Univ Of North Carolina Chapel Hill

NIH Research Projects · FY 2026 · 2022-01

PROJECT SUMMARY Neural dynamics in motor cortex are necessary for dexterous behavior, but the mechanisms that generate these activity patterns are unclear. The long-term goal of our research is to understand how cortical dynamics are constructed to control movement, so that therapies could be developed to identify and repair aberrant activity patterns associated with motor disorders. My laboratory recently showed that these cortical dynamics arise from a collaboration between the intrinsic properties of cortex and inputs from the rest of the brain, but how distinct input streams are received and processed by the cortex remains poorly understood. To characterize these operations, we must understand the identity of the contributing inputs and their relationship to cortical dynamics. The objective of this proposal is to directly test the role of two major inputs, from ventral anterior (VA) and ventral lateral (VL) thalamic nuclei, to primary motor cortex. VA and VL have distinguishable input/output features: VA receives more input from basal ganglia, VL receives more input from cerebellum, VA and VL project to distinct cortical targets, and their intrinsic physiological properties differ. The central hypothesis to be tested here is that the VA-to-cortex pathway modulates, while the VL-to-cortex pathway drives, cortical dynamics and control of movement. To test the roles of VA and VL in the construction of cortical dynamics and behavior, we produced and validated genetic tools in the mouse that allow selective monitoring and manipulation of specific thalamic nuclei. With these tools, we will assess the relationship between a cortically dependent prehension task and the activity patterns of VA and VL neurons. We will then determine how activity in VL and VA drive or modulate cortical activity. Efforts to model the production of cortical commands have focused almost exclusively on firing patterns of cortex, leaving aside the influence of external inputs, leading to a cortico-centric view of pattern generation. With the data we collect, we will generate a more realistic computational model for pattern generation that considers the role of both intrinsic cortical dynamics and external inputs. Thus completion of these aims will advance understanding of how the cortical dynamics underlying prehension are constructed through interactions with the basal ganglia and cerebellum. The proposed research is innovative because it will use a new genetic toolbox for exploring thalamus, will produce an in-depth assessment of thalamocortical dynamics during a new complex prehension task, will advance the use of causal perturbations for testing interactions between brain regions, and will generate a more holistic model for pattern generation for dexterous behavior. The proposed work is significant because understanding the relationships among cortex, cerebellum, and basal ganglia can elucidate how their damage or disease leads to motor disorders and support the development of therapies designed to replace lost or corrupted signals.

NIH Research Projects · FY 2025 · 2022-01

PROJECT ABSTRACT An estimated 1 in 2 US adults will have obesity by 2030, which is a major cause of morbidity and mortality. The highest risk of weight gain is among young adults ages 18-35 years. In-person behavioral interventions generally produce clinically significant weight losses, but cost and reduced reach limit their ability to impact obesity at a population level. Web-based interventions that mimic the structure of weekly face-to-face treatment have proven a viable alternative, though weight losses are generally smaller than in-person treatment. Mobile treatments have the potential for high reach, but have been less effective, producing 1-3 kgs over 6 months. Newer digital intervention approaches called “just-in-time adaptive interventions” (JITAIs) promise to improve upon mobile outcomes by offering adaptive, personalized feedback on behavior, which consists of providing the “right type of support” at “the right time” rather than on a fixed schedule. This “just-in- time,” or JIT, approach is made possible by the emergence of low-cost and widely available digital health tools that allow for the collection of continually updated health data. However, to date, no JITAIs have successfully targeted multiple weight-related behaviors (weighing, activity, and diet), and there has been no systematic examination of what types of messaging interventions best promote adherence to these three weight loss behaviors, for whom they are effective, and under what conditions. To address this problem, we will use a micro-randomized trial to evaluate the effects of 7 types of intervention messages targeting specific behavior change techniques (i.e., BCT messages) delivered in JIT moments on daily achievement of behavioral goals among n=201 young adults with overweight and obesity. All participants will receive a 6-month behavioral weight loss intervention using our Nudge mobile app, which includes evidence-based weekly lessons, tailored feedback, self-monitoring, and daily BCT messages. Participants will receive a wireless scale, activity tracker, and track “red” foods (high-calorie foods) in the app and have 3 goals: weigh daily, a daily active minutes goal that gradually increases if met, and a daily red foods limit. At 3 decision points per day, participants will be micro-randomized to receive or not receive 1 of 7 types of BCT messages. Each intervention message has unique decision rules for availability. Candidate intervention message options have been carefully selected from empirical evidence, tested in our prior studies, or are from our pilot micro-randomized trial. Assessments will occur daily, and at 0, 3 and 6 months, to accomplish the following specific aims: 1) Evaluate the effects of each behavior change technique message (i.e., BCT message) on daily adherence to weight loss behaviors; 2) Determine whether the effects of BCT messages on proximal outcomes change over time; and 3) Assess whether the effects of BCT messages on proximal outcomes are moderated by participants’ contextual factors. Findings will guide how adaptive, behaviorally- and contextually-dependent messages are incorporated into future JITAIs for weight loss.

NIH Research Projects · FY 2025 · 2022-01

Abstract (Metabolomics and Clinical Assay Center, MCAC) Determining how individuals differ in their metabolism, and in their response to dietary intake, is critical to developing personalized intervention strategies for preventing and delaying the onset of chronic diseases such as obesity, diabetes, cardiovascular disease, and cancer. The MCAC will a) acquire and process high quality targeted and untargeted metabolomics data, b) prioritize, predict, and confirm the identity of unknown peaks, c) provide CLIA certified clinical assays, d) collaborate with the Common Fund Data Ecosystem, e) construct a data infrastructure which ensures FAIRness and enables interoperability of the data with other Common Fund data sets, and f) collaboratively work with the NIH Common Fund Nutrition for Precision Health (NPH) Consortium. The MCAC brings an outstanding team of investigators from 3 UNC Systems Universities that are co-located on the North Carolina Research Campus (NCRC) and Duke University. Dr. Susan Sumner (UNC Chapel Hill, Nutrition Research Institute, NCRC, Untargeted Metabolomics) will serve as the PI with support from expert scientists who specialize in nutrition and targeted metabolomics of host metabolism (Dr. Christopher Newgard, Director, Sarah W. Stedman Nutrition and Metabolism Center and Duke Molecular Physiology Institute), dietary interventions and targeted phytochemical analysis (Dr. Colin Kay, North Carolina State University, NCRC), CLIA certified clinical assays (Dr. Steven Cotten, UNCCH), and Computational Metabolomics (Dr. Xiuxia Du, UNC Charlotte, NCRC). Our team provides a unique combination of long-standing expertise in metabolomics technologies, coupled with deep knowledge of nutrition, metabolic physiology, and chronic disease mechanisms. We are experienced with the application of targeted and untargeted metabolomics in large-scale clinical and epidemiology studies, including in other NIH Consortia. We have used metabolomics to define metabolic signatures and pathways associated with dietary intake, nutrition assessments, demographics, lifestyle factors, microbial populations, genetics, transcriptomics, clinical assays, and clinical phenotypes of health and wellness. We have developed comprehensive informatics capabilities for targeted and untargeted metabolomics and exposome research. We have developed an online mass spectral knowledge base resource for prioritizing and predicting unknown metabolites by leveraging publicly available data. Our high quality MCAC datasets produced under fine-tuned protocols with quality control and quality assurance metrics, will be essential for success of the NPH Consortium. The MCAC will provide data and expert biological interpretation in exploration of the heterogeneity in metabolism among study subjects, providing a roadmap that will help explain why individuals differ in their metabolic responses to dietary interventions, and what this portends for future disease risk. The MCAC will provide a robust data set to the Artificial Intelligence for Multimodal Data Modeling and Bioinformatics Center for use in development of algorithms to predict individual dietary responses that can ultimately be translated for design of targeted dietary interventions to improve health and quality of life.

NIH Research Projects · FY 2026 · 2022-01

Project Summary/Abstract Severe complications after thoracic surgery are common and lead to increased readmissions and mortality. The early symptoms of developing complications may not be detected by the usual scheduled postoperative care before they worsen and become severe. Postoperative care can be done remotely and in real-time with automated systems that electronically deliver surveys to patients to directly capture patient- reported outcomes and send alerts to providers for concerning responses (ePROs). ePROs improve quality of life, healthcare utilization, and survival in several large clinical trials as well as have emerging evidence of clinical effectiveness in real-world applications in oncology patients. ePROs also have been shown to be feasible for symptom management in small trials of thoracic and colorectal surgery patients. These data suggest ePROs have the potential to improve care after thoracic and other high-risk surgery. However, there are no widely implemented ePRO systems in routine surgical care, despite evidence from other settings to support the value of systematically identifying and then addressing anticipated barriers to implementation in the ePRO design. Current gaps in knowledge to designing ePROs for use in surgical care include identifying optimal survey/alert features and workflow, barriers to routine use, and clinical effectiveness. The candidate for this career development award, Dr. Mody, is a thoracic surgeon whose career goal is to improve clinical and patient-centered outcomes for patients with chronic lung conditions requiring surgery. The proposed award will build on her prior MPH that included formal training in biostatistics and health services research and will provide advanced training in areas necessary for her to achieve her career goals. Specifically, during the award period Dr. Mody will receive training in qualitative data analysis including mixed methods and implementation science research methods. Dr. Mody will perform a prospective study of implementation and effectiveness outcomes in thoracic surgery clinics using postoperative ePROs. To ensure her success, an interdisciplinary team of mentors and advisors with complementary expertise have been enlisted including Dr. Ethan Basch (clinical trials in oncology, PRO research), Dr. Jennifer Leeman (implementation, qualitative research), Dr. Antonia Bennett (quality of life measurement, qualitative research), Dr. Andrea Pusic (clinical trials in surgery, PRO research), Dr. Angela Smith (surgery, health information technology for PRO measurement), and Dr. Angela Stover (implementation of PROs). By the end of the award period, Dr. Mody will have the necessary preliminary data and training to successfully perform a large scale randomized controlled trial to evaluate the implementation and effectiveness of an ePRO system in cardiothoracic surgery patients. Designing and evaluating such a system in thoracic surgery patients first is important as they serve as a model for the increasing numbers of medically complex patients requiring invasive treatments for chronic conditions and for whom ePROs may substantially improve outcomes.

NIH Research Projects · FY 2026 · 2022-01

Nanoformulated small molecule immunotherapy for SHH medulloblastoma M. Sokolsky-Papkov, (PI) This project focuses on improving therapy of medulloblastomas. Despite aggressive and highly toxic multi-modality therapy, 30% of the children diagnosed with medulloblastoma will still die from recurrent disease. The survivors have increased risk for subsequent neoplasms and are often left with severe and lifelong treatment-associated cognitive and motor deficits. Development of novel modalities that are more effective and safer than the current therapies is paramount in improving the clinical outcomes in medulloblastomas. Cancer immunotherapy, the utilization of the patients’ own immune system to treat cancer, has emerged as a powerful new strategy in cancer treatment. A recent study by our collaborator, Dr. Dolores Hambardzymyan, suggested that SHH medulloblastomas are enriched in TAMs and our data shows that these TAMs express TLR7/8. An imidazoquinoline drug resiquimod [R848], a Toll-like receptor (TLR) 7 and 8 agonist, is evaluated as a single agent or adjuvant in combination with vaccines is several oncology clinical trials in patients with melanoma, bladder cancer, glioma, and other malignancies (ClinicalTrials.gov: NCT00470379, NCT00821652, NCT00960752, NCT01204684). However, resiquimod is nearly insoluble at neutral physiological pH, and there is no clinically approved formulation available for its systemic or local intratumoral administration. We have loaded resiquimod into our ultrahigh-capacity nanoparticle polymeric micelles (PMs) platform. Previously we have utilized this platform to deliver SMO inhibitor vismodegib, CDK4/6 inhibitor palbociclib and PIK3/AKT/mTor inhibitor Sapanisertib (INK-128). Delivery in POx PMs reduced toxicity and rendered these agents effective, while free drugs showed no survival benefit in G-Smo mice-genetically engineered mouse model (GEMM) of SHH medulloblastoma. Unlike cells based or patient derived implantable models these mice have endogenous tumors which form intact native tumor environment and blood brain barrier (BBB). Treatment with POx-resiquimod PMs (POx-Res PMs) significantly enhanced infiltration of macrophages into the tumors decreased tumor cells viability (pRB levels) and prolonged mice survival. This project aims to obtain mechanistic data to evaluate the effects of POx-res PMs administered systemically (IP) and locally (IT) and determine whether the anti- neoplastic agents that target SHH pathway can synergize with POx-res PMs to improve treatment outcomes. Specific aims are: 1. Delineate systemic vs. local effects of POx-res PMs on the tumor immunological status, disease progression, and therapeutic outcomes in GEMM model of SHH medulloblastoma. 2. Delineate the contributions of immune cell populations to the therapeutic effect of POx-res PMs and 3. Determine whether the anti-neoplastic agents that target SHH pathway can synergize with POx-res PMs to improve treatment of SHH driven medulloblastoma.

NIH Research Projects · FY 2026 · 2022-01

Project Summary Affective disorders are highly prevalent in women and associated with significant morbidity and mortality, particularly during times of reproductive transition, including the transition to menopause. Unraveling the pathophysiology of affective disorders is challenging because depressive syndromes are heterogeneous and have diverse etiologies. Thus, studies aimed at identifying biomarkers to improve the prediction of susceptibility and illness course as well as treatment response in affective disorders have yielded inconsistent results. We propose to address this challenge by studying symptoms that initially present during the menopause transition and thus have a common endocrine trigger. We believe that studying a relatively homogeneous group of participants with similar biological mechanisms of symptom onset will increase the likelihood of elucidating the pathogenesis of perimenopausal-onset symptoms. This proposal will use simultaneous positron emission tomography and functional magnetic resonance imaging (PET-MR) to examine relations between reward-related striatal activation measured by fMRI and tonic and phasic striatal DA activity measured by [11C]raclopride PET in a transdiagnostic sample of women with varying severities of perimenopausal-onset (PO) anhedonia and psychosis. Specific Aim 1 will examine associations between PO anhedonia and psychosis symptom severity and reward-related striatal activation measured by fMRI and tonic and phasic striatal DA activity measured by [11C]raclopride PET. Specific Aim 2 will examine relations between anhedonia reductions due to estradiol administration, relative to placebo, and changes in PET-MR metrics related to reward processing. Specific Aim 3 will examine relations between PO psychosis reductions due to estradiol, relative to placebo, and changes in PET-MR metrics related to reward processing. Our central hypotheses are that the mesolimbic dopamine system is impaired during reward processing in PO anhedonia and psychosis, that the effects of estradiol administration will be associated with normalization of neural responses to rewards measured by fMRI and striatal dopamine functioning measured by PET, and that the degree of change in striatal functioning measured by fMRI and PET will be associated with the magnitude of change in PO anhedonia and psychosis symptom severity. The results of this project will increase our understanding of anhedonia and psychosis vulnerability during the menopause transition and have the potential to deliver validated molecular imaging targets to use in future mechanistic clinical trials of novel treatments for perimenopausal-onset psychiatric disorders.

NIH Research Projects · FY 2025 · 2022-01

PROJECT SUMMARY This project will devise experimentally and clinically validated computer models to elucidate the causal mecha- nisms of leaflet thrombosis in bioprosthetic heart valves (BHVs) following transcatheter or surgical aortic valve replacement, and thereby improve risk stratification and device selection. Each year, nearly 300,000 aortic valve replacements are performed worldwide to treat severe aortic valve stenosis, and the rate of valve replacement is projected to exceed 850,000/year by 2050. Traditionally, surgical aortic valve replacement (SAVR) was the gold standard for treating aortic valve stenosis; however, transcatheter aortic valve replacement (TAVR) has emerged as an alternative to SAVR that has been demonstrated to provide outcomes comparable to SAVR for elderly patients. Until recently, patients receiving aortic BHVs were thought to require limited anticoagulation, but in the past few years, clinical studies have unexpectedly revealed high rates of subclinical leaflet thrombosis (SLT) in BHVs after both SAVR and TAVR. SLT is associated with increased transient ischemic attacks and strokes, has been shown to trigger acute myocardial infarction, and is suspected to accelerate structural valve deterioration. Critically, SLT can progress to clinical valve thrombosis, which is a devastating complication. Wor- ryingly, a very recent study on two-year data for the PARTNER 3 trial found a statistically significant increase in valve thrombosis following TAVR compared to SAVR (2.6% post-TAVR vs. 0.7% post-SAVR, p=0.02). Two mechanisms have been hypothesized for the increased early incidence of SLT in TAVR: 1) abnormal blood flow patterns in the vicinity of the transcatheter aortic valve (TAV) (e.g., flow stasis, turbulence, paravalvular leak) and 2) stent-crimp induced injury of the TAV leaflets, which activates coagulation and platelet deposition. Although clinical imaging can detect SLT following aortic valve replacement, there is currently no approach to predict which patients will develop SLT following either SAVR or TAVR. The goal of this project is to devise patient-specific computational fluid-structure interaction (FSI) models of BHVs coupled to biochemically and biophysically detailed thrombosis models to characterize the mechanisms that lead to leaflet thrombosis and, ultimately, to predict leaflet thrombosis risk using clinical data in patients undergoing TAVR and SAVR. This project promises to transform computation-based methods for AVR device selection and SLT risk assessment. The project goals will be accomplished through three Specific Aims. Aim 1 focuses on experimental validation of FSI models; Aim 2 studies mechanisms that lead to leaflet thrombosis after aortic valve replacement; and Aim 3 focuses on clinical validation and device selection. Through these studies, a multidisciplinary team with an established record of collaboration will integrate mathematical, computational, experimental, and clinical ap- proaches to yield substantial innovation by establishing novel, rigorously validated models of flow, FSI, and thrombosis post-AVR that will ultimately enable patient-specific SLT risk assessment. Further, because throm- bosis are major challenges for many types of implanted devices, the project promises to have a broad impact.

NIH Research Projects · FY 2026 · 2022-01

Project Summary Cytokinesis is the physical division of one cell into two. This final step of the mitotic or meiotic cell cycle partitions the duplicated and segregated genome into topologically distinct daughter cells, and thus ensures genome stability. Cytokinesis is essential for development of the fertilized egg into a multicellular organism, for the replenishment of tissues to compensate for wear and tear, and to avoid diseases of proliferation including cancer and some neutropenias (blood cell disorders). For over a century, people have marveled through the microscope at dividing animal cells, but major questions about the mechanisms of cytokinesis remain. Many of these questions fall under the three Themes of our research program: 1) the cytoskeletal rearrangements that drive contractility, 2) the role of feedback loops in cytokinetic regulation, and 3) modeling the mesoscale. In animal cytokinesis, the cell changes shape as a furrow forms at the cell equator, the region between the two masses of segregated chromatin, as defined by spatio-temporal cues from the anaphase spindle. These cues lead to local activation of RhoA at the plasma membrane. RhoA elicits non-muscle myosin II (NMMII) filament assembly and activity, the generation of long actin filaments (F-actin) by formins, and the cortical recruitment of crosslinkers including anillin and septins. In sum, a circumferential band of cortical actomyosin cytoskeleton assembles and contracts via rearrangement of these cytoskeletal components. F-actin is slid, bundled, crosslinked and coupled to the plasma membrane, polarity sorted, bent, broken and depolymerized. The biophysics of many nano-scale binding partnerships are well studied, but often with sparse collections and without confinement. Since the relative contributions of the many activities listed above to in vivo network dynamics are unknown, our first theme is to define the cytoskeletal remodeling that underlies contractility. After spindle cues pattern the cell equator, both biochemical and mechanical positive feedback boosts these signals. Concurrently, global and localized inhibition via negative feedback limits RhoA activity. Our unpublished observations of contractile oscillations suggest that multiple negative feedback loops coexist. The second theme of our work is the role of feedback loops in cytokinetic regulation. To develop a conceptual model of cytoskeletal rearrangements in cell division, one may imagine the nanoscale molecules and fibers and their millisecond behaviors literally woven into a dynamic material. Like biophysics and cell biology, respectively, mathematical modeling also describes cytoskeletal rearrangements at these two ends of the time- and length scales, via distinct approaches: particle-based modeling (nano- or micro- scale), or continuum mechanics theory (macro-scale). Since both families of approaches have limited ability to coarse grain the mesoscale spatial and temporal heterogeneities of the cytokinetic ring components’ activity states, behaviors, abundances, and combinations, we are working to understand cytokinetic cytoskeletal rearrangements and integrated regulation, by innovating methods to model the mesoscale (theme three).

NIH Research Projects · FY 2026 · 2021-12

ABSTRACT There is growing evidence that early-life environmental exposures are contributing to the increasing prevalence of allergic diseases including food allergy. Food allergy rates, particularly for peanut, have increased dramatically in industrialized countries over the last few decades, suggesting environmental factors are driving the epidemic. Recent studies show that inhalational or cutaneous exposure to peanut within the home may be a risk factor for peanut allergy. In addition to food antigens, the indoor exposome also includes immunostimulatory agents, such as microbial products and air pollutants, which can act as adjuvants and promote allergic sensitization to antigens. Whether exposure to environmental adjuvants influences peanut allergy development is unclear. We have developed a novel mouse model that mimics inhalational exposure to environmental peanut within the home. We have found that co-exposure to inhaled peanut and indoor dust, which contains environmental adjuvants to which children are exposed, induced allergic sensitization and the development of peanut allergy in mice. Moreover, we have found that co-exposure to inhaled peanut and air pollutants, including diesel exhaust particles and particulate matter, also induced peanut allergy in our animal model. In this proposal, we will determine if exposure to environmental adjuvants in indoor dust is associated with peanut sensitization in infants, and also investigate the mechanisms by which environmental adjuvants (e.g., indoor dust, air pollutants) promote peanut allergy development. In Aim 1, we will use an airway sensitization animal model and primary human bronchial epithelial cell culture system to compare the adjuvant activity of indoor dust samples collected from the homes of peanut- sensitized and nonsensitized infants, and determine if adjuvant activity is associated with peanut sensitization status. In Aim 2, we will use animal models to define the innate immune signaling pathways required for indoor dust-mediated airway sensitization to peanut. In Aim 3, we will investigate the immunological mechanisms by which inhaled air pollutants promote peanut allergy development in our animal model. These studies will greatly expand our understanding of how the indoor exposome influences food allergy development and help direct future environmental interventions aimed at preventing peanut allergy in children.

NIH Research Projects · FY 2026 · 2021-12

The need for more precise nutrition advice is widely recognized, yet specific differences in genetic, epigenetic, microbiome and phenotypic drivers of individual variability to diet are not well known. The National Institutes of Health initiative to fund Nutrition for Precision Health (NPH), powered by the All of Us Research Program, will enable major progress in the field of precision nutrition. Here we propose Nutrition for Precision Health: The University of North Carolina at Chapel Hill Clinical Center (UNC-CC). Because chronic inflammation promotes the pathogenesis of a wide range of diseases, including obesity, type 2 diabetes, and cardiovascular, neoplastic, and neurodegenerative disorders, we draw upon the anti-inflammatory Mediterranean diet as a viable strategy to improve systemic inflammation and reduce risk for many chronic diseases and their complications. A body of literature has emerged that demonstrates both genotypically- and phenotypically-driven differential responses to the Mediterranean diet relative to a range of outcomes. Our proposal will address the critical need to understand variability in physiologic responses to diet, anchored by the theme of inflammation. Diet preparation will be facilitated by two clinical locations with metabolic kitchens: the UNC Nutrition Research Institute (UNC-NRI) in Kannapolis, NC, and the Chapel Hill campus of UNC (UNC-CH). The UNC-NRI draws from relatively rural communities and UNC-CH draws from relatively urban communities. Specific Aims are: Aim 1. To participate actively in the Year 1 planning process and beyond, engaging across the NPH consortium to collaboratively develop and execute the final study protocol. Aim 2. To execute NPH Module 1. Following participant enrollment into All of Us, we will enroll and complete the Module 1 protocol for a total of 2,000 NPH participants (25% at UNC-NRI; 75% at UNC-CH), including two study visits with a 2-week remote data capture period and a mixed meal challenge test. Aim 3. To execute NPH Module 2. A subset of 500 Module 1 participants will complete a free-living, controlled feeding study of three 2-week diet intervention periods, separated by 3-week washout periods. Diets include: The Mediterranean diet adapted for the US (Med-USA; 40% fat calories, 40% carbohydrate), the Med-USA modified for high healthy fat content (60% fat calories, 20% carbohydrate), and Med-USA modified for high healthy carbohydrate content (20% fat calories, 60% carbohydrate). Differential effects of the diets on outcomes comprising inflammatory markers and metabolic parameters from the mixed meal challenge will be tested across genotypic and phenotypic subgroups, focusing on weight status, age, and diabetes status. The UNC-CC team brings impressive interdisciplinary strength in nutrition (basic science to public health) and has the capacity and experience in complex, multi-site trials to ensure the scientific rigor needed to execute this study. Results will generate predictive algorithms to inform individualized dietary guidance to improve health.

NIH Research Projects · FY 2026 · 2021-12

PROJECT SUMMARY/ABSTRACT Parkinson disease (PD) is a common and growing source of disability worldwide, and adjunctive surgical treatments are often necessary to optimize treatment in more advanced stages of the disease once medical therapy becomes insufficient. Deep brain stimulation (DBS) has become the most common and effective surgical neuromodulatory technique for motor symptoms of PD, however selection of patients and surgical targets is limited due to an incomplete understanding of predictive factors for DBS outcomes. Historically, levodopa responsiveness has been the primary factor used to establish DBS candidacy, but this correlates only modestly with motor benefit, does not predict cognitive and psychiatric effects, and offers little information on optimal DBS target. Alternative preoperative predictors based on demographics, volumetric analysis, and functional connectivity have been described, but these predictors vary across studies and have not been validated for clinical use. As such, a comprehensive understanding of clinical and neuroimaging predictors of DBS effects is necessary to improve outcomes for those with advanced PD. The purpose of this Mentored Patient-Oriented Career Development Award (K23) is to enable the candidate to develop a funded research program focused on the creation of a model of DBS effects, integrating clinical data and preoperative MRI data to improve patient and target selection in DBS for PD. The candidate's long term goal is to become an independent clinician-scientist investigator capable of developing and implementing clinical neuroimaging tools to investigate DBS mechanisms, improve DBS outcomes, and develop novel DBS applications for individuals with PD and other neurological disorders. Training and mentorship are proposed in three key areas: (1) conducting clinical research, including study design and ethical conduct, (2) performing advanced statistical analyses including multivariate modeling , and (3) obtaining additional skills in neuroimaging tools and analysis, including functional and structural MRI. The research plan for this award will be supported by the training plan as well as an expert team of mentors and an outstanding institutional research environment. The objective of this plan is to develop and validate a model of DBS responsiveness, integrating clinical data and preoperative MRI data, which will improve patient and target selection in DBS for PD. Specifically, this project aims to (1) build a model of motor response to DBS of the subthalamic nucleus (STN) using preoperative behavioral, volumetric, structural and functional connectivity measures, (2) validate this model using prospective data of individuals undergoing STN DBS for PD, and (3) construct similar predictive models for cognitive and psychiatric outcomes of STN DBS. This will set the stage for future interventional studies using this model as a basis for patient and target selection, and lead to use of more comprehensive objective behavioral and neuroimaging data in the preoperative evaluation and planning for DBS in PD.

NIH Research Projects · FY 2026 · 2021-12

The ability to make sense of sound relies, in some measure, on the fidelity with which the temporal information within that sound is encoded in the auditory system and interpreted by the brain. One facet of hearing where temporal processing plays an important role is spatial hearing. Good binaural hearing confers advantages such as spatial release from masking, which is the benefit to masked speech intelligibility of separating the target and masker speech sources in space. Older listeners – even those with ‘near-normal’ hearing – tend to have compromised binaural temporal processing and exhibit less binaural advantage. Determining the factors that underlie this is key to understanding the constraints on the abilities of older listeners to communicate and function in the spatially and acoustically complex soundscape of our every-day environment. The purpose of this project is to obtain a comprehensive characterization of the spatial hearing abilities of adults across a wide age range, with a particular emphasis on differentiating effects of age and hearing loss. This will have particular relevance to understanding the hearing difficulties of older listeners with otherwise ‘near-normal’ hearing. Specific Aims focus on binaural temporal processing and spatialized speech-in-speech recognition, particularly under dynamic conditions. The approach uniquely combines behavioral and electrophysiological measures, and also incorporates the listener’s cognitive profile. The findings will advance our understanding of the benefits of spatial hearing, and the dependence of these benefits on the fidelity of temporal information available to the listener. These outcomes will be directly relevant to the public health challenge of addressing the communication difficulties experienced by the burgeoning older population.

NIH Research Projects · FY 2024 · 2021-09

Improving the health outcomes for infants and children has been a national priority in the United States (US) for over a century. Despite great strides in improving perinatal health care and utilization among American women, key perinatal indicators have remained stagnant or worsened, the US continues to rank near the bottom, and racial disparities are persistent. While studies now have gone beyond behavioral and biomedical determinants of health and encompass the social environment, most research still remains focused on the time shortly before or during the pregnancy Improvements in perinatal health will require utilization of frameworks which integrate life-course and multiple-determinant models of health. Though the body of evidence linking the prenatal social environment, particularly maternal stress, and epigenome is growing, little work has yet explored the life course antecedents to the prenatal social environment and the impact on epigenetic methylation or telomere length. Based on our widely embraced framework for perinatal health that marries a multiple determinants model with a life course approach, we will investigate maternal social environmental influences on maternal methylation and telomere length. Change as well as critical periods will be assessed as the maternal social environment over the maternal life course may independently, cumulatively, and interactively impact the maternal epigenomic profile and its changes over the life course. Archived newborn blood spots, available for all pregnant women in this unique cohort of Black births in metro Detroit, will be assayed to determine the presence of epigenetic methylation and telomere length of mothers at their own birth; maternal measures at the index pregnancy will be derived from analogous blood spots collected in our study. Neighborhood level data will utilize both administrative and subjective measures of neighborhood. In addition to determining associations between the maternal social environment and her epigenomic features across her life course, we will endeavor to explore potential pathways linking the social environment and epigenome across the maternal life course with the perinatal outcomes of her offspring. Researchers have recently begun to consider social environmental factors and how they relate to epigenomic features as well as adverse perinatal outcomes. Yet those populations disproportionately affected by these outcomes are grossly underrepresented in genomic studies. Our sample of 1,000 births to Black women, with nearly half expected to women residing in Detroit, will provide a rich source of data on the maternal social environment across the life course and the epigenome. Our team possesses tremendous expertise in the study of perinatal outcomes as well as measures of social environmental factors often overlooked or not modeled in such a way as to provide understanding of mechanisms. Our study will substantially increase evidence about the importance of the maternal social context at multiple points in the life course on her epigenome and birth outcomes in offspring. The work holds promise for significantly increasing understanding about how social factors have influence across generations through epigenetic processes.

NIH Research Projects · FY 2025 · 2021-09

Neurodevelopmental processes are shaped by dynamic interactions between genes and environments. Maladaptive experiences early in life can alter developmental trajectories, leading to harmful and enduring developmental sequelae. Pre- and postnatal hazards include maternal substance exposure, toxicant exposures in pregnancy and early life, maternal health conditions, parental psychopathology, maltreatment, and excessive stress. To elucidate how various environmental hazards impact child development, it is imperative that a normative template of developmental trajectories over the first 10 years of life be established based on a sufficiently large and demographically heterogeneous sample of the US population. To accomplish this, the Healthy Brain and Child Development (HBCD) Consortium has been formed to deploy a harmonized, optimized, and innovative set of neuroimaging (MRI, EEG) measures complemented by an extensive battery of behavioral, physiological, and psychological tools, and biospecimens to understand neurodevelopmental trajectories in a sample of 7,200 mothers and infants enrolled at 27 sites across the United States (US). The HBCD Study will carry out a common research protocol under direction of the HBCD Consortium Administrative Core (HCAC) and will assemble and distribute a comprehensive and well-curated research dataset to the scientific community at large under the direction of the HBCD Data Coordinating Center (HDCC). The overarching goal of the HBCD Study is to create a comprehensive, harmonized, and high-dimensional dataset that will characterize typical neurodevelopmental trajectories in US children and that will assess how biological and environmental exposures affect those trajectories. A special emphasis will be placed on understanding the impact of pre- and postnatal exposure to opioids, marijuana, alcohol, tobacco and/or other substances. To address these broad objectives, the sample of women enrolled will include: 1) a varied cohort that is representative of the US population; 2) pregnant woman with use of targeted substances (opioids, marijuana, alcohol, tobacco); and 3) demographically and behaviorally similar women without substance use in pregnancy to enable valid causal inferences. In addition, the HBCD Study will identify key developmental windows during which both harmful and protective environments have the most influence on later neurodevelopmental outcomes. The large, multi-modal, longitudinal, and generalizable dataset that will be produced for the first time by this study will provide novel insights into child development using state-of-the-art methods. The HBCD Study will inform public policy to improve the health and development of children across the nation. This study is part of the NIH’s Helping to End Addiction Long-term (HEAL) initiative to speed scientific solutions to the national opioid public health crisis. The NIH HEAL Initiative bolsters research across NIH to improve treatment for opioid misuse and addiction.

NIH Research Projects · FY 2025 · 2021-09

Provider recommendations are uniquely powerful in improving health care use. However, primary care teams and healthcare systems experience challenges with clinical communication, and many questions remain unanswered about how to increase the potency of provider recommendations. We propose the P01 Program Project, “Improving Provider Announcement Communication Training (IMPACT).” The goal of IMPACT is to improve clinical communication and health care use among children ages 9-12 years. IMPACT's specific aims are to 1) Identify opportunities to improve clinical communication; 2) Evaluate the impact and cost of clinical communication interventions in cluster randomized clinical trials; and 3) Support implementation of clinical communication interventions in healthcare systems. The IMPACT Program Project's shared theme is amplifying the impact of a Cancer Control Program to improve clinical communication in healthcare systems. The projects will work together to enhance the impact of the Announcement Approach Training (AAT), a clinical communication training for primary care professionals, which received designation as a Cancer Control Program from the National Cancer Institute. Project 1 will establish how to involve the whole primary care team in recommendations for primary care. The project will examine whether optimizing the use of standing orders support increases health care use in clinics receiving the AAT. Project 2 will examine what motivates providers to make clinical recommendations for primary care. The project will establish whether clinic-level financial incentives increase heath care use in clinics receiving the AAT. Project 3 will examine who should facilitate the trainings. The project will establish whether engaging clinical champions in healthcare systems to implement the AAT within their own systems increases health care use. Project 4 will examine which interventions fit systems' resources. The project will examine the budget impact, cost-effectiveness, and population health impact of these interventions in rural and nonrural areas and aid decision makers with a decision support tool to facilitate the adoption of promising interventions. The research projects will receive support from 3 cores: Administrative, Data, and Intervention. IMPACT's activities will culminate with the creation of the Implementation Guide to support improving health care use in healthcare systems. Throughout the proposed Program Project, the shared theme and AAT focus will create synergies among the projects and cores that generate significant and novel insights into how to improve clinical communication and health care use. Our approach will also accelerate the evolution of communication trainings for primary care professionals, accomplishing in 5 years what might otherwise take two decades.

NIH Research Projects · FY 2025 · 2021-09

PROJECT SUMMARY The overall objective of my research program is to define fluid as an integral component of the cellular microenvironment and to better understand how movement of fluid in the microenvironment impacts cell and tissue processes. My laboratory employs a multidisciplinary approach merging microfabrication techniques and microfluidic devices, computational fluid dynamics, and cellular and molecular biology to define the mechanisms by which cells sense and respond to fluid flow. We are specifically interested in how forces from moving fluids impact cell adhesion and effector signaling, and to further our overall goals, we have identified three specific interests: (1) resolving the forces that moving fluids impart on cells, (2) identifying the molecular machinery that transduces these forces into biological responses, and (3) determining how molecular scale transduction is coordinated into a tissue scale response. While my training focused on understanding fluid flow and transport in cancer and the vasculature, my independent research laboratory seeks to focus on tissues and processes in which the effects of fluid transport are not as well defined, with an emphasis on development and morphogenesis. In line with these objectives, over the next five years, the specific goals of my research laboratory are to: (1) engineer cell surface receptors to better understand how the highly conserved Notch family receptors sense fluid flow, (2) map forces and cellular responses to flow through porous media by developing novel, integrated microfluidic and computational approaches, (3) develop a new class of microfluidic devices to recapitulate the native microenvironment using human-derived cells and matrix. The results of this research and the integration of the enabling technologies will contribute to the overall objectives of my research program of defining the scope and general principles of fluid forces in the cellular microenvironment, illuminating the mechanisms by which cells respond to these forces, and providing new tools for broader application among the mechanotransduction community. Furthermore, the technology developed within this proposal will form the basis for developing future disease models for mechanistic and translational applications.

NIH Research Projects · FY 2024 · 2021-09

Abstract Affecting >100,000 persons each year in the United States, primary hyperparathyroidism (PHPT) is a common disorder that leads to significant morbidity. For PHPT patients, surgically removing the affected parathyroid gland is the only curative option. The current state of the art is to use preoperative imaging to locate abnormal parathyroid glands, aiming to perform a focused surgical approach that can limit unnecessary dissection. In addition, localization can reveal abnormal locations of the parathyroid glands outside the neck which can prevent fruitless neck exploration and guide alternative surgical approaches. Despite the progress, current imaging techniques have several limitations on detecting small glands (especially in unusual locations) and multiple abnormal parathyroids (occurs in 15-20% of cases). This application proposes to develop new imaging agents that can efficiently detect parathyroid glands preoperatively, and be used intraoperatively to guide exploration. In detail, we will construct innovative positron emission tomography (PET) agents targeting markers specific for parathyroid glands, and PET/near-infrared fluorescence (NIRF) dual modality agents that seamlessly integrate parathyroid detection and image-guided surgery. This project is built upon our recent advances on radiofluorination, PET probe development and dual modality imaging. In detail, calcium sensing receptor (CSR) is a Class C G-protein coupled receptor that is highly expressed in the parathyroid gland and the kidneys. The development of CSR-specific pharmaceuticals for imaging could potentially lead to novel PET agents that are highly specific for parathyroid (kidneys are located far away from our area of interest, which will not interfere with PHPT detection). The use of a dual tracer (optical and PET) would not only introduce high sensitivity for parathyroid detection, but also facilitate subsequent gland localization during surgery. There are three aims for this project. Aim 1 will develop PET agents for parathyroid imaging based on novel ligands of CSR. Aim 2 will develop a robust radiofluorination method to generate 18F labeled NIRF dyes that could localize at parathyroid gland selectively. Aim 3 will evaluate our lead agents in rodent model bearing transplanted human hyperparathyroidism tissue. The lead agent will be further characterized in nonhuman primates. In our preliminary study, we have successfully introduced 18F (radio tag) into cinacalcet (a small molecule targeting CSR) using photoredox radiofluorination. The resulting agent could be preferentially taken up by parathyroid gland in rats. Initial study in non-human primate also suggested the great potential of using 18F- cinacalcet for parathyroid imaging. In aim 2, we successfully generated 18F labeled NIRF dyes for specific parathyroid and thyroid gland targeting. This approach would address the clinical need by integrating PET with image-guided surgery. In summary, the overarching goal of this multi-disciplinary research is to develop novel imaging agents that are highly sensitive and specific for parathyroid, which would greatly benefit the management of patients with primary hyperparathyroidism.

NIH Research Projects · FY 2025 · 2021-09

PROJECT SUMMARY/ABSTRACT Numerous endogenous agents, environmental carcinogens, and anti-cancer drugs produce bulky base adducts in the genome. It is expected that the location of these adducts is non-random and that their locations dictate their pathogenic or therapeutic effects as well as their susceptibility to DNA repair enzymes that modulate these effects. The long-term goal of our research program is to better understand DNA damage and repair at the genomic level to aid in predicting and potentially preventing DNA adduct-induced carcinogenesis as well as to design efficient chemotherapeutic regimens with minimal side effects. The objective of this particular proposal is to use our novel adductomic-mapping methods (Damage-seq and XR-seq) to locate the exact positions of DNA lesions in the mammalian genome and the exact positions of DNA incisions performed by the nucleotide excision repair enzyme system that removes the DNA damage. The rationale for the proposed research is that mapping damage and repair may reveal unexpected links between environmental carcinogens, mutagenesis, disease and ageing. We will accomplish this goal by carrying out the following three specific aims: 1) Genomic Single- nucleotide Resolution Analysis of DNA Damage by Endogenous Agents; 2) Genome-wide Single Nucleotide Resolution Maps of DNA Damage and Repair by Exogenous Carcinogens; 3) Genome-wide Damage and Repair Maps of Anticancer Drugs. For this proposal, we will focus on identifying the precise locations and removal of DNA base damage formed endogenously (glycosylation, oxidative damage) and damage caused by environmental carcinogens (aflatoxin, diethylnitrosamine) and anticancer drugs (cisplatin, melphalan). Methods that we developed and further optimized for mapping damage formation and repair will be used throughout this work. This proposal is innovative because of these unique sequencing technologies that provide high-resolution DNA sequence information on the formation and repair of damage throughout the entire genome and provide an unparalleled approach for characterizing endogenous DNA damage as well as damage induced by environmental carcinogens and anti-cancer drugs. The proposed research is significant because it will address the question of the role of DNA damage by endogenous agents (glycosylation) of various tissues and its overall contribution to aging by these methods developed in our laboratory which have unprecedented sensitivity for genome-wide mapping at single nucleotide resolution in different organs. In addition, the proposed research will expand our understanding of DNA damage formation and repair in the human genome at an unprecedented level of detail regarding genomic damage formed endogenously and by environmental carcinogens and anticancer drugs. Ultimately, this knowledge has the potential to improve the prevention strategies for environmental carcinogenesis and to lead to the development of new tools for diagnosing and treating cancer.

NIH Research Projects · FY 2025 · 2021-09

Dental health benefits of fluoride in drinking water have never been tested in a randomized controlled trial (RCT). Instead, results from observational studies and a few non-randomized, community intervention studies were sufficient to justify addition of fluoride to many public water systems during the 20th century and to defend against fluoridation’s critics. However, growth in fluoridated public water systems has stalled, leaving 100 million Americans living in places that do not have fluoridated water and which probably never will. A related problem is that, nationwide, 15% of children do not drink tap water for reasons ranging from consumer preference to distrust of public water. One solution, capitalizing on consumers’ demand for bottled water, is to increase consumption of fluoridated bottled water. However, RCT evidence of dental health benefits of fluoridated bottled water will be essential if public health is to embrace it as a strategy to extend fluoridation. In the absence of a precedent, and in the face of uncertainty as to compliance and likely effect size of the intervention, a fully powered RCT is premature. We instead propose a phase II, proof-of-concept RCT to evaluate dental caries preventive effects of fluoridated bottled water in a community not served by water fluoridation. The primary recruitment population is ~470 babies born during a one-year period in Kinston, NC, the state’s community with the largest non-fluoridated public water system where caries prevalence exceeds the state average. In households where measured content of fluoride in tap water is <0.2 ppm, we will randomize 200 infant/family dyads in a 1:1 ratio to receive either fluoridated or non-fluoridated bottled water. The two types of commercially water in 5-gallon bottles will be relabeled to mask infants, families and researchers as to the fluoride content. For 3½ years after randomization, each household will be provided with water, dispensers and other supplies to encourage water consumption consistent with nutritional recommendations. Bottled water consumption will be monitored and fingernail clippings collected to provide a biomarker-measure of fluoride intake. A dental examination conducted when children are aged 48?3 months will measure caries experience using the index of decayed, missing and filled tooth surfaces (dmfs). Statistical analysis will compare mean dmfs between study-groups to generate effect size estimates and standard errors needed to calculate sample size requirement for a future, multi-site, Phase III RCT. The investigative team has a strong record of accomplishment in observational and interventional studies of dental caries in children, and is experienced in work needed to plan (during the UG3 phase) and conduct (during the 5-year UH3 phase) the study as required by PAR-18-547. Local, state and national stakeholders have expressed support for the proposed study, noting its potential to improve oral health in underserved communities. By applying the rigor of a placebo-controlled RCT design, the study will address a serious shortfall in the evidence that hampers the nation’s primary public health strategy for dental caries prevention.

NIH Research Projects · FY 2024 · 2021-09

Cystic fibrosis (CF) lungs exhibit mucoinflammatory responses soon after birth, likely triggered by viral infections and/or aspiration. Respiratory syncytial virus (RSV) causes bronchiolitis leading to airway muco- obstruction in young CF children, who exhibit increases in MUC5B and MUC5AC mucins in their airways. Because no treatments are available for CF airway mucus overproduction, there is a clear unmet medical need for therapies that target mucin synthesis in CF airways. CF airway epithelial inflammation triggers endoplasmic reticulum (ER) stress and activates the inositol requiring enzyme 1 (IRE1), which exists in two isoforms, α and β. IRE1α is ubiquitous, but IRE1β is only expressed in mucous cells of the respiratory and GI tracts. We have shown that IRE1β (but not IRE1α) is required for airway mucin production. IRE1 is an ER transmembrane protein with a lumenal domain (sensor of unfolded proteins) and a cytoplasmic domain (effector) with kinase and RNase activities. It is unknown whether the IRE1 lumenal domain senses unfolded mucins and whether its cytoplasmic domains mediate mucin production; however, our previous studies suggested that mucin production triggers ER stress and activates IRE1β kinase-induced RNase activation. Because the activated IRE1 RNase splices the mRNA of X-box binding protein-1 (XBP-1s), a transcription factor that up-regulates mucin production, this may provide a mechanism for CF airway epithelial mucin overproduction. In non-mucous cells, IRE1 kinase activates JNK, p38 MAP kinase and NF-B via protein interactions, but it is unknown whether the IRE1 kinase activates these pathways, which are relevant to CF airways because they can promote mucin production. Our preliminary data indicate that IRE1β, MUC5AC and MUC5B levels are up-regulated in native CF human airways and in freshly isolated CF human distal airway epithelia. Over-expression of wild type IRE1 in primary human bronchial epithelia (HBE) increased mucin production, whereas over-expression of IRE1 mutants that lack kinase and/or RNase activities decreased mucin production. IL-1 and TNF, predominant CF airway cytokines, differently affected XBP-1s (only IL-1 increased XBP-1s) and mucin production (IL-1 > TNF) in HBE, suggesting that they up-regulate mucin production via IRE1β RNase-dependent and independent mechanisms. KIRA6, an IRE1 kinase + RNase inhibitor, blunted IL-1-increased XBP-1s and mucins in CF HBE. Notably, a combination of CFTR modulators (VX-445, VX-661 and VX-770) had no effect on mucin production. RSV infection of HBE increased XBP-1s and mucin production/secretion, and these responses were blunted by KIRA6. Finally, murine parainfluenza virus type 1-infected mice developed viral bronchiolitis and airway muco-obstruction, modeling the bronchiolitis in CF infants infected by RSV. Our aims will test the role of IRE1β protein domains in CF airway cytokine-increased mucin production in CF HBE. We will also evaluate the therapeutic effect of IRE1β inhibition on respiratory virus infection-induced mucin production in CF HBE and murine airways, including a CF mouse. Our studies may lead to the generation of IRE1β inhibitors as novel therapeutics for CF airway muco-obstruction.

NIH Research Projects · FY 2025 · 2021-09

Autism spectrum disorder (ASD) has historically been diagnosed at a rate of four males to one female. Autistic females are diagnosed later than males and present with a nuanced profile of strengths and weaknesses that vary by developmental stage. In early childhood, our team, and others, have identified social motivation (SM) and restricted and repetitive behaviors (RRBs) as features that distinguish autistic males and females, with females showing greater SM and different patterns of RRBs. These relative strengths have been hypothesized to be potential mechanisms underlying autistic camouflage. However, camouflaging is also associated with detrimental outcomes, including poorer mental health. No study has charted sex-specific developmental trajectories in autism during early childhood. As such, representative, longitudinal studies are required to elucidate the developmental and etiological significance of previously observed sex differences (social motivation, RRBs, adaptive behavior, executive functioning, mental health) and to characterize early markers of camouflaging in childhood. We will conduct an Accelerated Longitudinal Design (ALD) across two sites (UNC and CHOP) in a sample of 140 neurotypical (NT) and 140 autistic children, equally split by sex, aged 4 to 8, recruited in 5 cohorts and studied over four timepoints. ALDs have been identified as a promising methodology to study development in ASD and recruit hard-to-reach groups. This multi-site effort will enable us to recruit sufficient autistic females to examine age- and sex-linked developmental trajectories. Our team is uniquely positioned to study how sex impacts the trajectories of young autistic children across domains (SM, RRBs, executive functioning, adaptive behavior, mental health) through multimodal measures (parent-report, direct observation, eye tracking) that can probe the mechanisms that underlie cross–sectionally observed sex differences in ASD. Our study has three aims designed to evaluate the impact of biological sex on developmental trajectories of young autistic children and NT controls. In Aim 1, we will probe phenotypic and mechanistic sex differences over time, focusing on SM and RRBs using across measurement modalities. In Aim 2, we will examine potential early sex differences in key areas of adaptive behavior, executive functioning, and mental health. In Aim 3 (exploratory), we will analyze the emergence of behavioral markers of camouflage (linguistic, gestures, smiling). This R01 project will chart the dynamic interplay between emergent ASD symptomology, sex, and development across early childhood. Our findings will inform sex-sensitive screening protocols and provide evidence for targeted supports to better address the needs of young autistic females.

NIH Research Projects · FY 2025 · 2021-09

PROJECT SUMMARY Candidate: Tessa M. Andermann, MD, MPH is a fellowship-trained Infectious Diseases specialist who has been involved in patient-oriented research throughout her medical training. As an Assistant Professor of Medicine at UNC, she has specific interests in translational research and is invested in precisely tracking the development and dissemination of antibiotic resistant organisms in immunocompromised patients in order to prevent untreatable infections. The specific training objectives for the proposed award include gaining expertise in: 1) applying next-generation sequencing technologies to characterize antibiotic resistance genes in gut flora, and 2) designing clinical studies to prevent infections with multidrug-resistant organisms in patients with cancer. Her expert team of mentors include Drs. Jonathan Juliano, MD, and Anthony Fodor, PhD. Environment: As one of the nation's premier research institutions, the University of North Carolina provides an optimal environment for the proposed research. The Division of Infectious Diseases is home to a number of extremely accomplished basic, clinical, and translational research scientists; within the Division, there is active work investigating antimicrobial resistance that will provide Dr. Andermann ample guidance and leadership. The UNC research community's collegial nature is demonstrated in the seamless incorporation of experts in cancer, the gut microbiome, and microbial genomics with whom Tessa has developed the necessary relationships to accomplish the proposed research. UNC, in kind, has demonstrated its support of Tessa's research career by providing the salary support that allowed her to develop this current proposal. Research: Patients undergoing hematopoietic stem cell transplantation (HCT) whose gut flora are colonized with antibiotic-resistant bacteria have a higher frequency of bloodstream infections (BSI), and an increased mortality. Despite the significant burden of antimicrobial resistance (AMR) in this population, knowledge of how antibiotic-resistant bacteria develop and disseminate in patients is limited. Prior studies in HCT recipients have not yet investigated the acquisition and transfer of AMR genes within and between gut bacteria that may contribute to infection. The overarching goal of the proposed research is to assess the impact of gut AMR gene dynamics on the risk of systemic infections using novel sequencing technologies. The specific aims are to determine: 1) the timing of AMR gene acquisition relative to transplant, 2) the extent of AMR gene transfer and dissemination between bacteria in the gut, and 3) the relationship between AMR gene burden and BSI risk after HCT. To accomplish this, next-generation sequencing will be performed on stool samples from 70 HCT recipients at two different institutions. We hypothesize that the increased antibiotic resistance gene burden in the gut resistome after transplant is due primarily to expansion of pre-transplant AMR genes and is associated with an increased risk of BSI after HCT. We expect that this research will yield a greater understanding of how antimicrobial resistance develops in gut bacteria that can be used to prevent infections in patients with cancer.

NIH Research Projects · FY 2025 · 2021-09

Abstract Low bone mineral density (BMD) during adolescence is associated with fractures in adolescence and adulthood as well as increased risk of osteoporosis, a chronic bone disease affecting more than 10 million older adults in the U.S. The majority of Americans are exposed to perfluoroalkyl substances, phthalates, and organophosphate esters, synthetic endocrine disrupting chemicals (EDCs) that have adverse skeletal effects in laboratory studies. In humans, these EDCs are associated with lower BMD in limited cross-sectional studies and prospectively associated with lower BMD at age 12 years in our preliminary data. However, few studies have assessed relationships of EDCs with bone health in adolescence, a period of rapid bone mineralization that may be highly sensitive to environmental exposures and is strongly predictive of adult BMD. Therefore, the overarching objective of our proposal is to determine whether exposure to individual EDCs or their mixtures causes reduced bone accrual and strength in adolescence. We will address our aims within the Health Outcomes and Measures of the Environment (HOME) Study, a prospective birth cohort study of mothers and their children enrolled in Cincinnati, Ohio. The HOME Study has amassed detailed longitudinal exposure biomarker measures and covariate data on participants from gestation through 12 years of age. We will conduct a new follow-up visit of 225 participants at approximately 17 years of age to measure EDC biomarkers; perform detailed skeletal assessments; and collect information on diet, physical activity, anthropometry, and pubertal status. Using these data, we will determine whether EDC exposures are associated with peripheral quantitative computed tomography measures of volumetric BMD, bone geometry, and strength strain index at age 17 years (Aim 1); dual-energy X-ray absorptiometry measures of areal BMD at age 17 years and rate of aBMD accrual from age 12 to 17 years (Aim 2); and fracture history at age 17 years (Aim 3). We will elucidate the impact of lifetime cumulative EDC exposures and identify periods of heightened susceptibility by applying sophisticated statistical approaches including Bayesian and lagged kernel machine regression and latent profile analysis. This work will inform the development of targeted interventions for optimizing bone health in adolescence with the long-term goal of reducing risk of fractures and osteoporosis throughout life.

NIH Research Projects · FY 2025 · 2021-09

ABSTRACT More than 63% of US adults are employed, and work exerts an independent, powerful influence on their health. At UNC Chapel Hill, our recognition of the role of work in health has driven our long history of occupational safety and health promotion activities, including surveillance, basic etiology, intervention and translation research, practice, and influence on public policy. As we conducted needs and strengths assessments in preparation for this Center proposal, we saw how the COVID-19 pandemic created a massive re-shaping of work, work conditions, and worker health – particularly related to mental health and well-being among essential workers. This observation created tremendous interest among investigators at UNC Chapel Hill, the NC Occupational Safety and Health Education Research Center, UNC's Center for Health Promotion and Disease Prevention and Injury Prevention Research Center, collaborators at Duke University and UNC Greensboro, and key stakeholders from public and private sectors to join forces to establish a new Carolina Center for Total Worker Health and Well-Being. The mission of the Carolina Center is to generate new knowledge and implement activities to improve worker health and well-being in North Carolina, the southeast region, and the nation. Strong leadership, national experts on our External Advisory Committee (EAC) and at RTI International will work with us to conduct the overall Center evaluation, with a goal of continuous quality improvement that informs strategic planning efforts. Within the Center's Pilot Project Program, we will employ data-driven approaches to prioritize proposals funded, be responsive to emerging issues, and support the work of the four proposed research projects which address three essential worker groups (nurses/physicians, firefighters and childcare) and an under-studied group of LGBTQ workers. Given the current and growing needs we identified, we will focus our attention on mental health and well-being of these workers, as well as traditional occupational safety outcomes such as slips, trips and falls. We will investigate different participatory approaches to engaging with workers and other stakeholders as we move the research enterprise from basic etiology and surveillance, to intervention and translation. Our Center's work directly addresses NORA and TWH Research Agenda priorities with important, innovative research, as well as outreach and education activities that will communicate the benefits of a TWH approach to businesses and key stakeholders, translate our findings and disseminate them to improve policy and practice, and build capacity for TWH among new and current occupational safety and health professionals through the expansion of our existing TWH certificate to non-degree seeking health professionals. As evidenced by enthusiastic letters of support from existing partners at UNC, our EAC members and others in Region 4, and several other TWH Center representatives, the Carolina Center is uniquely positioned to address the challenges of improving worker and workplace health in North Carolina, the southeastern region, and nationally.

NIH Research Projects · FY 2025 · 2021-09

ABSTRACT Projects like The Cancer Genome Atlas (TCGA) have generated a tremendous amount of data characterizing the genomic events in cancer and highlighting the deep complexity and significant heterogeneity that can make precision medicine challenging. Molecular subtyping has helped to identify groups of samples with shared genomic characteristics that can be used for clinical decisions. RNA expression has played a strong role in molecular subtyping over the last twenty years. Integration of RNA expression data with other data types that are being generated as part of the Genome Data Analysis Network have improved our knowledge of tumorigenesis and separating driving events from passenger events. Our team has over a 20 year history of innovation in expression technologies, innovating across generations of assays and projects. We propose to apply our knowledge, experience, and methods to address the projects that will be addressed in this cooperative agreement including clinical trial samples from ALCHEMIST or the Clinical Trials Sequencing Program. We propose to address four specific areas of research including `expression/mRNA analysis', `Spatial genomics data analysis', `data integration', and “clinical outcomes.” We will provide 1) analysis of RNA sequencing and expression data, 2) normalization and analysis methods of spatial transcriptomics data, 3) integrative genomic approaches for cancer classification and characterization, and 4) analysis of biomarkers for association with clinical and other molecular features. We will provide our data to other GDACs and work collaboratively with them to integrate our analyses and generate data for sharing with the larger scientific community through the Genome Data Commons.