically linked to the persistent vulnerability to relapse that characterizes opioid use disorder. Emerging data from our lab, using genetic calcium indicators (GECIs) to analyze neuronal activity and head-fixed in vivo 2-photon imaging during drug taking and subsequent drug seeking, demonstrate that unique neuronal ensembles form within the dorsomedial prefrontal cortex (dmPFC) during drug exposure, SA, and withdrawal. These data support the hypothesis that discrete neuronal ensembles encode specialized information pertaining to reward-associated cues, and reward delivery, and that these ensembles drive reward seeking behaviors in operant drug-reward learning and drug-seeking tasks. Importantly, manipulation of these ensembles serves as an effective means to reduce or eliminate cue-induced drug seeking. Despite these advances, very little is known about how dmPFC neuronal ensembles are formed and refined to control drug seeking. We hypothesize that astroglia, critical mediators of this synaptic plasticity, are required for this process. Yet very little is known about how astrocyte activity patterns adapt across reward learning and how this coincides with neuronal ensemble formation. Further, it also remains to be elucidated what role cortical astroglia play in regulating or directing the adaptations in neuronal activity driven by drug-reward learning. A growing body of evidence now indicates that astrocytes respond to altered patterns of synaptic activity by engaging mobilization of internal Ca2+ stores to drive Ca2+- mediated astroglial cellular processes that coordinate and integrate action potential firing within neuronal networks. Considering these new and exciting data, astroglia serve as an excellent candidate for a crucial regulatory force required to shape drug reward-learning neuronal ensemble formation, and as such are an underexplored research direction that could lead to viable means to limit relapse vulnerability. Our overarching hypothesis is that coordinated dmPFC astrocyte activity during heroin SA is required to shape the neuronal ensembles underlying heroin seeking. Throughout the proposal, we will employ intersectional viral vector strategies. In Aim 1 we will utilize neuronal and astroglial GECI expression and analysis pipelines to analyzed and relate activity within each cell type, and in Aim 2 we will use an intersectional approach for astroglial activation and simultaneous neuronal GECI expression and analysis. In Specific Aim 1, we will establish how neuronal and astroglial activity patterns evolve as heroin SA progresses to heroin seeking, using parallel sucrose controls. We will also specifically compare astrocytic responses to neuronal ensembles, during both heroin or sucrose taking and seeking. In Specific Aim 2, we will establish how chronic astroglial activation, via chemogenetic stimulation of Gq signaling, impacts neuronal ensemble formation during heroin or sucrose SA, extinction, and cue-induced seeking.

NIH Research Projects · FY 2025 · 2025-07

PROJECT SUMMARY Over two-thirds of children experience traumatic events such as child maltreatment, violence, or sudden or violent loss. Many of these children sustain significant emotional and developmental difficulties including trauma symptoms, aggression, and suicidality. Emotional support from a caregiver is theorized to buffer against the effects of trauma; however, many caregivers lack the self-efficacy and skills to effectively support their child, or struggle to apply these skills during the stressful time following trauma. Unfortunately, programs designed for caregivers following child trauma are scarce. Existing interventions are lengthy (lasting 8-20 sessions) and result in families placed on long waitlists. This proposal asserts the adverse effects of child trauma can be interrupted though a brief intervention (the Project Support Positive Parenting Module) that enhances supportive parenting – delivered via telehealth to families on waitlists for trauma-focused services. Pilot data collected by the candidate suggests this intervention can be delivered by paraprofessionals, improve parenting self-efficacy and emotional support, and increase later trauma-focused treatment attendance. However, the provider characteristics (e.g., knowledge, experiences), as well as inner (e.g., organizational support) and outer (e.g., patient needs, attitudes) contextual factors that influence uptake of a brief intervention for families on the waitlist for trauma services is unknown. Aims 1 and 2 comprise the K99 Mentored Research Phase and Aim 3 comprises the R00 Independent Research Phase. Specific Aims include: 1) examine barriers and facilitators to delivering Project Support via telehealth with n = 20 caregivers and n = 10 treatment providers; 2) examine the feasibility and acceptability of Project Support via telehealth in a mixed-methods proof-of-concept pilot trial with n = 30 families waiting for trauma-focused services and n = 4 treatment providers; and 3) evaluate the preliminary efficacy of Project Support in a randomized controlled trial (Project Support vs. treatment as usual) among n = 100 families waiting for trauma-focused services. The proposed research activities coincide with training that will support the candidate’s transition to an independent investigator. In the K99 phase the candidate will receive training via coursework, workshops, and consultation in: (1) implementation science frameworks and dissemination strategies, (2) qualitative and mixed methodology, and (3) grantsmanship and scientific communication. Mentorship and consultation from experts in child trauma, caregiver-child relationships, implementation science, qualitative methods, and statistical analyses will ensure training goals are met. This proposal will support the candidate’s long-term career goal to become an independently funded tenure track faculty who advances the field of child trauma research by studying the consequences of children’s trauma exposure and developing and testing innovative parenting-based interventions for victims of trauma and their families. This K99/R00 mechanism is a critical step to obtaining the experience and independence necessary to obtain this goal.

NIH Research Projects · FY 2025 · 2025-06

PROJECT SUMMARY Pulmonary disease due to Mycobacterium abscessus complex (MABC) causes significant morbidity, particularly in older women and people with underlying lung disease. MABC is intrinsically resistant to most antimicrobials. Existing treatments have poor efficacy, effectiveness and tolerability. Moreover, knowledge gaps have hampered the design and implementation of clinical trials of new antimicrobial therapies for this disease. Omadacycline is a relatively new tetracycline antibiotic that has promising in vitro and in vivo activity against MABC. Observational studies by our team and others support a role for omadacycline in treatment of MABC pulmonary disease, but rigorous clinical trials have not been performed. We propose a clinical trial that addresses two key knowledge gaps. First, in a randomized, blinded, placebo-controlled trial we seek to determine the efficacy and safety of omadacycline, in combination with other antimicrobials, for treatment of MABC pulmonary disease. Second, we seek to define a strategy for conducting clinical trials for treatment of MABC pulmonary disease, as currently there is no established clinical trial paradigm. To do this we will incorporate microbiologic, radiographic, and patient reported outcomes and explore pharmacokinetic drivers of efficacy and safety outcomes. The specific aims of this R34 clinical trial planning grant are AIM 1) to develop the detailed trial protocol and additional documentation required for initiation of the trial; AIM 2) to secure a study- specific supply of omadacycline and matched placebo; AIM 3) to identify additional enrollment sites (in addition to sites of the proposing investigators); AIM 4) to complete the regulatory approvals necessary for implementation of the trial; and AIM 5) to apply for NIH R-level funding to support the future conduct of the trial. We have gathered a team whose members have the requisite experience and expertise to successfully design, plan, and execute the future clinical trial. Regardless of outcome, the proposed novel clinical trial will meaningfully inform clinical practice and advance the science of clinical trials for MABC pulmonary disease, and thereby will have potential for high impact on the field and on health.

NIH Research Projects · FY 2026 · 2025-06

SUMMARY Alcohol and opioid use disorders are characterized by both the facilitation and disinhibition drug seeking and use. Despite this knowledge, the influence of alcohol and opioid use on brain circuits responsible for facilitating and inhibiting natural reward-seeking behaviors remains unclear. Surprisingly, until recently no study had tracked activity in single neurons from the onset of drug use to relapse, limiting our understanding of how these circuits computationally change to prioritize drug-motivated behaviors. We recently overcame this issue by developing a mouse behavioral assay that allows longitudinal tracking of activity in precisely defined neurons across alcohol and opioid self-administration, extinction, and reinstatement. Using this model, we identified precise neuronal ensembles based on in vivo dynamics within key behavioral facilitation and inhibition circuits, namely from dorsomedial prefrontal cortex and paraventricular thalamus to the nucleus accumbens (dmPFCàNAc; PVTàNAc). Ensembles within each projection showed divergent adaptations predictive of drug seeking, whereas functional manipulations could prevent the facilitation (dmPFCàNAc) or disinhibition (PVTàNAc) of drug seeking. However, the transcriptomic identity and function of each neuronal ensemble remains unknown. Here we will test the overarching hypothesis that dmPFCàNAc and PVTàNAc projections are composed of unique neuronal ensembles organized based on multiplexed gradients of activity, gene expression, spatial location, sensitivity to drug use and seeking, and causal function for the facilitation and disinhibition of drug seeking. We test this hypothesis by employing a combination of innovative tools, now in use within our laboratories, such as single-nucleus RNA sequencing (snRNA-seq), Xenium spatial sequencing (spatial-seq), in vivo two-photon calcium imaging, and single-cell holographic optogenetics. Overall, this project will characterize the transcriptomic profile and function of single neurons and computationally unique neuronal ensembles in key brain circuits that causally govern the facilitation and disinhibition of alcohol and opioid seeking. The groundbreaking strategies employed will be transformative for the field of addiction research, providing comprehensive understanding of gene expression and targetable substrates within relevant cell populations for further study and manipulation for treatment of opioid and alcohol use disorders. Large-scale multimodal calcium imaging and RNA sequencing datasets will be made freely available to the public and scientific community for further study.

NIH Research Projects · FY 2026 · 2025-06

PROJECT SUMMARY/ABSTRACT Opioid use disorder (OUD) continues to be associated with high rates of morbidity and mortality and has a significant impact on affected individuals, their families, and their communities. Problems related to social functioning are part of OUD criteria and a wealth of research suggests that individuals with OUD may be prone to experiencing isolation, loneliness, lack of social support, and poor conflict resolution and problem-solving skills in interpersonal contexts. Emerging evidence suggests that OUD treatment, particularly behavioral treatments adjunctive to medications for OUD (MOUD), may improve social functioning and that gains in social functioning may have beneficial impacts on OUD recovery; however, the specific social functioning metrics that are associated with positive OUD treatment trajectories are understudied. Further, much of the extant literature has only examined social functioning from the lens of the patient with OUD, even though reports from concerned significant others (CSOs) may have valuable predictive utility. The proposed study seeks to address gaps in the field by examining how affiliative social engagement behaviors, social reward, and social connection change and are associated with positive OUD treatment outcomes among a sample of 100 patient-CSO dyads. The study will combine established ecological momentary assessment (EMA) methods with the use of an innovative smartwatch-based application (i.e., SocialBit) in a single-armed trial to assess both subjective self-reports and objective measurements of social functioning from patients with OUD and a non-substance using CSO. Aim 1 will determine how patient-reported and CSO-reported social behaviors, social reward, and social connection change during OUD treatment; Aim 2 will identify if patient-reported and CSO-reported social behaviors, social reward, and social connection predict MOUD adherence and opioid craving; Exploratory Aim 3 will validate the use of SocialBit for assessing social connection in an OUD treatment sample. Drs. Jarnecke and Tomko (MPIs) have assembled a team of renowned investigators with expertise in OUD, social functioning, dyadic data, EMA methods, and the translation of clinical data into novel therapeutics. There is an urgent need to address how social functioning contributes to OUD and opioid overdose, and to take a “whole person” approach to treatment. Findings have strong potential to inform future precision-medicine approaches focused on the dual targets of OUD and social functioning.

NIH Research Projects · FY 2026 · 2025-05

This application requests support for the K12 Mentored Career Development Program (formerly KL2), an integral part of the NCATS-supported South Carolina Clinical & Translational Research Institute (SCTR) at the Medical University of South Carolina (MUSC). Established in 2009, the overall objective of the K12 program is to deliver high-quality mentoring and training to promising emerging scholars to support their progression to independent translational science careers and to facilitate translation of observations in the laboratory, clinic, and community into interventions that improve the health of individuals and the public. There are 5 scholar positions in the program (3 funded by this award and 2 funded by institutional funds). Each scholar is appointed to the program for two years. If scholars are making satisfactory progress but have not yet obtained independent funding, they may be considered for a third year of programmatic support. Scholars will be junior faculty members who are recruited from internal and external pools. In the previous funding periods, scholars have had significant success with 86% of program graduates obtaining independent extramural funding. This application requests support to build on our programmatic strengths and transition our focus to training in translational science as well as in translational research. The specific objectives of the MUSC K12 Program are to: 1) provide innovative personalized training in translational science and research methods through mentoring, coursework, and programmatic support to prepare our scholars for sustained and productive careers as independent investigators; 2) prepare our scholars to be biomedical research leaders through immersion in MUSC’s rich interdisciplinary team science environment that features training across the translational spectrum and is focused on improving efficiency of scientific translation; and 3) ensure that a pool of highly trained scientists from a range of disciplines receives the appropriate training to address our state’s and nation’s critical health care needs and to improve health.

NIH Research Projects · FY 2026 · 2025-05

PROJECT SUMMARY Opioid use disorder (OUD) and Post-Traumatic Stress Disorder (PTSD) are highly comorbid and mutually exacerbating. There is a critical unmet need for pharmacotherapeutics targeting stress-precipitated relapse, as stress-conditioned stimuli are a major driver of relapse in comorbid patients. Classical psychedelics like psilocybin are appealing candidates as therapeutics for OUD, as they do not lead to physical dependence and demonstrate promising potential in reducing stress and addictive behaviors in humans. These effects appear to be long-lasting from one to few treatments, suggesting adaptation to neural circuits affected by chronic stress and substance use. Despite promising clinical evidence suggesting the efficacy of psychedelics in the treatment of stress and substance use disorders, there is a critical gap in the preclinical profiling of psychedelics in OUD models. Understanding the neural mechanisms underlying the therapeutic effect of these compounds is necessary for future development of novel OUD therapeutics with reduced hallucinogenic side effects. We have developed a novel mouse model for studying relapse induced by cues associated with prior stressful life events. My preliminary data from the Smith Laboratory demonstrate that the psychedelic 2,5,dimethoxy-4-iodoamphetamine (DOI) blocks stress-cued reinstatement to heroin in mice. We identified the anterior insular cortex (aIC) as a brain structure that may mediate the interaction between psychedelics, stress, and OUD, and find that DOI reduces reinstatement-induced c-Fos in the aIC. We propose that psychedelic- induced plasticity promotes lasting adaptations to circuitry affected by stress and heroin seeking, resulting in an attenuation of stress-cued heroin seeking. Aim 1 will identify the whole-brain pattern of neuronal activity and behavioral effect of psilocybin on stress-cued reinstatement to heroin. Using cell-type specific circuit manipulation via chemogenetics, we will gain valuable insight into the necessity of aIC 5HT2AR in modulating stress-cued reinstatement to heroin. Understanding the role of the 5HT2AR, which mediates hallucinogenic activity of psychedelics, in the therapeutic effects of psychedelics will provide critical information to steer drug discovery efforts aiming to treat stress and substance use disorders with serotonin agonists. Aim 2 will use fiber photometry to record aIC calcium dynamics during a stressful experience and re-exposure to stress-cue, and determine how treatment with psilocybin impacts these responses. Together, these experiments seek to elucidate circuit mechanisms underlying the effect of psilocybin on stress-induced heroin seeking behaviors. This study will be conducted at the Medical University of South Carolina, a leading center in the field of addiction neuroscience. Under the mentorship of Drs. Alexander Smith and Christopher Cowan, I will receive training in rodent intravenous drug self-administration, whole brain c-Fos mapping, chemogenetics, in vivo recording of neural activity with fiber photometry, and computational tools for data analysis.

NIH Research Projects · FY 2026 · 2025-05

The aging population has increased globally, leading to an increased incidence of aging-related comorbidities including periodontitis. Our long-term goal is to develop effective new therapies to alleviate periodontal inflammatory bone loss associated with aging-related periodontitis and help prolong the healthspan of human beings. It is well-known that nicotinamide adenine dinucleotide (NAD+) plays essential roles in the healthspan of human beings. Previous studies demonstrated that a decline of NAD+ in the aged population contributes to the pathogenesis of various aging-associated diseases, including type II diabetes and Alzheimer’s disease. Moreover, CD38 (an inflammatory marker and an enzyme active in degrading NAD+) enhanced in the aged population. Inhibition of CD38 by a specific inhibitor (78c) reversed age-related NAD+ decline and increased the lifespan and healthspan of naturally aged mice. However, significant knowledge gaps exist. It is unclear how oral bacterial pathogens influence aging-associated immune responses, and how the CD38 signaling pathway regulates aging-associated immune responses induced by oral bacterial pathogens. The goal of this application is to define how oral pathogens affect aging-associated immune responses and whether inhibition of CD38 can attenuate inflammatory bone loss and alleviate aging-associated immune responses induced by oral pathogens. Our preliminary results are the first to show that the oral pathogen Aggregatibacter actinomycetemcomitans (Aa) or Porphyromonas gingivalis (Pg), enhanced CD38 levels and significantly decreased the NAD+ levels in old murine bone marrow-derived monocyte and macrophages (BMMs), compared with control levels derived from young murine BMMs. Moreover, inhibition of CD38 by 78c reduced CD38 levels and reversed the decline of NAD+ in murine BMMs infected with Aa. Additionally, in murine BMMs infected with Aa, treatment with 78c enhanced the mRNA and protein levels of pro-longevity genes (Sirtuin1, PARP-1, and NAMPT) and superoxide dismutase1 (SOD1, an antioxidant enzyme), but reduced NADPH oxidase1 (Nox1) expression. Furthermore, treatment with 78c attenuated IL-1b, IL-6, and TNF-a cytokine levels induced by Aa and inhibited osteoclastogenesis induced by RANKL. Thus, we hypothesize that inhibition of CD38 by 78c is a novel therapeutic strategy to treat aging-associated periodontitis. Our specific aims are as follows: 1) We will determine if murine BMMs derived from old mice have higher levels of CD38 and lower levels of NAD+ with or without Aa or Pg infection, when compared with the murine BMMs derived from young mice, and if knockdown or inhibition of CD38 in vitro in BMMs can reduce CD38, increase NAD+ and NAD+ biosynthesis salvage pathway (Sirtin1, PARP-1, NAMPT) signaling, and reduce oxidative stress induced by Aa or Pg. 2) We will generate a periodontitis animal model in mice, and determine if treatment with the CD38 specific inhibitor (78c) in vivo can reduce CD38, attenuate periodontal inflammatory bone loss, decrease oxidative stress, enhance NAD+, and increase Sirtin1, PARP-1, NAMPT genes in the tissues, compared with controls.

NIH Research Projects · FY 2026 · 2025-04

Since 2009, the South Carolina Clinical and Translational Research Institute (SCTR) has transformed the research environment across South Carolina (SC), facilitating the translation of innovative science into clinical practice. Headquartered at the Medical University of South Carolina (MUSC), SCTR has engaged community members and other stakeholders and created statewide collaborations to address SC’s priority healthcare issues. Most (>75%) of SC is rural, with medical provider shortage areas in all 46 counties, and characterized by poor health outcomes and less healthy behaviors. We have been steadfast in our mission to engage communities statewide, increasing research access in rural areas amid the expansion of the MUSC Health Network. Over the next seven years, SCTR will strengthen its outreach to rural areas, leveraging our strengths with the MUSC Telehealth Center of Excellence and collaborations with SC State University, and the University of SC. With a focus on innovation, implementation, and impact, we will develop, demonstrate, and disseminate technologies and outreach strategies to improve the health of those we serve. We will build on prior successes and introduce innovations to expand translational science across SC via the following aims: Aim 1. Provide an agile, responsive, and collaborative infrastructure that catalyzes community-engaged, patient-focused clinical and translational science (CTS). Aim 2. Support further development of a clinical and translational research (CTR) workforce enabled with the knowledge and skills to effectively enhance research participation across all South Carolina populations, ensure alignment between research and community health priorities, and implement clinical discoveries that improve the health of South Carolinians. Aim 3. Remove barriers to implementation of efficacious treatments and practices by creating and adapting scientific and operational innovations and providing resources that increase the quality, safety, efficiency, effectiveness, and informativeness of clinical and translational research. Aim 4. Facilitate and support innovative research projects that address significant CTS roadblocks through multidisciplinary team science. As SC’s academic home for CTS, SCTR supports innovative, efficient, multidisciplinary research and is integrated with a healthcare system that spans the state. Our mission is to catalyze CTS innovations that lead to more efficient translation of biomedical breakthroughs into interventions that improve individual and public health. We will work within SCTR, with collaborators across SC, and with the CTSA Consortium to achieve our mission and realize our vision for improved human health for SC and beyond.

NIH Research Projects · FY 2026 · 2025-04

Corticospinal function is essential in generating and controlling voluntary movements. Cervical spinal cord injury (SCI) disrupts corticospinal connections, therefore, often results in weak voluntary activation of muscles and impaired motor control in the upper limb (UL). An intervention that improves corticospinal function could enhance motor function recovery; however, such interventions are not currently readily available to people with incomplete SCI. Operant up-conditioning of a motor evoked potential [MEP] to transcranial magnetic stimulation (non- invasive brain stimulation) that can increase corticospinal excitability for the targeted muscle may be able to fill this gap. The overarching hypothesis is that targeting beneficial plasticity to the corticospinal pathway can change the brain and spinal cord and improve upper limb motor function in people with chronic cervical SCI. As initial steps towards testing this, the proposed project aims to apply MEP operant up-conditioning in the wrist extensor of the affected UL, improve corticospinal activation of the wrist extensor, and thereby improve motor functions in which the wrist is involved in individuals with cervical SCI. Recent studies suggest that MEP up- conditioning is feasible and can increase MEP size that reflects corticospinal excitability. Building on those studies, this project will examine the effects of wrist extensor MEP operant up-conditioning in people with chronic cervical SCI. Individuals with weak wrist extension due to incomplete cervical SCI will undergo a standard MEP up-conditioning protocol (6 baseline and 24 up-conditioning sessions over 10 weeks). Before and after the intervention period, neurophysiological measurements, clinical and functional assessments, neuroimaging of the spinal cord and brain will be performed. The results will facilitate development and clinical translation of MEP operant conditioning as a novel non-invasive therapy that may complement other therapies and further enhance motor function recovery in people with SCI or other disorders, which aligns with the mission of NICHD to optimize the abilities of individuals with neurological disorders. The proposed project serves as a career development and research training opportunity for the applicant. Over the course of proposed two years, the applicant will acquire unique research skills that are essential in the applicant’s future SCI research as an independent principal investigator; those include, but not limited to, MEP operant conditioning (which is available only at the Medical University of South Carolina [MUSC] EPOC lab), neurophysiological assessment, spinal imaging, and advanced brain imaging. The applicant will also receive career development education/training, such as clinical trial design/implementation, grant writing, and leadership skills. In combination with frequent virtual meetings with non-MUSC mentorship team members, most of in-person training will occur at MUSC. Neuroimaging, neuromodulation, and rehabilitation research programs have been rapidly growing at MUSC, providing an ideal training environment for the applicant to start developing own independent career as a successful academic researcher in neurorehabilitation.

NIH Research Projects · FY 2026 · 2025-04

ABSTRACT One of the key-confounding factors that hampers the adoptive T cell therapy is the presence of immunosuppressive cells like myeloid-derived suppressor cells (MDSCs), Tumor associated macrophages (TAMs) in the tumor microenvironment (TME). Thus, strategies to boost the anti-tumor T cell function in vivo by overcoming immunosuppression holds merit. In addressing the role of sphingolipids in TME we noted that MDSCs obtained from Sphingosine-kinase-2 knock-out (SphK2 KO) mice, and not SphK1 KO mice, had reduced immunosuppressive phenotype as evident from the increased proliferation and IFN-γ secretion by T cells co- cultured with SphK2 KO MDSCs. The reduced suppressive capacity of SphK2 KO MDSCs correlated to reduced expression of signature immunosuppressive molecules like Arginase, IDO, IL10, TGFβ whereas high levels of immunogenic cytokine IL12 compared to wild-type (WT) MDSCs. SphK2 KO MDSCs also exhibited upregulated expression of co-stimulatory molecules CD80, CD86, and MHC Class-I expression that correlated to the accumulation of fatty acids (FA) and enhanced activity of Acetyl CoA carboxylase (ACC), an enzyme that catalyzes conversion of acetyl CoA to malonyl CoA, a carbon donor for long chain FA synthesis. Since Acc1 is inactive when phosphorylated, we hypothesize that SphK2 mediated S1P regulates ACC activity, and its inhibition leads to increased fatty acid synthesis and immunogenic phenotype of the myeloid cells in the tumor microenvironment. Furthermore, inhibiting the MDSC suppressive function by pharmacological inhibition of SphK2 (using ABC294640) along with adoptive transfer of T cells and a checkpoint inhibitor (anti-PD1 antibody) improved the control of subcutaneously established B16-F10 melanoma. These observations have led us to propose the following specific aims for this project: 1) Determine how SphK2-mediated S1P induces MDSC suppressive phenotype, 2) Determine the mechanism of how SphK2-mediated S1P alters MDSC metabolism, and 3) Determine if SphK2 inhibition improves tumor control and enhances immunotherapy outcomes in vivo. These studies hold immense translational significance for patients with cancer where SphK2/S1P axis can be targeted to overcome immunosuppression and improve immunotherapeutic control of the tumors.

NIH Research Projects · FY 2026 · 2025-02

ABSTRACT Stroke has remained a leading cause of disability for the past thirty years and the number of people living with stroke and subsequent economic burden is expected to continue to grow over the next several decades. Chronic survivors of stroke have substantially reduced levels of aerobic and muscular fitness and, paradoxically, routine stroke rehabilitation is not delivered at an intensity sufficient to drastically augment aerobic and muscular capacities. Consequently, there is a critical need to develop comprehensive and appropriately dosed exercise programs that are scalable and complementary to current stroke rehabilitation practices. Cardiac rehabilitation is designed to enhance physical capacity via progressive exercise (aerobic and strengthening) and has been shown to improve physical and psychosocial impairments that are highly prevalent in patients following cardiac events (e.g., heart attack). Despite the cardiovascular origins of stroke, survivors are not eligible for cardiac rehabilitation programs. Consequently, survivors of stroke commonly experience a self-perpetuating cycle of reduced aerobic and muscular capacities, difficulties performing activities of daily living, and impaired psychosocial function. Experimental modified cardiac rehabilitation programs for stroke have utilized intensive aerobic exercise to improve aerobic capacity and locomotor function. Yet, despite representing at least one-third of survivors of stroke, those with post-stroke depression (PSD) have remained largely underrepresented in such programs. Given the negative effects of PSD on rehabilitation outcomes and the favorable effects of cardiac rehabilitation programs on physical function and depression, this represents an opportunity to improve our current approach to stroke rehabilitation. The proposed study directly addresses this gap in the literature by testing the effects of Physical Capacity training for ChroniC stroke – Building Aerobic capacity and Muscle Strength (PC3-BAMS), a 12-week modified cardiac rehabilitation program, on physical and psychosocial function in community-dwelling survivors of stroke with and without PSD. Subjects, with and without PSD, will receive 36 sessions of PC3-BAMS to determine the impact of a comprehensive modified cardiac rehabilitation program on post-stroke physical capacity and psychosocial function. Specifically, we hypothesize that subjects without PSD will demonstrate greater improvements in walking capacity as measured by the six-minute walk test and improvements in psychosocial function, as measured by the Stroke Impact Scale, will be associated with improvements in walking capacity. The results of this study will provide vital data describing the effects of a comprehensive modified cardiac rehabilitation program on improving physical and psychosocial function in survivors of stroke with and without PSD and will inform stakeholders and policymakers on the benefits of such programs. The findings from this study may help reduce the impact of chronic stroke and PSD on our public health system and improve the lives of the millions of survivors of stroke, their care partners, and families.

NIH Research Projects · FY 2026 · 2025-02

In 2018, roughly 74% of people reported psychological stress within the past year. Chronic psychological stress has been associated with increased risk for developing cardiovascular disease and hypertension, however the exact mechanism linking the two is unknown. Patients with post-traumatic stress disorder (PTSD), a disorder of extreme stress, have higher heart rates and blood pressures as well as an increased prevalence of resistant hypertension. Resistant hypertension is likely neurogenically derived as stress-induced changes in blood pressure are mediated, in part, by an amygdala-hypothalamic pathway contributing to sympathetic overactivation. This pathway is regulated by inhibitory GABA-ergic circuits. Elevations in blood pressure have been shown to influence extracellular matrix (ECM) remodeling leading to disruption of aortic wall homeostasis and increased vascular fibrosis predisposing to aortic pathology such as aortic aneurysms. Allopregnanolone is a neurosteroid that functions as a positive allosteric modulator of the GABAA receptor and has been shown to reverse neurogenic hypertension and treat PTSD symptoms in both animal and human studies. Our lab has demonstrated that mice with generalized anxiety and neurogenic hypertension exhibit elevated medial collagen and collagen cross-linking, and decreased thoracic aortic compliance. Additionally, these mice have an accelerated rate of thoracic aortic aneurysm progression demonstrating a predisposition to vascular pathology. Furthermore, our lab has developed a PTSD-like mouse model that exhibits higher blood pressure that is renin independent, elevated medial collagen, and increased thoracic aortic stiffness. Importantly, PTSD mice that underwent thoracic aortic aneurysm induction displayed an accelerated rate of aneurysm development. Thus, we hypothesize that stress-dependent hypertension alters homeostatic ECM remodeling which can accelerate vascular pathology. This hypothesis will be tested using two mouse models, a generalized anxiety model and a PTSD model. Aim 1 will investigate the determinants of stress-induced ECM remodeling by examining the role of sympathetic overactivation in neurogenic hypertension, the mechanism of TGF-b signaling driving stress-induced ECM remodeling, and novel signaling pathways directing stress-induced ECM remodeling through bulk RNA sequencing. Aim 2 will demonstrate that allopregnanolone, a novel therapeutic, can suppress stress-induced neurogenic hypertension and acceleration of aortic pathology. Following allopregnanolone administration to both mouse models, attenuation of sympathetic overactivation, stress-induced ECM remodeling, and thoracic aortic aneurysm acceleration will be determined. Preliminary data has demonstrated the expression of the GABAA receptor in the thoracic aorta. Thus, local effects of allopregnanolone on contractility and relaxation will be examined. Results from this proposal will increase our understanding of the link between stress and aortopathy as well as the development of a novel therapeutic. In addition, this fellowship will provide me with training in cutting-edge techniques that will support my development as a surgeon-scientist.

NIH Research Projects · FY 2024 · 2025-01

PROJECT SUMMARY/ABSTRACT Approximately 30% of the 35 million Americans with temporomandibular joint (TMJ) disorders experience TMJ disc degeneration and mechanical dysfunction, and around 10% of these cases require surgery. Replacement of the fibrocartilage using muscle/fascia flaps or fat and/or dermis grafts is common, but also comes with complications necessitating the search to find alternatives. The research to replace the TMJ disc involves the need to replicate its morphological, biological, and mechanical properties. Utilizing a TMJ disc allograft would be an ideal option given its natural properties closely resembling those of the original tissue. The use of fresh allograft TMJ discs in animals has been studied and a similar synovial joint, the knee meniscus, already utilizes allograft transplantations. Limited refrigeration storage periods of fresh TMJ discs and tissue damage during conventional cryopreservation by slow-freezing are two of the more significant reasons that TMJ allografts are not a treatment option. The use of slow-freezing leads to the formation of ice crystals inside the cells and extracellular matrix causing damage and cell death. To overcome these limitations this project proposes the use of vitrification, which avoids ice crystal formation by transforming the liquid solution into a glassy solid using high concentrations of cryoprotectants (CPAs), with a commonly used solution being the 55% multi-CPA cocktail known as VS55. Given that high concentrations of CPAs are required for vitrification procedures to avoid ice crystal formation, an essential challenge lies in finding methods to minimize the cytotoxicity of CPAs while ensuring their sufficient diffusion into the tissue. Specifically, we propose the following aims: Aim 1: To investigate different VS55 loading periods on cell viability, ECM integrity, and mechanical functionality in vitrified TMJ discs and Aim 2: To investigate different DP6 (a lower toxic alternative compared to VS55) loading periods on cell viability, ECM integrity, and mechanical functionality in vitrified TMJ discs. The proposed work will enable us to establish an optimal vitrification procedure as an effective cryopreservation technique for the long-term storage of donor TMJ discs. Through our exploration of vitrification, we expect to significantly improve the prospects of successful donor TMJ disc transplantation in the future. This fellowship will assist me in advancing my understanding of cryopreservation and therapeutic approaches designed to treat the loss of TMJ discs, as well as provide me with cutting-edge training that will support my development as a clinician scientist.

NIH Research Projects · FY 2026 · 2024-12

PROJECT SUMMARY Swallowing impairment, dysphagia, is common after stroke and can have serious consequences, leading to morbidity and reduced quality of life. Despite the significance of dysphagia, we lack fundamental knowledge regarding the neuroanatomical mechanisms underlying oral and pharyngeal dysphagia to allow us to accurately predict which patients will 1) spontaneously recover swallow function, 2) need treatment to recover function, or 3) have limited potential for recovery leaving clinicians making “best guesses” for prognosis guided decisions such as feeding tube placement and treatment. Such knowledge is critical to improving patient care and outcomes. It will ultimately lead to being able to prescribe swallowing treatment targeting precise brain network elements for optimal recovery. Current reasons for our limited understanding of the neural control of swallowing are three-fold. Most prior research has 1) used approaches to measure dysphagia that cannot quantify oral and pharyngeal swallow physiology, 2) neglected the simultaneous and concerted contribution of connected brain areas to swallowing, and 3) drawn inferences from small patient samples recruited from a single institution. Thus, we propose a mechanistic study to identify and assess the importance and generalizability of brain networks in oral and pharyngeal swallow impairments in a large cohort of patients. To overcome limitations from prior studies, we propose to use validated and standardized measures derived from the Modified Barium Swallow Study, use modern lesion-based symptom mapping analyses to identify a network of regions and connections (the circuitry) that collectively contribute to swallowing physiology, and recruit from two major stroke centers in the southern U.S. with a recruitment goal of N=400 individuals. Further, we will assess the impact of stroke damage on brain circuitries and the impact of age-related neuroanatomical changes, i.e., white matter hyperintensities. We hypothesize that both stroke lesions and white matter hyperintensities damage brain networks and contribute to the severity of oral and pharyngeal dysphagia after stroke. Our study has three aims: 1) to determine the neuronal circuitry supporting the oral phase of swallowing after stroke, 2) to determine the neuronal circuitry supporting the pharyngeal phase of swallowing after stroke, and 3) to determine the additional impact of disconnections caused by white matter hyperintensities on the neuronal circuitry supporting oral and pharyngeal swallowing after stroke. From our study, we expect to identify a set of brain regions and connections that form a brain network supporting oral swallowing and to identify an overlapping, albeit different, network supporting pharyngeal swallowing. Our findings will provide a theoretical foundation of swallowing control and contribute to a comprehensive explanatory neuroanatomical model of dysphagia. In the short term, our findings can improve estimations of dysphagia risks and patient counseling in the early stroke stages. In the long term, our findings will aid in identifying neuroanatomical targets for interventions and potentially prevent life-threatening complications associated with dysphagia.

NIH Research Projects · FY 2026 · 2024-12

SUMMARY Human papillomavirus-associated oropharyngeal cancer (OPC) is one of the fastest rising causes of cancer incidence (3%/year) in the US, with a pronounced increase (≥4%/year) among older adults (≥65 years). The OPC burden is projected to double (>30,000 new cases annually) over the next few decades, with >60% of new cases occurring in patients aged ≥65 years. Although standard of care treatment for OPC results in excellent survival, it can cause devastating chronic toxicity and impaired long-term quality of life (QOL). As a result, a number of clinical trials and real-world studies have evaluated protocols to de-intensify treatment for patients with OPC. However, none of the studies considered the evolving OPC epidemiology and assessed the effect of aging and multimorbidity on treatment toxicity, oncologic outcomes, and QOL. Due to their comorbidity burden and narrow therapeutic index, older adults with OPC are more susceptible to treatment-related adverse events (AEs), suffer from worse QOL, and have an increased mortality risk from competing events. In addition, patient preferences regarding the tradeoff between survival and treatment toxicity, data that are critical to guide preference-concordant shared decision-making, have not been fully characterized in this population. As a result, treatment of OPC among older adults is guided by inappropriate extrapolation of data from studies in younger patients. To address this critical gap, disease simulation modeling can be used to generate in-silico trials to compare harms vs benefits of different treatment paradigms over the patient’s lifetime in the context of aging and multimorbidity. This project will leverage several large representative data sources with over 200,000 OPC (>122,000 older adult) cases to characterize treatment outcomes among patients with OPC as a function of age and multimorbidity and evaluate preferences for the tradeoff between survival and treatment toxicity among 150 OPC survivors. We will use these collective inputs to synthesize a novel micro-simulation model (Simulation model of OropharyngeaL cAnCEr treatment among older adults [SOLACE]), and then perform in- silico trials using SOLACE to compare harms and benefits of OPC treatment, particularly among older adults and those with multimorbidity. Our Aims are: (1) To characterize the impact of aging and multimorbidity on (a) treatment outcomes (AEs, oncologic outcomes, QOL) and (b) treatment priorities and preferences among patients with OPC; (2) To synthesize, calibrate, and validate a micro-simulation model (SOLACE) of OPC treatment outcomes over the survivorship duration in association with age and multimorbidity; and (3) To compare the harms vs benefits of common treatment paradigms (including de-intensification) over the lifetime of patients with OPC in the context of aging and multimorbidity using SOLACE. Study findings could transform clinical decision-making for OPC, maximize benefits and reduce harms, and inform evidence-based, patient- centered, and preference-concordant decision-making for this rapidly growing patient population.

NIH Research Projects · FY 2026 · 2024-12

PROJECT SUMMARY The prevalence of noncommunicable diseases such as diabetes and metabolic syndrome is increasing in settings where infectious diseases like tuberculosis (TB) are common. There is a clear bidirectional interaction between diabetes and TB. However, less is known about the intersection of TB and metabolic syndrome, a multifaceted condition of which glucose dysregulation is one component. The proposed K23 work seeks to go beyond unidimensional glycemic measures in order to gain a more comprehensive understanding of the metabolic profiles of people with TB and how metabolic parameters change over the course of TB treatment. To do this we will leverage an ongoing prospective cohort of adults newly diagnosed with TB in Tanzania. We will focus on the group with newly recognized pre-diabetes at the time of TB diagnosis, since our prior work has demonstrated that this subpopulation is heterogeneous, and this health state is dynamic. In Aim 1 we will measure and describe a set of blood-based and anthropometric metabolic markers and characterize TB severity at the time of TB diagnosis, testing the hypothesis that metabolic syndrome is directly associated with TB severity. In Aim 2 we will measure and describe metabolic outcomes at completion of TB treatment and identify risk factors for different metabolic outcomes. Dr. Alkabab is committed to improving health by advancing understanding of the biologic interplay between communicable and non-communicable diseases and developing interventions that address both in an integrated manner. She is in an extraordinarily supportive research environment within the Division of Infectious Diseases, Department of Medicine at the Medical University of South Carolina. To accomplish the proposed work and transition to research independence, the applicant has assembled a mentoring team with decades of experience in relevant disciplines to guide her. Training in advanced statistics, the science of diabetes and metabolism, human subjects research, and grant writing will provide a strong foundation for success.

NIH Research Projects · FY 2026 · 2024-12

Cholangiocarcinoma (CCA) is an epithelial cancer arising in the biliary mucosa lining the ducts that carry bile from the liver to the small intestine. CCA is the second most common type of liver cancer after hepatocellular carcinoma (HCC) and is a highly lethal cancer. CCA is classified based on the anatomic location into intrahepatic CCA (iCCA), perihilar CCA (pCCA), or distal (dCCA) subtypes. The limited clinical presentation of these tumors contributes to late diagnosis with surgery being possible in less than 25% of patients and this, combined with high tumor recurrence after surgery, results in dismal prognosis and high mortality rates. Indeed, and in contrast to many other cancers, the overall mortality of CCA has not significantly improved, resulting in unsatisfactory 5-year survival rates (7–20%). The serum tumor marker carbohydrate antigen (CA) 19-9 is used in routine practice to help CCA diagnosis and to monitor disease progression once diagnosis has been achieved. The major limitation is the low sensitivity and specificity of this marker, thus not allowing the early detection of CCA. We have recently identified changes in glycosylation that occur in both tissue and serum of those with CCA. Importantly, these glycan changes could be used to differentiate CCA tissue or serum from healthy or diseased serum or tissue, including hepatocellular carcinoma and PSC. We hypothesize that these changes in glycosylation observed directly in CCA tissue, and in serum, may be useful as a non- invasive liquid biopsy biomarker of CCA. Thus, in this application we propose to develop new and novel biomarkers of CCA based upon the glycan changes observed in tissue and serum.

NIH Research Projects · FY 2026 · 2024-12

ABSTRACT The development of T cell immunotherapies over the past decade revealed that the reinvigoration of anti-tumor immunity could be achieved by manipulating mitochondrial dynamics in T cells. The endoplasmic reticulum (ER) and the mitochondria coordinate to maintain cellular homeostasis, metabolism, and death. While persistent ER stress responses cause mitochondrial collapse, moderate ER stress conditions promote mitochondrial function. Strategies to boost anti-tumor T cell function by targeting ER-mitochondrial crosstalk have not been exploited yet. We used carbon monoxide (CO), a short-lived gaseous molecule, to test if engaging in moderate ER stress conditions can improve T cells' mitochondrial and anti-tumor functions. Using melanoma antigen-specific T cells, we identified that CO-induced transient activation of the ER stress sensor ‘protein kinase R-like endoplasmic reticulum kinase (PERK)' dramatically increases anti-tumor T cell function by engaging autophagy. Using a dual reporter, the LC3-GFP-RFP mouse, we found that, in response to transient ER stress (imposed by CO), T cells substantially increase the LC3-GFPpos population (that prepare themselves to undergo active autophagy) compared to those that fail to enter the process (LC3-GFPneg). We noted that the LC3-GFPpos T cells inherited healthier mitochondria and showed improved tumor control. Moreover, LC3-GFPpos and LC3-GFPneg T cells showed distinct metabolic epigenetic profiles. Overall, our preliminary data highlights that transient ER stress- activated autophagy pathways modify mitochondrial function and epigenetically reprogram T cells towards a superior antitumor phenotype. Based on the existing literature and our preliminary data, CO-induced transient PERK activation followed by autophagy influences a combination of events, including mitochondrial quality, metabolic, and epigenetic programming, leading to the reinvigoration of exhausted anti-tumor T cells and increased T cell effector function in the TME. Experiments are proposed to test this hypothesis with the following aims: 1) To determine how CO-induced mitochondrial quality control mechanisms regulate T cell effector function. 2) To determine how autophagy-induced altered metabolite ratios epigenetically reprogram anti-tumor T cells. 3) To determine if CO induced autophagy improves the anti-tumor efficacy of human TILs and CAR-T cells. We believe the successful completion of the proposal will: a) help us identify mitochondrial signaling molecules that regulate T cell effector functions to improve tumor immunotherapy. b) will identify the dysfunctional mitochondria-derived metabolites and the epigenetic programs that regulate the gene expression profile associated with effector functions and longevity of the T cells in the TME. c) Finally, successful completion of the proposed studies will provide a comprehensive mechanistic understanding and testing strategies (such as using CO) with TILs and TCR/CAR-transduced T cells, which will lead to improved translational outcomes required for treating solid tumors and drastically reduce the cost of ACT.

NIH Research Projects · FY 2026 · 2024-12

ABSTRACT The prevalence of cigarette smoking is high for patients being treated for cancer care, and it is critical for these patients to quit smoking. The National Cancer Institute (NCI)’s Cancer Center Cessation Initiative (C3I) provided funding to selected NCI-designated cancer centers to support the integration of evidence-based tobacco treatment into routine cancer care. Yet, only 15.4% of patients at C3I funded centers received at least one component of treatment. Indeed, data from our own C3I funded NCI-designated cancer center show that 23% of oncology outpatients refuse all tobacco treatment. For these patients, novel and appealing interventions that can reduce cigarette smoking and reduce harm from tobacco are urgently needed. Switching from cigarettes to e- cigarettes reduces exposure to carcinogens and may be an appealing harm reduction intervention for patients in cancer care who refuse traditional treatment. We propose a type 1 hybrid effectiveness-implementation trial among oncology outpatients at an NCI-designated cancer center who smoke and refuse all components of tobacco treatment (N=208). We will directly compare rates of switching to e-cigarettes to standard care, and advance understanding of key barriers and facilitators of implementation processes. Participants will be randomly assigned to either 1) an e-cigarette switching approach (Switch), or 2) a control group that receives the standard of care (SC, provision of additional tobacco treatment resources). Participants in the Switch Group will receive a 13-week supply of e-cigarettes (1-week to use ad libitum in advance of switching and 12 weeks to use following their Target Switch Date). The primary outcome is complete switching (abstinence from cigarettes) at Week 12 (Aim 1). We will conduct a mixed methods evaluation of implementation processes for the e-cigarette switching approach (Aim 2). To further evaluate the impact of harm reduction in this population, we will collect exploratory data on the impact of switching to e-cigarettes on the biological effects of cancer risk (i.e., inflammation and DNA damage) and subjective effects of product use on health-related quality of life (Exploratory Aim 3). This study builds upon our preliminary data across a range of studies demonstrating that 1) a sizable portion of oncology outpatients nationally who smoke refuse traditional treatment and plan to continue smoking, 2) an e-cigarette switching approach can significantly reduce cigarette smoking and promote smoking abstinence, even among difficult-to-treat populations, and 3) a harm reduction approach is feasible and acceptable to oncology outpatients. The proposed trial will be led by two seasoned investigators in collaboration with a strong group of Co-Investigators with expertise in smoking cessation, cancer care, harm reduction, non-combustible tobacco products, and clinical trials. The proposed trial is highly significant, no matter the results, and has the potential to influence harm reductions approaches for tobacco among patients in cancer care.

NIH Research Projects · FY 2026 · 2024-12

Interventions that address families’ quality of life and emotional and behavioral needs after pediatric traumatic injury (PTI) are a public health priority, with nearly 120,000 children hospitalized annually for severe injuries. PTI is associated with annual individual and societal costs of $87 billion and elevates risk for posttraumatic stress disorder (PTSD), depression, and other health risk consequences that affect quality of life, physical recovery, family roles and routines, and academic functioning. Caregivers are a key source of support for preadolescent children following PTI, and caregivers’ emotional health is highly correlated with children’s outcomes. One in three children endorse PTSD and/or depression symptoms after PTI, and over 50% of caregivers develop high distress and significant PTSD symptoms. Therefore, interventions targeting caregiver and young child distress that have high potential for uptake in pediatric trauma centers are critically needed. Pediatric trauma centers recognize the need to support behavioral recovery, particularly in response to the American College of Surgeons’ 2022 guidelines to provide mental health screening and intervention to trauma patients at high risk. However, no clear roadmap exists for these centers to support emotional recovery and established, scalable and sustainable models of care are lacking. We are in the final stages of an NICHD K23 where we are piloting CAARE (Caregivers’ Aid to Accelerate Recovery after pediatric Emergencies), a technology-assisted, stepped care intervention informed directly by patients and caregivers after PTI that provides children under age 12 and their caregivers: (1) inpatient emotional and behavioral screening and education, (2) brief inpatient risk reduction intervention, (3) mHealth-facilitated symptom self-monitoring and coping tools, and (4) 30-day evidence-based treatment referrals for families who need it. CAARE was well received by caregivers and providers, with pilot data indicating that this model is appealing to caregivers and has high potential to address service barriers by providing real-time assistance to help caregivers manage their own distress and their children’s behavioral recovery. We now propose to conduct a hybrid effectiveness-implementation trial to examine the extent to which CAARE improves children’s and caregivers’ quality of life, clinical and functional health outcomes, and follow-up treatment engagement and to inform widescale implementation of CAARE. We will conduct a randomized controlled trial with 348 families randomly assigned to CAARE (n=174) vs. enhanced usual care (n=174). Caregivers of children under age 12 hospitalized for traumatic injury will be recruited and assessed by independent, blind evaluators at baseline, 3-, 6-, and 12-months. We will assess CAARE acceptability, feasibility, and appropriateness and identify barriers and facilitators that influence implementation, sustainability, and ability to address the unmet needs of all traumatically injured and sociodemographic groups. The ultimate goal of this line of work is to achieve population-level impact in U.S. pediatric trauma centers through enhanced service quality and reach.

NIH Research Projects · FY 2025 · 2024-10

Neonatal Intraventricular hemorrhage (IVH) originates from the underdeveloped germinal matrix, a site of cell rapid cell division adjacent to the lateral ventricles of the brain. IVH leads to post-hemorrhagic hydrocephalus (PHH). Within the same time frame that neonatal IVH occurs, the neonatal brain is also rapidly producing the cells needed for myelination. Oligodendrocytes, the myelin-forming cells of the brain, are derived from oligodendrocyte progenitor cells (OPCs). OPCs are fragile cells - exquisitely sensitive to many factors that are present across multiple neurological diseases such as excitotoxicity, inflammatory cytokines, and oxidative stress. Across a wide spectrum of neurological diseases, neuroinflammation causes OPC loss and failure of myelination. Infiltrating brain macrophages are implicated in many forms of neonatal brain injury. Macrophages are activated by many different stimuli in CNS injury and disease, including blood products released into the ventricular space. Understanding the role of macrophages after IVH is critical to improving outcomes, as macrophage activation mediates white matter injury in other forms of neonatal brain injury. Azithromycin is a commonly prescribed antibiotic that is safe in neonates. Besides its antibiotic properties, azithromycin is also anti-inflammatory and shifts macrophage activation into an anti-inflammatory phenotype that actually promotes tissue recovery rather than injury. Azithromycin has been used in a variety of anti-inflammatory applications including preclinical work in spinal cord injury where it improves tissue sparing and neurological function. Importantly, azithromycin has already undergone rigorous clinical trials in neonates for inflammation-induced lung injury. This study will pharmacologically block infiltrating macrophages in IVH/PHH and test azithromycin’s ability to protect OPCs from macrophage-induced injury in a rat model of neonatal IVH. I will use a combination of in vivo and in vitro experiments to examine macrophage activation, OPC death and myelination with and without azithromycin treatment. My in vivo work will allow us to use neurobehavioral outcomes to assess the efficacy of azithromycin while my in vitro model will allow for in-depth mechanistic studies of macrophage-OPC interaction. This project will support Dr. Miller’s training in studies of neuroinflammation and neurotherapeutics. If successful, this project will pave the way for clinical studies of azithromycin for improving neurological outcome after neonatal IVH.

NIH Research Projects · FY 2025 · 2024-09

ABSTRACT This resubmitted proposal is in response to RFA-DA-25-012 (reissue of RFA-DA-24-003) for “Antibody- mediated enhancement of HIV infection/replication following B-cell responses can result in depletion and blunted recovery of CD4+ T-cells and poor immune recovery despite suppressive ART. How these immune components in the context of HIV infection and substance use disorder contribute to the pathology of both conditions represents a significant knowledge gap. Studies focused on inflammasome cascades and pathogenic antibodies mediated by chronic drug use and HIV infection are warranted”. About 25% HIV patients under anti-retroviral therapy (ART) fail to recover CD4+ T cell counts to a level comparable to healthy people. Because CD4+ T cell is critical for immune response to foreign pathogens, it is critical to develop new medications to recover CD4+ T cell counts to reduce co-morbidity and mortality in HIV. Our preliminary studies reveal anti-CD4 autoantibodies to be increased in HIV+ drug abusers and to play a key role in inducing CD4+ T cell death. How cocaine (proinflammation) and cannabis (anti-inflammation) use affect B cell function, pathogenic anti-CD4 autoantibody development, and CD4+ T cell recovery from ART in PWH remains unclear, thus, we propose two aims here: Aim 1. Determine mechanisms of affinity maturation and CD4 recognition for anti-CD4 autoantibodies presenting ADCC activity in HIV+ drug users. Aim 2. Determine drug use-mediated B cell perturbations, anti-CD4 autoantibody production, and HIV immunopathogenesis.