Medical University Of South Carolina

NIH Research Projects · FY 2025 · 2022-05

PROJECT SUMMARY/ABSTRACT Annually, traumatic injuries affect roughly 3 million people in the US and account for over $650B in costs. Many patients are resilient and recover well emotionally, but over 20% (~600,000 people per year) develop mental health problems such as posttraumatic stress disorder and depression, both major risk factors for social and occupational impairment; poor physical health and quality of life; and lost productivity, work, and financial resources. Most trauma centers do not address the mental health recovery of patients after a traumatic injury. This gap in the quality of patient care, combined with unique barriers to mental health services that traumatic injury patients face, necessitates a cost-effective intervention that meets the needs of these patients at each stage of the recovery process. We will test the Trauma Resilience and Recovery Program (TRRP), a scalable, sustainable technology-enhanced intervention to support the mental health recovery of patients who have experienced a traumatic injury. The model includes education, risk screening, and brief intervention at the bedside (Step 1); symptom self-monitoring and continued education via a daily text messaging system (Step 2); mental health screening at 30 days via chatbot or telephone (Step 3); and, when appropriate, mental health treatment referrals (Step 4). Our previous work has provided strong support for the acceptability and feasibility of TRRP: (1) 98% of patients approached at Step 1 by TRRP staff at the bedside enroll in mental health follow- up, (2) more than 2 in 3 patients enroll in the symptom self-monitoring system (Step 2), and (3) 75% of patients who screen positive for PTSD or depression at the 30-day call (Step 3) accept treatment referrals (Step 4). TRRP staff has provided mental health follow-up to over 8,000 patients to date, only about 400 of whom would have received mental health follow-up services under usual-care conditions based on the results of our needs assessment. We are implementing TRRP in 12 trauma centers in the Carolinas, 4 of which already have fully implemented it. This experience has informed the approach we propose to use in partnership with George Washington University (GWU) hospital. We will conduct a randomized controlled trial with 1-year follow up of TRRP vs. enhanced usual care with 350 patients at GWU, which serves a diverse population of ~2000 traumatic injury patients per year (15% penetrating mechanism). Engagement in mental health services and clinical and functional outcomes will be assessed 3, 6, and 12 months post-baseline by trained interviewers blind to study condition. Qualitative interviews will be conducted with 20 TRRP patients who have experienced violent trauma as well as 15 African American and 15 Latinx patients who have experienced non-violent trauma. These data will inform improvements to the TRRP model as well as the implementation process in preparation for a future hybrid implementation-effectiveness trial with 8 trauma centers. This body of work is critical to informing the field as it continues to move toward national standards and recommendations.

NIH Research Projects · FY 2026 · 2022-05

Project Summary Pulmonary arterial hypertension (PAH) is a lethal disease with a median survival of only 5-7 years. Pathophysiologically, PAH is a progressive vasculopathy of the precapillary pulmonary vessels that increases pulmonary arterial pressures and pulmonary vascular resistance while reducing pulmonary arterial compliance. The changes in the pulmonary vasculature augment the work load of the right ventricle, which ultimately results in right ventricular dysfunction (RVD). The presence of RVD is the greatest risk factor for death in PAH; however, no current PAH therapies actually target the RV directly. In this proposal, we will investigate the hypothesis that sex-differences in RV function in PAH are in-part mediated by an inhibitory action of estrogen on microtubule dynamics. We will employ state of the art microscopy and computational analysis to define how estrogen regulates microtubules. Then, in translational studies we will determine modulation of the estrogen- microtubule interaction impacts right ventricular function in pre-clinical PAH using advanced hemodynamics and molecular phenotyping of the RV microtubule cytoskeleton.

NIH Research Projects · FY 2025 · 2022-04

In this project we aim to determine the role of epicardially-derived cells (EPDCs) in the formation of the atrioventricular (AV) valves and to investigate their potential role in the pathogenesis of myxomatous valve disease (MVD). A few years ago, we published a study in which we described how EPDCs at the atrioventricular (AV) junction contribute to a specific set of leaflets of the AV valves. To obtain insight into how these events are regulated, we initially focused on growth factor signaling through the Bone Morphogenetic Protein (BMP) pathway. We deleted the BMP receptor ALK3/BMPR1A from the epicardial cell lineage using the epicardial-specific WT1cre mouse. We observed that this led to abnormalities at the AV junction, including a significant decrease in the number of AV-EPDCs in the lateral valve leaflets. We also found that, after birth, the valves developed a myxomatous valve phenotype, reminiscent of that being observed in patients suffering MVD. Deleting the transcription factor SOX9 from the epicardial cell lineage led to similar results. The goals of this project are to determine the mechanisms regulating the migration of AV- EPDCs into the parietal AV valve leaflet, to establish how AV-EPDCs regulate AV valve development, and to elucidate their role in the pathogenesis of mitral valve disease.

NIH Research Projects · FY 2024 · 2022-04

PROJECT SUMMARY Nationally, South Carolina (SC) ranks among the worst for poor pregnancy outcomes and high maternal and infant mortality rates, with vast racial/ethnic disparities present. Infection with the novel SARS-CoV-2 during pregnancy has been associated with pregnancy complications and poor infant and maternal outcomes including mortality. Moreover, the effect of social determinants and inequities in healthcare received and health outcomes have been heightened by the COVID-19 pandemic caused by SARS-CoV-2. Cardiovascular risk factors during pregnancy (e.g., obesity, diabetes, and hypertension) and pregnancy complications such as pre-eclampsia are common, can result in morbidity and mortality for the mother and the baby, and are well-known risk factors for maternal cardiovascular and vascular disease short and long-term. Infection with SARS-CoV-2 during pregnancy has also been related to complications (e.g., intensive care unit (ICU) admission, invasive ventilation, myocardial infarction, embolism). Less information is available regarding the impact of the COVID-19 pandemic or specifically SARS-CoV-2 infection on maternal and infant morbidity and mortality. The objective of our study is to understand the impact of both the COVID-19 pandemic and infection with SARS-CoV-2 on the risk of maternal and infant morbidity and mortality including pregnancy complications (e.g., pre-eclampsia, ICU admissions, mechanical ventilation), adverse birth outcomes (e.g., preterm birth, small for gestational age), and maternal cardiovascular events (e.g., coronary heart disease, stroke, embolism) during and post-pregnancy. Data from statewide administrative datasets (e.g., hospitalizations, vital records, Medicaid, positive COVID-19 tests) will be linked to create a diverse, longitudinal cohort of women who gave birth between 2018-2021 with at least one year of follow-up through 2022. Approximately 45,000 live birth pregnancies take place in SC each year for a total of ~180,000 deliveries anticipated over the 4-year study period. As of June 1, 2021, 2600 pregnant women in SC were diagnosed with COVID-19. The proposed project aims to evaluate the impact of the COVID-19 pandemic (Aim 1) and the impact of SARS-CoV-2 infection (Aim 2) at the population level in SC on (1) pregnancy complications, adverse birth outcomes, maternal cardiovascular events, and maternal and infant mortality; (2) maternal one-year post pregnancy cardiovascular and mortality outcomes; and (3) to examine differences by race/ethnicity, social vulnerability, distance to main medical facility, and pre-pregnancy obesity and diabetes. This study will be among the first to evaluate the COVID-19 pandemic and SARS-CoV-2 infection during pregnancy in relation to maternal and infant morbidity and mortality in a population-based study. Determining the impact of the COVID-19 pandemic and SARS-CoV-2 infection on infant and maternal morbidity and mortality and the extent of social and racial-ethnic differences is critical to improving pregnancy outcomes and health disparities in the U.S. Findings are expected to inform clinical care of pregnant women and public health policy.

NIH Research Projects · FY 2026 · 2022-04

SUMMARY/ABSTRACT Reward-associated cues are unlikely to provoke reward seeking when that behavior is inappropriate, yet cues elicit opioid seeking in patients with opioid use disorder (OUD) when that behavior is unproductive or maladaptive. There is little understanding of how brain systems that can normally suppress unproductive reward seeking are modified by opioid use and causally contribute to opioid seeking. This is in part due to technical feasibility, as measuring adaptations in single neurons across the onset, maintenance, and relapse phases of opioid use is challenging. Here, I overcome this issue using a novel assay developed in my lab, wherein I longitudinally track activity in precisely defined neurons throughout heroin self-administration, extinction, and reinstatement using two-photon calcium imaging in head-restrained mice. We test the overarching hypothesis that a thalamostriatal subcircuit is inhibited by opioid use and by the presentation of stimuli that initiate opioid- seeking behaviors. In support of this hypothesis, my preliminary data suggest that posterior paraventricular thalamic neurons that project to the nucleus accumbens (pPVT NAc) become hypoactive and hypoexcitable as a result of repeated heroin use and display rapid reductions in activity during cue- and drug-induced reinstatement of heroin seeking. Furthermore, I show that optogenetically mimicking this inhibition during extinction initiates heroin seeking. To test my specific hypotheses, in Aim 1, I will longitudinally track the activity dynamics of single pPVT NAc neurons and neuronal ensembles throughout heroin self-administration, extinction, and reinstatement. In Aim 2, I will evaluate the long-lasting intrinsic and synaptic adaptations among pPVT NAc neurons at multiple timepoints following heroin self-administration. In Aim 3, I will determine the function of pPVT NAc neuronal activity for the suppression of heroin seeking during extinction, and expression of heroin seeking during reinstatement. Overall, this project will identify how a brain circuit that inhibits reward seeking in inappropriate conditions is modified by opioid use and causally influences opioid-seeking behavior.

NIH Research Projects · FY 2026 · 2022-03

SUMMARY Stressful life experiences are risk factors that play considerable roles in the development and maintenance of alcohol (ethanol) abuse, excessive drinking, and relapse. Preclinical studies from the INIAstress Consortium that examined chronic ethanol-stress interactions in mice have demonstrated elevations in ethanol drinking, cognitive deficits, metaplastic adaptations, and emergence of negative affective behaviors. The INIAstress investigators also performed mechanistic and pharmacological studies that revealed key biological targets that are responsible for driving these aberrant behaviors in stressed, chronic intermittent ethanol (CIE) exposed mice. However, the brain-wide neural adaptations produced by ethanol-stress interactions are unknown, and a better understanding of the brain-wide activity patterns that underlie alcohol and stress interactions will lead to effective strategies for treating individuals with alcohol use disorder. Recent advancements in brain-wide mapping and innovative network neuroscience statistical approaches prompted the formation of the CIE-Stress Mouse Brain Activity Mapping Core (BAMC). In this application, we provide preliminary data showing whole-brain light sheet imaging of c-Fos expression and functional connectivity mapping in CIE-FSS treated mice and in mice drinking in the intermittent access model. Thus, the primary goals of the BAMC are to 1) apply cutting-edge technology in whole- brain light sheet imaging and expertise in network analyses to provide investigators in the INIAstress Consortium and the scientific community with novel brain regions, circuits, and networks that drive increased drinking in mice with a history of forced swim stress (FSS) and CIE exposure, and 2) provide brain-wide signatures of immediate early gene (IEG) activity in response to pharmacological agents that are known to reduce the excessive drinking phenotype in stress, ethanol dependent mice. The secondary goals of the BAMC are to 1) provide the whole- brain mapping data to the Computational and Statistical Analysis Core (CSAC) for integration with additional neural and behavioral data collected across all components, and 2) perform cross-INIA Consortia analyses of whole-brain IEG expression. In Aim 1, the BAMC will generate whole-brain IEG mapping data using the standard INIAstress Consortium model of stress-induced excessive drinking for INIAstress investigators and the scientific community. Studies in Aim 2 will determine brain-wide IEG signatures after pharmacological treatment of drugs that reduce drinking in the CIE-FSS model. By applying cutting-edge light sheet imaging, advanced network analysis, and pharmacological interrogation of IEG expression across the whole mouse brain using a reliable model that results in escalated voluntary ethanol intake in stressed, ethanol dependent mice, the BAMC will help to generate new hypotheses and unbiased insights into systems and circuitry underlying alcohol-stress interactions. Finally, through its interactions with the CSAC and BRAIN Initiative investigators, the Brain Activity Mapping Core will contribute to Open Science practices that will provide the greater scientific community with whole-brain IEG mapping data from excessively drinking mice.

NIH Research Projects · FY 2026 · 2022-03

PROJECT SUMMARY Alcohol use disorder (AUD) is a devastating neuropsychiatric condition that is characterized by chronic and relapsing episodes of excessive, uncontrolled alcohol consumption. AUD is also associated with significant disruption of brain function and behavior, frequently presenting with cognitive deficits and comorbid negative affective disorders (e.g., anxiety and depression). These negative affective and cognitive disturbances that are present during abstinence from alcohol drinking can drive relapse-like behaviors in both humans and rodent models and are often exacerbated by stress. Thus, alcohol and stress may be working synergistically to cause more profound cognitive deficits that lead to decreased cognitive control over alcohol consumption, but the molecular and cellular adaptations and the neurocircuitry underlying these concerted changes are not well understood. The ventral striatum, specifically the nucleus accumbens (NAc), mediates aspects of alcohol taking and seeking, negative affect, and is one of the primary outputs of both the medial prefrontal cortex (mPFC) and the anterior paraventricular thalamus (aPVT). These circuits mediate appetitive and reward-motivated behaviors, are sensitive to stress and alcohol, and are involved decision making and choice behaviors particularly during motivational conflict. Additionally, in both the mPFC and aPVT, pro-stress molecules, like corticotropin-releasing factor (CRF), are recruited and have been implicated in regulating responses to stress and/or alcohol. Thus, this component of the INIAstress Consortium seeks to understand the mechanisms and circuitry involved in the complex interaction between stress and alcohol exposure that engender such high rates of alcohol consumption, cognitive impairments, and negative affective states. We provide evidence that the chronic intermittent ethanol (CIE) exposure model and repeated forced swim stress (FSS) alter reward-choice behaviors under conditions of motivational conflict. We also show that mPFC CRF knockout blocks the escalation of alcohol drinking in the CIE-FSS model. The overarching hypothesis is that CIE-FSS hyper-recruits CRF in the mPFC and aPVT to promote excessive drinking, cognitive deficits, and anxiety-like phenotypes. In Aim 1, we will identify chronic alcohol- and stress-induced changes in synaptic and functional plasticity that occur in a CRF-dependent and independent manner in mPFC®NAc and aPVT®NAc circuitry. Studies in Aim 2 will focus on understanding the influence of CRF on mPFC function and circuitry using high-density silicon Neuropixels probes and fiber photometry. Finally, Aim 3 will identify the role of CRF in the aPVT and its influence on aPVT®NAc projections in the CIE-FSS model. The focus of this new INIAstress Consortium component is to understand the broader implications of CRF modulation of neurocircuitry regulating reward-guided behaviors in chronically stressed, alcohol dependent mice, which is critical to our understanding of the complex interaction between alcohol and stress, and aid in identifying promising therapeutic targets.

NIH Research Projects · FY 2026 · 2022-02

Systemic lupus erythematosus (SLE) is one of many autoimmune diseases that disproportionately affects females. Although many risk factors for lupus are identified: >170 genes including GPR174, myriad environmental exposures, and aberrant X chromosome inactivation, none of these sufficiently explain the steep rise in incidence of ADs at the time of puberty in a female-specific manner. Epidemiology suggests a major role for sex hormones and their receptors in autoimmune diseases. We previously showed that female lupus-prone mice, expressing only a short form of estrogen receptor alpha (ERα short), have significantly reduced renal disease and increased survival. Determining the mechanism of this protective effect, which is estrogen dependent, is the primary goal of this proposal. Of note, ERα-/- (null) lupus prone mice were not similarly protected. Combined, our data suggest that the presence of the short form of ERα confers protection, not the absence of full-length ERα. Others and we demonstrated a critical role for ERα in dendritic cell (DC) development and endosomal Toll-like receptor (TLR) responsiveness. Interestingly, the ERα expressed in ERα short mice is similar in structure to an endogenous ERα variant (ERα46) that lacks the same AF-1 domain, and differentially regulates gene transcription compared to full length ERα. Overexpressing ERα46 in vitro also modulates TLR- induced responses, relevant to this proposal. In the proposed study, we will further investigate the role of ERα short variants in modulating TLR7-induced immune responses, and determine whether genomic and/or non- genomic mechanisms of ERα short variant action are protective. Our overall hypothesis is that increasing expression of ERα short or ERα46 in immune cells will be anti-inflammatory, and that the ratio of ERα46 to ERα66 is decreased in lupus patients versus healthy controls. We also hypothesize that targeting immune cells with novel anti-inflammatory selective estrogen receptor modulators (SERMs) that alter ERα membrane signaling and/or ERα-induced transcription will uncouple estrogen-mediated anti-inflammatory responses from those impacting reproductive tissues. We will test our hypotheses by accomplishing these Specific Aims: 1) Overexpress ERα short or treat immune cells with novel SERMs (OBHS, PaPE) that select for anti-inflammatory properties of ERα and determine the effect on known TLR7-induced inflammatory endpoints, 2) Investigate effects of membrane-only ERα signaling vs. nuclear only ERα expression on TLR7-induced pathways in mice, and 3) Identify ERα variants in human monocyte-derived dendritic cells (mo-DCs) and B cells using droplet digital PCR and Iso-Seq technology, to determine whether ERα46 is differentially expressed in lupus patients vs. controls, potentially explaining a biologic difference in females predisposed to autoimmunity. These aims will allow us to determine if we can separate ERα's reproductive effects from its potentially modifiable immune effects as a therapeutic strategy, which if successful, will provide novel approaches to immune modulation in lupus and other immune mediated diseases, especially those with a significant sex bias.

NIH Research Projects · FY 2025 · 2022-01

ABSTRACT Cigarette smoking causes 480,000 premature deaths each year in the United States, of which 36% are due to cancer. Two-thirds of smokers want to quit, but fewer than one-third make a quit attempt using an evidence- based approach. Consequently, fewer than one in ten smokers report quitting successfully in the last year. Comprehensive dissemination strategies are needed to increase utilization of evidence-based cessation treatments and improve cessation among adult smokers. The vast majority (>70%) of smokers visit a primary care physician (PCP) at least once per year. As such, primary care offers a ripe opportunity through which to proactively deliver cessation treatment to adult smokers. All primary care practices that qualify for Centers for Medicare and Medicaid Services reimbursement are required to maintain electronic health records (EHRs) with coded smoking status data for adult patients. These data can be utilized to proactively identify smokers and deliver treatment. Our team recently completed a pilot study to develop, refine, and preliminarily evaluate a proactive asynchronous smoking cessation electronic visit (e-visit) delivered via the EHR. The goal of the e-visit is to automate best practice guidelines for cessation treatment via primary care to ensure that all smokers receive an evidence-based intervention. An initial baseline e-visit gathers information about smoking history and motivation to quit, followed by an algorithm to determine the best FDA-approved cessation medication to prescribe. A one-month follow-up e-visit assesses progress toward cessation. Clinical outcomes of our pilot (N=51) were promising. At study end (three months), e-visit participants, relative to treatment as usual (TAU), were 4.7 times more likely to have used a cessation medication, 4.1 times more likely to have reduced their cigarettes per day by >50%, and 4.2 times more likely to report 7-day point prevalence abstinence. Feasibility outcomes were similarly promising, with >85% of e-visit participants reporting that they found the e-visit easy to use, would use an e-visit again, and trusted their provider with their care during the e-visit. We now propose a Hybrid Type I effectiveness-implementation trial to comprehensively assess e-visit effectiveness relative to TAU while simultaneously evaluating implementation when delivered across primary care settings. Effectiveness outcomes will be assessed through 6-months of follow-up and include: 1) evidence-based cessation treatment utilization, 2) reduction in cigarettes per day, and 3) biochemically verified 7-day point prevalence abstinence. Implementation outcomes will be assessed at patient, provider, and organizational levels. This program of research has the potential for broad and direct benefits to: 1) smokers, who will have increased treatment access, 2) PCPs, who can more efficiently treat smokers while also having an additional reimbursable service, and 3) care systems, who can improve compliance with Joint Commission recommendations for cessation treatment.

NIH Research Projects · FY 2026 · 2022-01

PROJECT SUMMARY Head and neck cancer (HNC) caregivers face significant challenges at the end of treatment as they transition to the home setting and care for survivors with devastating late and long-term treatment effects. The overall goal of this research is to improve post-treatment recovery outcomes in HNC survivors and their caregivers through the delivery of a tablet-based, dyadic survivorship needs assessment planning (SNAP) tool implemented into clinic workflow at the end of treatment. SNAP is a technology-enabled survivorship care planning (SCP) system that uses a self-management focus to: 1) prepare caregivers as they transition to the next phase of caregiving and 2) optimize healthcare utilization (e.g., receipt of recommended medical and supportive care) in caregiver- survivor dyads. Our interdisciplinary team will conduct a randomized controlled trial to test the effects of SNAP compared to usual SCP care on caregiver and survivor outcomes (N=176 dyads) and gather crucial data to guide best practices for disseminating the system to diverse HNC care settings in the future. Specific Aim 1 will evaluate the effects of SNAP on caregiver burden in caregivers, symptom severity in survivors and psychological well- being in dyads at 6 months. Specific Aim 2 will evaluate the effects of SNAP on healthcare utilization uptake, unmet needs and self-efficacy in dyads at 3 months. Specific Aim 3 will use mixed methods to characterize key barriers and facilitators to SNAP system adoption in HNC healthcare settings diverse by practice structure, patient volume and rural/urban status using surveys in a national panel of HNC healthcare providers (N=200) and 5 in-depth case study visits with HNC centers in the southeastern United States to guide refinement of SNAP program delivery strategies and tools. SNAP is novel in its focus on using technology to build a clinic infrastructure to automate care practices to assess, address and support survivorship needs in HNC caregiver-survivor dyads at the end of treatment. SNAP invests in the critical roles played by caregivers through a stepped, dyadic approach to accelerate recovery. Results will provide critical evidence to finalize this sustainable, technology-enabled care planning system for a multi-site implementation study.

NIH Research Projects · FY 2025 · 2022-01

Summary: Approximately 1.5% of individuals have a Bicuspid Aortic Valve (BAV) that can result in insufficient blood flow and organ damage (1, 2). A BAV is also an independent risk factor for ascending aortic wall complications that can lead to rupture and sudden death. However, the cell and molecular basis for the BAV is unknown. Even basic aspects of BAV formation are undefined due to contributions from multiple cell lineages and a lack of highly penetrant viable BAV mouse models. Dysfunctional aortic valves exhibit massive accumulation of the extracellular matrix (ECM) proteoglycans versican (Vcan) and aggrecan (Acan) (3-7) but the origin and consequence of excess proteoglycans is largely unknown. Since proteoglycans are highly stable, abundance is regulated primarily by proteolytic degradation which led us to investigate a role for proteoglycan cleavage. We discovered that loss of a single ECM proteoglycanase, Adamts5, results in enlarged aortic valves with ascending aortopathies (100%). These defects co-localize with substantial increases in Vcan and Acan in the affected tissues (8-10) that mirror the human condition. Mechanistically, in Adamts5-/- aortic valve primordia with excess Vcan there is a reduction of pSmad2, and when Smad2 is reduced further by generating Adamts5-/- ;Smad2+/- mice, there is a high penetrance of BAV (75%), much higher than seen in other mouse BAV models. The objective of this proposal is to utilize the viable Adamts5-/-;Smad2+/- mice that exhibit a high percentage of BAV, to define morphological events, cell behaviors and factors that when disrupted contribute to BAV formation. Since excess Vcan is a hallmark of dysfunctional and diseased valves, use of a model with mutations that impact the control of Vcan content, may shed light on how proteoglycan metabolism is regulated in development and may also give insight into disease. Experiments test the hypothesis that ECM Vcan cleavage coordinates mesenchymal cell behaviors and myocardial cell contributions that are required for the tricuspid morphology of aortic valves. The hypothesis is tested in two aims: Aim 1 tests the impact of altered Vcan cleavage on mesenchymal cell lineage behaviors that are required for aortic valve formation. Our preliminary data show that loss of Vcan cleaved fragments and excess intact Vcan, disrupted lineage-specific patterning in the developing aortic valves of the BAV Adamts5-/-;Smad2+/-mice. A combination of ex vivo, and in vivo approaches will decipher the lineage-specific cell behaviors, and guidance factors that are dependent on Vcan cleavage and to prevent BAV. Although dogma states that valve cusps arise from mesenchymal cells, Aim 2 investigates the consequence of excess Vcan on the myocardial cell lineage contributions to the developing aortic valve in Adamts5-/-;Smad2+/- mice and other murine models of BAV. Our preliminary data show myocardial lineage expression of Adamts5 is required to clear Vcan-rich ECM and to form the non-coronary cusp of the aortic valve. Due to the emerging prevalence of excess Vcan in BAV, the investigation into ECM turnover will allow insight into the molecular and cellular origins of aortic valve diseases, which may lead to therapeutic advances.

NIH Research Projects · FY 2025 · 2022-01

PROJECT SUMMARY: Allogeneic hematopoietic stem cell transplantation (HSCT) is the only curative cellular therapy for many pediatric patients with malignant and non-malignant disorders. Approximately 2500 pediatric HSCT are currently performed annually in the U.S. Unfortunately, transplant-related complications remain a major barrier to successful outcomes particularly graft-versus-host disease (GVHD). The lung is a target of GVHD leading to noninfectious acute lung injury and respiratory failure called idiopathic pneumonia syndrome (IPS), often fatal. The significance of respiratory failure occurring after HSCT was recently underscored by a June 2018 NIH workshop specifically convened to identify clinical challenges and scientific knowledge gaps regarding pulmonary dysfunction after HSCT in pediatric patients. Mechanistic basic understanding is lacking, and thus there remains a paucity of therapies and biological correlative studies offered. The Paczesny laboratory has discovered that: (1) soluble STimulation-2 (sST2), the “alarmin” interleukin-33 (IL-33) decoy receptor, as a biomarker for risk of GVHD as well as of IPS (N. Engl. J. Med, 2013; Biol Blood Marrow Transplant. 2018); (2) Mechanistically, we have shown that sST2, secreted by cytopathic T effector cells, sequesters IL-33, limiting its availability to T cells expressing the transmembrane molecule form of ST2, mostly cytoprotective regulatory T cells (Science Translational Medicine, 2015); (3) blockade of sST2 with a neutralizing monoclonal antibody (anti-ST2 mAb) or small molecule compounds reduced GVHD severity and mortality (Science Translational Medicine, 2015; Journal of Clinical Investigation Insights, 2019), and (4) In preliminary unpublished data, IL-33 local treatment or blockade of sST2 decrease frequencies of donor IFNγ producing T cells while increasing recipient IL-9 producing innate lymphoid cells type 2 (ILC2s) that controls acute lung injury after HSCT. This significant body of preclinical and clinical data provides the basis for the following hypothesis: Early after HSCT, the ST2/IL-33 pathway regulate IL-9-mediated ILC2s activation and integrity, decreasing sST2 and cytopathic T effector cells, and preventing the development of IPS. Our new hypothesis will be tested with three specific aims: 1) Confirm the pathogenic cellular mechanisms of anti-ST2 neutralizing antibody mediated regulation of inflammation in the lung following HSCT in several experimental IPS models; 2) Establish the role of IL9-ILC2s on inducing cytoprotective regulatory T cells; and 3) Elucidate the molecular mechanisms of endogenous IL-33/membrane ST2 signaling that stimulates IL-9 production by lung recipient ILC2s and the source of secreted soluble ST2 as a barrier to IL-33 protective effect on ILC2s. The translational research potential of this application is significant as these studies will enhance our understanding of how alarmins and their receptors after HSCT contribute to lung injury with the potential to modulate these pathways and reduce the risk and severity of respiratory failure in pediatric HSCT recipients, and thereby improve outcomes and extend the use of HSCT as well as other novel cellular therapies.

NIH Research Projects · FY 2026 · 2021-12

PROJECT SUMMARY Triple negative breast cancer (TNBC) is the most aggressive breast cancer subtype. It accounts for ~15% of all breast cancer patients yet is responsible for 30% of breast cancer deaths. TNBC is treated primarily by conventional chemotherapy; however, resistance to therapy is common leading to high mortality rates. Recently, we identified hypoxia-induced ECM re-modeler, lysyl oxidase (LOX) as a key mediator of doxorubicin resistance in TNBC (Saatci et al, Nature Communications, 2020). LOX inhibition offers a unique opportunity to re-sensitize the most aggressive breast tumors to standard-of-care chemotherapeutics. The overall objectives of this project are to (i) delineate the roles of LOX in chemoresistance, (ii) determine the mechanisms through which LOX exerts these roles, (iii) and generate prototypes of potent and selective LOX inhibitors to overcome chemoresistance in TNBC. We hypothesize that (i) LOX induces resistance not only to doxorubicin but also to other chemotherapeutic drugs by its enzymatic activity; (ii) LOX exerts this effect both by increasing collagen cross-linking/fibronectin assembly (canonical LOX function) leading to reduced drug penetration and increased integrin-mediated signaling and by regulating transcription (non-canonical LOX function) via interacting and oxidizing its substrates, culminating in activation of FAK/Src signaling and cell survival; and (iii) targeting LOX activity with selective small-molecule inhibitors will overcome chemoresistance by blocking both canonical and non-canonical LOX functions in TNBC. These hypotheses will be tested by pursuing three specific aims: 1) To determine the role of canonical ECM cross-linking function of LOX in resistance to different chemotherapeutics in TNBC. We will test the general chemosensitizer role of LOX and necessity of its enzymatic activity by generating cells with CRISPR-mediated LOX knock-out and reconstitution and testing their effects on chemoresistance in vitro and in vivo. LOX-mediated ECM changes will be analyzed by advanced microscopy techniques, e.g. MP-SHG, and the resulting drug penetration will be studied by IF and MALDI-MSI. 2) To determine the role of non-canonical transcription-regulating functions of LOX in TNBC chemoresistance. We will determine if LOX controls global transcription and identify novel LOX substrates by combining transcriptomics (RNA-Seq) and proteomics (TurboID) approaches. We will generate oxidation-deficient LOX substrates and test their effects on LOX-mediated chemoresistance. 3) To characterize novel LOX enzymatic inhibitors and test their potential as chemosensitizers in TNBC. We will test the selectivity of our inhibitors in cells with LOX knock-out/reconstitution and their off-target profiles and test their chemosensitization ability in organoids. We will perform PK/PD and toxicity profiling studies and test the inhibitors for overcoming chemoresistance in TNBC PDXs. The proposed project is expected to provide key mechanistic and phenotypic pre-clinical data to show that targeting LOX will overcome chemoresistance in the most aggressive breast cancer subtype, with a potential to reduce mortality rates.

NIH Research Projects · FY 2026 · 2021-12

Major barriers to chronic graft-versus-host disease (cGVHD) research and preemptive treatment are the inability to predict early following allogeneic hematopoietic cell transplantation (HCT), who will develop cGVHD, and lack of specific and sensitive risk biomarkers of cGVHD before onset is detectable by clinical symptoms. This project will use already collected plasma and PBMCs samples from BMTCTN 0201, 1202 and multicenter pediatric and adults studies (NCT00075816, NCT01879072, and NCT02194439) and the Pasquarello tissue bank at the Dana–Farber Cancer Institute to analyze proteomic and cellular signatures associated with impending onset of clinical cGVHD, and overall survival using machine learning (ML) versus established statistics. Proposed markers are based on previous published and unpublished studies and will include other novel or hypothesized factors. We will use the tow BMT CTN and NCT02194439 biorepositories with sample size totaling ~1300 HCT patients (669 cGVHD in comparison to 664 non-cGVHD controls) at day +90 post- HCT and 14 plasma proteins [Stimulation 2 (ST2; the interleukin (IL)-33 receptor), chemokine (C-X-C motif) ligand 9 (CXCL9), matrix metalloproteinase 3 (MMP3), osteopontin (OPN), and C-C motif chemokine 15 (CCL15), CD163, CXCL10, IL17, BAFF, B7H3, DKK3, IL1RACP, MCSF, CCL5] as well as 35 markers on 10+ populations totaling up to 300 parameters in a cohort of 200 patients with available PBMCs and paired plasma at day +90±10 post-HCT with mass cytometry. We will then be in a unique position in the field of cGVHD to address major questions: (a) Are plasma biomarkers or cellular biomarkers or the combination of both more amenable to provide better specificity/sensitivity? (b) Can we increase sensitivity and specificity of cGVHD biomarkers panels by using ML statistics? (c) Can we discover new key biologic drivers of cGVHD using ML algorithms? As ML techniques are likely to provide better prediction when large amount of data with high- dimensional covariates and nonlinear relationships are used, we hypothesize that ML analysis will increase sensitivity and specificity of our panels as well as increase biology granularity. Specific Aim 1 will address if a day-90 fourteen-plasma biomarker panel on 1300 patients’ samples, using ML, predicts risk of cGVHD with higher specificity and sensitivity than established statistics. Specific Aim 2 will address if a day-90±10 thirty- five-cellular biomarker panel, using single-cell mass cytometry and ML, is predictive of development of cGVHD in a 30 cases vs 30 controls discovery cohort. Specific Aim 3 will address if a comprehensive day-90±10 proteomic biomarker panel only, or cellular biomarker panel only, or a combined proteomic and cellular biomarker panel in a validation cohort of 200 paired plasma/PBMCs samples, will improve prediction of cGVHD risk. Upon completion, these studies will result in novel biomarker panels that may facilitate cGVHD risk stratification for HCT patients and identify candidates for new preemptive approaches.

NIH Research Projects · FY 2025 · 2021-12

PROJECT SUMMARY/ABSTRACT Cochlear implants (CIs), which directly stimulate the auditory nerve (AN), are widely considered to be the most successful neuroprosthetic device. However, patients with CIs do not understand speech as well as people with normal hearing, and there remains an unmet clinical need to improve performance in established CI users. CIs are adjusted for each listener by varying the stimulus parameters on each electrode (“programming”); however, programming techniques have largely remained unchanged since CIs were first approved by the FDA in 1984. Studies have shown that 1) the estimated density of AN fibers affects speech recognition outcomes in CI users, 2) AN density can be estimated at each electrode site in CI users, and 3) speech recognition improves for some CI users when stimulating electrode sites with higher AN density. While these studies show that speech recognition seems to be at least somewhat dependent on the ability of AN to precisely code the signal, encoding of information at the level of the auditory cortex is also important for adequate speech understanding. The present studies will define the role of AN density in the precise coding of “timing” (temporal) information and quantify the extent to which stimulating electrodes with higher AN density affects encoding of temporal information at the level of the auditory cortex. We hypothesize that users will show improved speech understanding when using a CI program that stimulates electrodes with higher AN density, but these improvements will be associated with more precise encoding of temporal cues within the auditory cortex.

NIH Research Projects · FY 2025 · 2021-09

The goal of this K23 award is to develop the applicant into an independent investigator with advanced multimodal neuroimaging and clinical research methods skills to support his career objective of establishing a line of research investigating reward brain circuitry as a shared etiological vulnerability to substance use disorder and major mood disorder co-occurrence. With this award, the applicant will investigate the structure and function of reward brain circuitry in co-occurring alcohol use disorder (AUD) and bipolar disorder (AUD+BD) which remains largely unknown to support the development of more precise neurobiological targets for the treatment of AUD+BD. The proposed career development and training plan is directly aligned with his prior experience in child/family clinical psychology, social reward and decision-making, utilization of high-risk designs, and ongoing adult AUD(+/-BD) neuroimaging research. With the support of this renowned mentorship team, the applicant will: 1) gain advanced knowledge and proficiency in functional magnetic resonance imaging (fMRI), diffusion kurtosis imaging (DKI), and sophisticated analyses with these data; 2) develop a deep understanding of the neurobiology of AUD and BD from adolescence into adulthood; 3) become highly adept at conducting family-related alcohol and BD clinical research; and 4) improve his grantsmanship for a smooth transition to research independence. These goals will be achieved through rigorous hands-on training in fMRI and DKI; the successful completion of neuroimaging statistics coursework with expert consultation support; guided reading series on AUD and BD neurobiology, assessment, and treatment; intensive mentorship in conducting neuroimaging research with families; and the successful completion of various on-campus grantsmanship trainings. The objective of the proposed multimodal neuroimaging study is to define reward brain circuitry structure and function among sets of parents with AUD+BD and their unaffected adolescent offspring (dyads) against dyads defined by parental AUD alone (n=25 per group). This study is directly aligned with two foremost NIAAA initiatives through focus on increasing understanding of AUD neurobiology in the context of co-occurring psychopathology across age groups. The proposed aims will measure reward circuitry brain function using social reward and decision-making fMRI tasks paired with DKI for measurement of white matter (WM) pathway microstructure. The central hypotheses are: 1) sets of adults and their unaffected offspring (dyads) with AUD+BD relative to AUD alone will exhibit hyperactivation to reward (with perturbed functional connectivity) due to BD co-occurrence, and 2) WM microstructural integrity will be reduced in sets of AUD+BD dyads relative to AUD dyads. The results of this K23 study will generate important preliminary data for a longitudinal R01 establishing reward-related endophenotypes for AUD+BD patients who are currently underserved by existing clinical treatments. The applicant will receive support and guidance from expert mentors successfully conducting AUD+BD studies for the past 10+ years.

NIH Research Projects · FY 2025 · 2021-09

Project Summary / Abstract There is an 8-fold increase in the prevalence of cannabis use disorder (CUD) in individuals with bipolar disorder (BD) relative to the general population, and individuals with co-occurring BD and CUD (BD+CUD) have substantially worse clinical outcomes (e.g., elevated rates of suicide) than those with either BD or CUD alone. Response to traditional mood-stabilizing medications is poor, yet little is known about optimal treatment as there have been no randomized medication trials for BD+CUD to date. Convergent evidence supports disrupted brain gamma-Aminobutyric acid (GABA)/glutamate homeostasis as a promising target for pharmacological intervention, and gabapentin as a candidate adjuvant medication to normalize frontal and striatal brain GABA and glutamate levels, in BD+CUD. Against this background, we recently completed an NIH/NIDA-funded (R21DA043917), double-blind, randomized, crossover, MRI (i.e., proton magnetic resonance spectroscopy [1H- MRS], functional MRI [fMRI]) study of gabapentin (1200mg/day) vs. placebo in BD+CUD (n=22) which found that, a) gabapentin increased dorsal anterior cingulate cortex (dACC) and right basal ganglia (rBG) glutamate levels, the latter only in cigarette-smokers, b) relative elevations of rBG glutamate and dACC GABA levels in gabapentin-treated participants were associated with lower cannabis use and mood symptoms, respectively, and c) gabapentin increased activation to visual cannabis cues in the posterior midcingulate (pMCC) gyrus, which was associated with increased rBG glutamate and GABA levels, as well as reduced cannabis use, however only in smokers. Though promising, these findings must be interpreted with caution due to the study's small sample size, observed randomization order effects, and post-hoc identification of statistical moderators, in part guided by a failure of simple randomization to balance condition orders on participant characteristics; effects of gabapentin on brain GABA, as opposed to glutamate, levels were additionally not as robust as anticipated. The proposed randomized, placebo-controlled, double-blind, parallel-group, MRI study aims to evaluate whether gabapentin increases dACC and rBG GABA and glutamate levels in BD+CUD, and whether normalization of these levels will be associated with changes in brain cannabis-cue activation, cannabis use and craving, and mood symptoms. This study will overcome the limitations of our preliminary study via, a) parallel-group study design, b) a larger sample of enrolled BD+CUD individuals (n=68 vs. 22), c) urn-randomization to treatment group, and d) a higher dose of gabapentin (1800mg/day) delivered over a longer period (17 days vs. 5 days/condition) to increase our likelihood of observing gabapentin effects on brain GABA levels. Positive results may support investigation of gabapentin for the adjuvant treatment of BD+CUD in more clinically-focused RCTs. The proposed study will also add to the literature on associations of regional brain GABA/glutamate levels with constructs related to BD+CUD, including cue reactivity, cannabis use/craving, and mood and anxiety symptoms.

NIH Research Projects · FY 2025 · 2021-09

Project Summary Out-of-hospital cardiac arrest (OHCA) in children is a tragic event that usually results in death or permanent brain injury in survivors. More than 7000 children suffer OHCA each year in the US and improvements in pediatric OHCA outcomes, just as in adults, is very much limited by our ability to protect the brain from global cerebral ischemic injury in those who are successfully resuscitated. Targeted temperature management (TTM) is currently guideline-recommended in children following OHCA with preference stated for therapeutic hypothermia (TTM 32-34°C) over normothermia (TTM 36-37.5°C) in order to prevent fever which could amplify brain injury. The optimal duration and patient selection criteria for therapeutic hypothermia in children remain unknown and cooling devices are not specifically FDA approved for this indication. Preclinical data and mechanistic studies strongly suggest that durations of hypothermia longer than those typically used in adults may minimize brain injury. This study will determine if identifying an optimal duration (dose) of therapeutic hypothermia can improve outcomes, and if development of a duration response curve can confirm efficacy in a wider pediatric population of OHCA survivors. We hypothesize that longer durations of cooling will improve survival and result in better neurologic recovery in survivors compared to shorter cooling durations, as assessed by the Vineland Adaptive Behavior Scales–Third Edition (Vineland-3) score. The primary goal of this project is to identify clinical strategies that will increase the number of patients with improved neurological recovery from OHCA. The results of this trial will be extremely significant in children and will immediately impact both clinical practice and regulatory evaluation. The Pediatric Influence of Cooling duration on Efficacy in Cardiac Arrest Patients (P-ICECAP) trial, modeled after the ongoing adult ICECAP trial, uses innovative adaptive dose finding methods that allow exploration of a wide range of potential durations and efficiently allocate subjects where they will be most informative. The study will be conducted using resources of the NHLBI/NINDS Strategies to Innovate Emergency Care Clinical Trials Network (SIREN), which is experienced in both pediatric and adult trials, and is currently conducting the current adult ICECAP Trial. SIREN leverages existing resources to achieve economies of scale and to conduct important clinical investigations spanning from pre-hospital, through both the emergency department and ICU stay, and post hospital discharge.

NIH Research Projects · FY 2025 · 2021-09

Increasing participation in the biomedical workforce is essential to ensuring scientific excellence. Theoretically-grounded, mentored research experiences have been shown to increase participation and persistence in STEM fields. Most existing programs focus on undergraduate and post-baccalaureate students, as opposed to the critical foundational period of high school. Thus, the primary objective of the proposed mentored research program, titled MUSC High School Teen Science Ambassador Program, is to provide early clinical research experiences and professional development to high school students with the long-term goal of growing the biomedical workforce. The program will be supported by MUSC’s Youth Collaborative, which is comprised of faculty and trainees focused on adolescent substance use and mental health research, which will provide a rich training ground for real-world research experiences. The proposed program is aligned with NIH’s mission to support educational activities that complement and enhance the training of a workforce to meet the nation’s biomedical, behavioral, and clinical research needs. The specific aims of the Teen Science Ambassador Program are to: provide courses for skills development and hands-on research experiences, as well as mentoring and professional development training to youth interested in STEM careers. This will be accomplished through three focused phases: (1) a mentored didactic training on clinical research skills and professional development; (2) near-peer mentorship training and experience, as well as an internship in an NIH-funded lab focused on adolescent substance use and mental health research; and (3) continued networking with peers, faculty, and alumni for long-term career success. Input from community stakeholders and an Advisory Committee will be collected to assess and improve program goals and outcomes, and all program materials will be made publicly available for dissemination and implementation at other institutions. The highly-qualified, multidisciplinary faculty mentorship team, partnerships with community schools and leaders, and rigorous program evaluation from independent evaluators will ensure that the proposed program meets the stated objective to increase the biomedical workforce.

NIH Research Projects · FY 2024 · 2021-09

PROJECT SUMMARY/ABSTRACT Children and adolescents from low-income households are an important focus for human papillomavirus (HPV) vaccination because the risk of HPV-associated cancers for individuals from low socioeconomic status is markedly higher (up to 20% for cervical, 20% for oropharyngeal, 17% for vulvar, and 50% for anal cancer). The HPV vaccine protects up to six cancers (cervical, vaginal, vulvar, oropharyngeal, anal, and penile cancers) and can reduce the incidence of these cancers by nearly 90% if administered before 17 years of age. However, vaccination rates are suboptimal in many states. Texas (the state with 3rd highest burden of HPV-associated cancer in the nation) has underperformed on HPV vaccination. Children from low-income families constitute half of Texas’ HPV vaccine-eligible population. In 2018, only 30% of the boys and girls from low-income families had received the recommended doses of the HPV vaccine. The lack of valid and robust area-level (ZIP code level) estimates of vaccination rates for low-income children and adolescents is a major barrier to strategizing vaccination efforts in Texas. Addressing these data deficiencies is necessary for mobilizing resources and invigorating HPV vaccination outreach in Texas. The applicant proposing this K01 research (Dr. Kalyani Sonawane) is a trained pharmacist and health services researcher who is well-positioned to address disparities in HPV-associated cancer prevention. Kalyani will receive training in disparities research, advanced data analytics and visualization, geospatial techniques, and ethics and dissemination under the mentorship of nationally recognized experts Dr. Xianglin Du (cancer health services research and claims data analysis), Dr. Anna R. Giuliano (HPV vaccine and HPV-associated cancer prevention), Dr. Maria E. Fernandez (implementation and dissemination science research to reduce cancer disparities), Dr. Ashish A. Deshmukh (population health with a focus on HPV and associated cancers), and Dr. Ruosha Li (biostatistical methodologies for health care data research). This proposal will utilize cutting-edge methods devised for healthcare data analytics to quantify area-level (5-digit ZIP code level) HPV vaccination rates by harnessing healthcare claims information of over 4.8 million low-income children and adolescents (Aim 1). Sophisticated geospatial models will be utilized to identify geographic areas that are underperforming on HPV vaccination (Aim 2). Subsequently, a novel web-based portal will be created for HPV vaccination data visualization and disseminating evidence-based HPV vaccination resources to healthcare providers (Aim 3). This K01 award will provide Dr. Sonawane a structured and tailored mentoring program and resources for synthesizing preliminary data that will be critical for her to become an independently funded investigator in cancer health disparities research. The proposed work and subsequent research will invigorate outreach efforts for HPV-associated cancer prevention in vulnerable individuals.

NIH Research Projects · FY 2024 · 2021-09

PROJECT SUMMARY/ABSTRACT Pediatric traumatic injury (i.e., injury of sudden onset and severity requiring immediate attention) is the leading cause of death and morbidity among US adolescents and are associated with mental health and health risk outcomes. Pediatric traumatic injuries are associated with medical and societal costs of $87 billion and elevates risk for a wide range of health risk consequences that affect quality of life, physical recovery, social functioning, and return to previous activities. The prevalence of PTSD and depression is high among pediatric traumatic injury patients; however, most pediatric trauma centers don’t have the resources to implement models of care that address mental health following injury. Current guidelines by the American College of Surgeons (ACS) Committee on Trauma strongly recommend screening and addressing emotional recovery in traumatic injury patients. The ACS Committee on Trauma has identified this as a priority and likely will begin to mandate mental health programs in Level I and II pediatric trauma centers nationally. It is therefore critical that policy and practice is guided by the implementation and evaluation of scalable and sustainable models of care. In 2015 our team launched the Trauma Resilience and Recovery Program (TRRP), a scalable and sustainable, technology-enhanced, multidisciplinary stepped model of care – one of the few in the US - that provides early intervention and direct services to improve access to evidence-based mental health care after traumatic injury for children, adults and families. We have found this model of care to be feasible and acceptable to adolescent patients (ages 12-17) at each level of service. TRRP includes 3 major steps: (1) in-hospital education, brief risk reduction session, and tracking patients’ emotional recovery via an automated text-messaging system, (2) conducting a 30-day screen via telephone to identify patients who are good candidates for psychological treatment, and (3) providing referral to best-practice telehealth-based or in-person assessment and treatment. We have partnered with three accredited Level I and II pediatric trauma centers and propose a multi-site hybrid 1 effectiveness-implementation trial with 300 adolescent (ages 12-17) traumatic injury patients to: 1) assess the extent to which TRRP promotes improvement in quality of life and emotional recovery and 2) gather preliminary data on the potential for TRRP to be implemented in other Level I trauma centers. Directly in line with NICHD’s Pediatric Trauma and Critical Illness Research and Training (PTCIB) Strategic Research and Training agenda, this study will provide valuable data on the efficacy, preliminary effectiveness and potential for implementation of an innovative, cost-effective, sustainable technology-enhanced intervention designed to address the unique needs of adolescent injury patients and mitigate short- and long-term impact of injury on mental health, quality of life, and overall well-being.

NIH Research Projects · FY 2025 · 2021-09

Sterile processing departments (SPDs) clean and pack reusable surgical instruments. They directly affect productivity, efficiency, safety, and infection control within acute interventional care. About 15% of surgical instrument trays have missing, broken or dirty instruments, that can lead to surgical site infections and a range of safety, procedural, and inefficiency problems. Rather than being the fault of individuals, our prior funded R03 Work Systems Analysis demonstrated a range of performance-shaping factors and the need for staff and administrators to balance of multiple interacting system components and resources. We propose to extend or R03 work to develop interventions, improve data-analytic approaches, and predictive models, across multiple facilities. The overall aim is to harmonize the SPD work system to create optimized safety and quality, controlled production costs, and increased efficiency through systems modelling, interventions, data visualization, and prediction tools. Our first aim is to develop multiple system models of five sterile processing units across two hospital systems that will provide a comprehensive understanding of SPD system function, allow the comparison of methods for representing SPD work and the prediction and evaluation of interventions to improve point-of-use reprocessing, tray composition, and interruption management. Our second aim is to create data visualization tools that highlight systems interactions and thus enhance decisions making. Our third aim is to develop discrete event simulations that predict performance based on system parameters, providing a tool for making decisions and for understanding how decisions are made. This will be the biggest program of research in sterile processing ever conducted.

NIH Research Projects · FY 2025 · 2021-09

I am an assistant professor in the Division of Physical Therapy in the College of Health Professions at the Medical University of South Carolina in Charleston, South Carolina. My long-term goal is to become a well-funded, independent researcher investigating post-acute care of individuals with Alzheimer’s Disease and Related Dementias (ADRD). To achieve this goal, I will build upon my clinical expertise and current research training. For the K01 period, I have set four short term training goals/objectives: (1) Develop competence in post-acute care policy impacting people with ADRD, (2) Develop skills in management and manipulation of Medicare data of people with ADRD, (3) Develop competence in propensity score methods and data analysis for data of people with ADRD, and (4) Enhance my grantsmanship, ethical conduct of research, and mentorship skills for career development and advancement. Mentoring Team: My Primary Mentor is Kit Simpson, DrPH and my Co-Mentor is Kenneth Ottenbacher, PhD, OTR. Additional members of the mentoring team include Annie Simpson PhD, Jacobo Mintzer, MD, MBA, and Kathryn H Bowles PhD, RN, FAAN, FACMI. My mentoring team is highly qualified and includes nationally and internationally recognized experts in health services research (K. Simpson), post-acute care quality measures (K. Ottenbacher), ADRD (J. Mintzer), study design and analysis methods for observational studies (A. Simpson), and home health practice, policy, and research (K. Bowles). My mentoring team will guide career development activities and participate in the K01 research. Research Strategy: Medicare home health underwent unprecedented changes in 2020, including the implementation of a new payment model. These vast changes threaten to exacerbate existing barriers to home health access for people with ADRD. Decreased access to home health causes harm to people with ADRD and can trigger a cascade of resource and financial implications for the health care system. The impact of recent system-level changes on home health access and quality for people with ADRD has not been examined, but is urgently needed. This K01 project will use well-matched groups, to show the impact of system-level policy changes on home health access and outcomes for people with and without ADRD through analysis of Medicare assessment and billing data. Propensity score methods will be used to balance patient risk factors for comparison groups. Aim 1: Describe differences in home health access and outcomes between well-matched groups of Medicare Beneficiaries (MBs) with and without ADRD in 2019. Aim 2: Examine changes in home health access and outcomes for well-matched groups of MBs in 2019 vs 2020. Aim 3: Examine changes in home health access and outcomes for well-matched groups of MBs in 2019 vs 2021. Findings from this study can help to optimize access, cost, and outcomes for people with ADRD and the Medicare system and inform advocacy efforts, current home health practice, and future post-acute care policies.

NIH Research Projects · FY 2025 · 2021-09

Project Summary Neuropsychiatric disorders are a very serious medical and societal problem with many different origins, however, a common and prevalent deficit found in these disorders is hypofrontality. Emerging theories posit that hypofrontality [alterations in the ratio of excitatory (E) and inhibitory (I) synaptic transmission] underlie schizophrenia, anxiety, addiction, autism spectrum disorders and depression. Methamphetamine (METH) addicts frequently develop hypofrontality and deficits in working memory (WM), attention, and impulsivity. Similarly, in rodents, repeated psychostimulant administration or self- administration elicits hypofrontality, WM deficits, psychosis-like behaviors, decreased interest in external stimuli and surroundings, and decreased social functioning, suggesting that psychostimulant administration in rodents represents a strong, face-valid model for studying the basic brain mechanisms that underlie hypofrontality and cognitive disabilities in METH addiction. The overall objective of the proposed studies is to identify the effects of METH-SA on the activity of cortical parvalbumin positive fast spiking interneurons (PV+FSIs) and the resulting changes in E-I ratio. The central hypothesis- informed by strong preliminary data and literature- is that METH treatment elicits cognitive deficits due to an increase in GABAergic synaptic transmission in the PFC via D1R activation of PV+FSIs. The proposal’s rationale is that the experiments will yield fundamental knowledge pertaining to the understanding of the cellular and synaptic mechanisms underlying hypofrontality induced by METH and will provide new insights into the basic mechanisms governing E-I balance in the prefrontal cortex. We will test the central hypothesis by pursuing the following specific aims: Aim 1 will determine the role of PV+FSIs in METH- induced cognitive deficits. Aim 2 will determine whether D1R signaling in PFC PV+FSIs is required for METH- induced enhancements of GABAergic transmission. Aim 3 will determine whether D1R signaling in PFC PV+FSIs is required for METH SA-induced cognitive deficits and METH reinstatement. The proposed research is significant because it will fill a fundamental gap in knowledge pertaining to the mechanisms underlying hypofrontality in METH-addiction and the effects of the psychostimulant in the activity of cortical PV+FSIs. Furthermore, the knowledge obtained from the proposed experiments will help to develop effective treatments to ameliorate drug-related cognitive deficits and can provide new insights into the basic mechanisms underlying hypofrontality in other neuropsychiatric conditions.

NIH Research Projects · FY 2025 · 2021-08

Project Summary: Total pancreatectomy and islet autotransplantation (TP-IAT) are currently performed in around 20 centers worldwide for the treatment of chronic pancreatitis (CP). Major problems associated with TP-IAT are poor islet engraftment and dysfunction after intraportal infusion. Because of these issues, only around 20% of the non- diabetic CP patients are insulin-independent after surgery. Currently, interventional protocols to increase the survival of the islet graft following transplantation are empiric. Thus, effective therapies that can facilitate islet cell engraftment and promote survival after transplantation are urgently needed. Multiple studies including our own demonstrate that islet co-transplantation with mesenchymal stem cells (MSCs) enhances islet engraftment, decreases number of islets needed to achieve normoglycemia in rodent and nonhuman primate islet transplantation models. MSCs exert such effects mainly via direct cell-cell contact and their paracrine secretion of protective molecules including insulin growth factor-1 (IGF-1), hepatocyte growth factor (HGF), transforming growth factor β (TGF- β) and others. We are the first group who performed a pilot NIH-funded clinical trial evaluating the feasibility of autologous bone marrow-derived ex vivo-expanded MSCs (BM-MSCS) and islet co-transplantation in CP patients. Although only three subjects received MSC and islet co- transplantation due to the pilot nature of the grant, our data showed that BM-MSCs and islet co-transplantation was a safe and promising strategy to improve islet engraftment after transplantation. Based on this unique clinical trial experience and animal studies, the goal of this study is to further evaluate the safety and efficacy of autologous MSCs and islet co-transplantation in a larger TP-IAT patient population. Our hypothesis is that co- transplantation of islets with autologous BM-MSCs can enhance islet survival and function after transplantation, resulting in more CP patients being diabetes free after TP-IAT. A critical part of this trial will be to define the mechanisms by which MSCs modulate β cell survival and explore cellular and molecular biomarkers that can be used as indicator(s) for β cell death and the potential response/efficacy of MSC therapy. Results from these studies are not only urgently needed for the prevention of post-surgical diabetes in CP patients, but also may offer useful information on which to address the more complex allogeneic islet cell transplantation for patients with type 1 diabetes.