University Of Wisconsin-Madison

NIH Research Projects · FY 2025 · 2021-07

We seek continued support of the Waisman Center Intellectual and Developmental Disabilities Research Center, a comprehensive interdisciplinary program focused on IDD spanning the biological, behavioral, and biomedical sciences. The Waisman IDDRC brings together 60 PIs from 24 academic departments from the UW-Madison’s Schools of Medicine and Public Health, Veterinary Medicine, Agriculture and Life Sciences, Letters and Science, Education, Engineering, Social Work, and Human Ecology. This application requests support for an Administrative Core (Core A), providing scientific leadership, program and faculty development, facilitation of interdisciplinary collaboration, oversight of training programs, biostatistical and bioinformatics expertise; and dissemination of knowledges and best practices; and three innovative scientific core services: Clinical Translational (Core B), providing services, resources, and training in the recruitment of human participants, clinical research coordination/navigation, clinical assessment, behavioral methods development, and production of clinical grade biotherapeutics for use in clinical trials; Brain Imaging (Core C), providing access to state-of- the-art neuroimaging instrumentation for both human and animal studies (3T MRI, PET, and microPET scanners for human, non-human primate, and rodent scanning, an fNIRS, and an EEG recording system), as well as expertise and tools for image acquisition and analysis; and IDD Models (Core D), providing resources, expertise, and technical services in cellular and molecular neuroscience, the generation and manipulation of human pluripotent stem cell (hPSC) lines from humans with IDD conditions, as well as the generation and behavioral phenotyping of mutant or genetically engineered strains of mice and rats as models of IDD conditions. In addition, we request support for a Research Project that addresses a fundamental question on the emergence of ADHD symptoms in children with ASD, using a multidisciplinary approach that combines the power of neurobehavioral, brain imaging, statistical genomics, and machine learning analyses. We propose to provide core support to 69 research projects headed by 44 PIs addressing three broad themes relevant to IDD: 1) neurodevelopment and mechanisms, 2) disorders of the nervous system, and 3) assessments and interventions. Collectively the core services and the research project of the Waisman Center IDDRC will stimulate new interdisciplinary IDD research and enhance existing IDD investigations, with a sharp focus on discovery, prevention, and treatment for IDD conditions, and improvement of the quality of life of individuals with IDD and their families.

NIH Research Projects · FY 2025 · 2021-07

PROJECT SUMMARY / ABSTRACT Investigation of cytoplasmic-to-nuclear (C→N) NF-κB signaling pathways induced by various cell surface receptors has significantly expanded the knowledge regarding the role of this transcription factor family in regulating immune/inflammatory responses and tumorigenesis. By contrast, the physiological role of DNA damage-induced nuclear-to-cytoplasmic (N→C) NF-κB signaling remains poorly understood. The proposed study will fill this knowledge gap by elucidating a surprising and crucial role of N→C NF-κB signaling in sustaining anti-tumor CD8 T cell responses during radiotherapy (RT) in vivo. The current proposal utilizes a genetically modified mouse model that selectively disables N→C NF-κB signaling in vivo. Our preliminary data show that radiation therapy can induce sustained regression of syngeneic tumors in a manner dependent on CD8 T cells. We also found that a special type of memory CD8 T cells implicated in tumor control is expanded in this mouse model. Finally, we have generated an encouraging data with an NF-kB DNA binding inhibitor to induce sustained tumor regression following radiation therapy. Based on these observations, we hypothesize that inhibition of N→C NF-κB signaling in the host improve radiation therapy via generation of tumor antigen-specific memory CD8 T cells. We will test this hypothesis by define the cellular mechanism of sustained tumor control mediated by inhibiting host N→C NF-κB signaling in radiation therapy (Aim 1), elucidate the molecular mechanism of sustained tumor control mediated by inhibiting host N→C NF-κB signaling in radiation therapy (Aim 2) and target host N→C NF-κB signaling with a chemical inhibitor to improve radiation therapy (Aim 3). The proposed study is significant because the physiological role of N→C NF-κB signaling in modulating host tumor response is completely undefined and this study will fill this knowledge gap. It is innovative because a new mouse model and a novel chemical inhibitor currently undergoing Phase 2 clinical trials will be employed. Finally, a high impact is expected because chemical targeting of N→C NF-κB signaling by the above inhibitor may expedite timely translation to clinical trials.

NIH Research Projects · FY 2025 · 2021-07

ABSTRACT Human Papilloma Virus (HPV) causes nearly 5% of all cancers worldwide and is implicated in 95% of cervical and 70% of oropharyngeal cancers (OPC). Curative platinum-based chemoradiation is the standard of care for patients with locally advanced cervical and OPC but patients with cervical cancer have significantly worse survival despite sharing the same viral etiology. Thus, there are significant differences in the radiation response between, and within, these two HPV+ cancers yet we continue to treat all patients similarly without consideration of individual tumor biology. Patients with HPV+ and HPV- cancers are also treated identically despite the significantly worse outcome of HPV- cancers in both sites. It is therefore imperative to gain a better understanding of tumor biology in order to tailor radiotherapy to improve patient outcomes and minimize toxicity. Chromosomal instability (CIN) is an ongoing rate of chromosome missegregation events over the course of multiple cell divisions, and when increased beyond a certain threshold can lead to cell death due to loss of both copies of one or more essential chromosomes. We, and others, have shown that very high levels of CIN are associated with cell death, tumor suppression, and improved prognosis in certain cancers. Moreover, combining two sources of CIN can increase it beyond the viable threshold resulting in cell death. Because both HPV and radiation induce certain types of CIN, I hypothesize that cells with pre-existing CIN will be more sensitive to radiation. Additionally, both CIN and radiation can induce innate and adaptive immune responses which are expected to affect overall treatment response, but predictive markers and mechanistic insights are lacking. This proposal aims to 1) define the types and extent of CIN caused by different HPV genotypes and viral oncogene levels, 2) determine if pre- existing CIN sensitizes HPV+ and HPV- cells to radiation in vitro, in vivo, and in patient tumors, and 3) determine how CIN affects innate and adaptive immunity in the context of radiation. Together, this proposal aims to determine HPV+ and HPV- tumor intrinsic and extrinsic factors that affect radiation response such that tumor and host biology can be incorporated into radiation treatment paradigms to decrease toxicity and increase cure. Dr. Cosper is a post-doctoral fellow in Radiation Oncology and will use this award to gain expertise in virology, chromosomal instability and immunology, in order to determine biomarkers that allow for personalization of radiotherapy. Dr. Cosper’s mentorship team consists of world-renowned experts in HPV virology (Dr. Paul Lambert), CIN (Dr. Beth Weaver), head and neck cancer radiobiology (Dr. Randall Kimple), and tumor immunology (Dr. Doug McNeel). The academic environment at the University of Wisconsin is superb, with abundant resources and collaborative opportunities. Further mentorship and training afforded by this award will provide Dr. Cosper a unique set of skills that will enable novel translational research to personalize radiation treatment for head and neck and cervical cancer patients and result in transition to a successful independent investigator.

NIH Research Projects · FY 2025 · 2021-07

PROJECT SUMMARY My goal is to become an exceptional tenure track physician-scientist focused on identifying diverse and unexpected cellular factors and pathways that regulate hematopoiesis, and elucidating the molecular mechanisms of their function. This K08 Mentored Clinical Scientist Research Career Development Award would provide me with the necessary support to complete a rigorous and structured training program and establish myself as a successful independent investigator. My proposed research focuses on the transcription factor GATA2, which is critical for emergence of the blood and bone marrow during development and maintenance of the bone marrow stem cell compartment in adults. Clinically, germline mutations in GATA2 cause the poorly understood GATA2 Deficiency Syndrome. I hypothesize that there is a diverse and undiscovered network of proteins that interface with GATA2 to modulate the process of hematopoiesis. To this end, I have developed uniquely effective and specific anti-GATA2 antibodies that react with mouse and human GATA2 and utilized these to identify 153 putative GATA2 interactors in erythroid precursor cells. In this proposal, I plan to establish how these proteins function in GATA2 biology and in human and mouse erythropoiesis. I am supported in these efforts by a team of accomplished investigators and mentors who constitute my Research Advisory Committee: my primary mentor Dr. Emery Bresnick, an international expert in red cell biology, hematopoiesis and GATA factors; Dr. Igor Slukvin, an international expert on induced pluripotent stem cells and their application for basic and applied science; Dr. Jing Zhang, an internationally recognized expert on malignant hematopoiesis; and Dr. Andreas Friedl, Chair of the UW-Madison Department of Pathology and Laboratory Medicine who has guided my career development and organized my recruitment. I will also enjoy technical support from Dr. Ying Ge, Professor of Cell and Regenerative Biology and Director of the Human Proteomics Program at UW-Madison. These studies have the potential to radically expand our understanding of how a small number of transcription factors accomplish the wide variety of functions necessary to successfully establish and maintain a healthy bone marrow. The results will form the foundation for independent studies and future R01 proposals. The mentoring and career development that I receive during the course of this research will prepare me to excel as a physician- scientist and integrate me into the greater hematology community.

NIH Research Projects · FY 2025 · 2021-07

Autism Spectrum Disorder (ASD) is a neurodevelopmental disorder affecting >1.5% of children in the United States. Individuals with ASD experience deficits in social communication along with restricted interests or repetitive behavior. The severity and patterns of symptoms can vary greatly and be lifelong in duration. It is unclear how the presentation of ASD changes from early childhood into adolescence or adulthood. The causes of ASD are also unknown, though substantial evidence supports the contribution of both genetic and environmental factors. Major gaps in knowledge exist because US studies to date have lacked the sample size, depth of data collection, or appropriate life course timing to address important questions. The Study to Explore Early Development (SEED) is now poised to overcome these limitations. SEED is a large case-control study of children ages 2-5 years and their families, implemented across eight states over three phases. SEED collected detailed data on children's core ASD symptoms, cognitive status, and presence of co-occurring conditions in early childhood, along with extensive risk factors related to maternal health and the perinatal environment as well as genomics. The SEED sample includes ~2,044 children with ASD, 1,950 with non-ASD developmental disabilities (DD), and 2,285 population control children (POP), making this the largest etiologic study of ASD in the US. Recent ancillary studies - the SEED Teen Pilot and SEED COVID studies -- will soon add data on adolescent health and the consequences of the pandemic, respectively, for some SEED participants. The work proposed here, SEED Follow-up Studies (SEED FU), will maximize the impact of extant SEED data through analyses that characterize ASD phenotypes and assess the potential interplay between genetic and other risk factors. SEED FU will also facilitate new data collection in middle childhood, adolescence and early adulthood to characterize changes in ASD phenotype across developmental stages, and the associated health, educational, and service needs across the early life course. These data will further enable prospective analyses of associations between early life factors and later childhood through early adulthood outcomes. Studying risk factors in relation to life course phenotypic subgroups may also help elucidate etiologies previously masked in ASD case-control studies. The WI SEED Team in combination with the SEED Network's collaborative infrastructure and extensive extant data resources, will ensure the successful implementation of the SEED FU Study in Wisconsin and contribute to success across the network. SEED is well powered to make significant contributions to our understanding of the complex autism phenotype and identifying factors associated with ASD risk in the population. The knowledge gained by SEED FU will greatly advance our ability prevent adverse developmental outcomes and to support individuals with ASD and their families to ensure optimal wellbeing through early adulthood.

NIH Research Projects · FY 2025 · 2021-07

PROJECT ABSTRACT Perinatal stroke can result in motor impairments, and is one of the major causes of cerebral palsy (CP) diagnosis later in childhood. Because of the rapid development and heightened neuroplasticity in the first years of life, intervention provided earlier rather than later is thought to offer the best chance of recovery following perinatal stroke. However, the evidence for early interventions is lacking, mainly due to the paucity of data regarding brain organization, connectivity and resulting motor development after perinatal stroke in humans. Therefore, in this proposed study, our objective is to perform a multimodal, non-invasive assessment of infant brain and behavioral development over the first two years of life to identify possible bioindicators of recovery and repair which may be targeted by future interventions. Our study design incorporates longitudinal assessment over the first two years of life after perinatal stroke of brain excitability and organization using non- invasive brain stimulation, in addition to neuroimaging and age-appropriate behavioral assessments. We will recruit 50 infants with perinatal stroke from local and regional neonatal intensive care units for assessment at 4 time points up to 24 months of age. Measures of brain excitability and connectivity will be correlated with motor development and possible CP diagnosis to study the trajectory and patterns of recovery over time. If the child has been diagnosed with CP, a trained investigator will also assign a Gross Motor Functional Classification Scale level and a mini-Manual Ability Classification Scale level to predict motor function and plan for care. Ultimately, identifying structure/function relationships discovered in this study will allow development of tailored early interventions, based on individual patterns of brain development, designed to improve life-long motor function in infants with CP due to perinatal stroke, as well as development of early interventions for other related neurologic diagnoses.

NIH Research Projects · FY 2025 · 2021-07

Project Summary/Abstract Individual and household debt plays an increasingly important role in the dynamics of inequality in the United States. However, current data limitations impede scientific understanding of the role of indebtedness in reducing or exacerbating economic insecurity. At best, existing social surveys collect data on a subset of mainstream debts most often encountered by middle-class populations (mortgages, credit cards, auto loans, student loans), while debts common to low-income populations (payday loans, legal debts, past due bills, child support arrears, loans from employers, family, and friends) are less well represented. Without better data, scientific analyses of population health and wellbeing may understate and misidentify crucial sources of economic insecurity and disadvantage, as well as reciprocal effects of debt with poverty, health, and family functioning. This project consists of a multi-pronged data collection and analysis effort to build a stronger data infrastructure, more adequate and accurate measures of indebtedness, and best practices for analyzing various forms of indebtedness and their relation to economic hardship and financial strain for low-income families. The project has three Specific Aims: (1) To conduct qualitative cognitive and developmental interviews with low-income families on their experiences with debt and use these results to develop an enhanced survey instrument that comprehensively and accurately captures low-income debt holding; (2) To field a two-wave pilot study designed to allow comparison of data quality and accuracy when collected via the enhanced instrument versus current ‘gold standard’ instruments (instruments will be randomly assigned); and (3) To analyze linked pilot survey, high-quality administrative (employment, earnings, and benefit receipt), and individual credit report data to (a) document consistency of self- reported debt data collected via each instrument with credit report data; (b) examine whether consistency and differences by data collection instrument differ by respondent financial literacy and sociodemographic characteristics (education, race); (c) estimate associations of types and amounts of debt using the enhanced module, existing modules, and credit report data with economic hardship and financial strain; and (d) investigate the causal order of associations of (the three measures of) debt with economic hardship and financial strain. The study will be the first to provide detailed data on the full range of types and amounts of indebtedness among low-income populations and their associations with hardship and financial strain. By improving data collection and analysis, the study had the potential to identify policy levers that could reduce potential negative effects of debt on disadvantaged families and better target interventions to lessen economic insecurity and improve well-being.

NIH Research Projects · FY 2025 · 2021-07

Abstract The goal of this proposal is to establish whether decreasing fatty acid-binding protein 7 (FABP7) expression ameliorates motor neuron degeneration in amyotrophic lateral sclerosis (ALS) models. The FABPs belong to a family of small (~15kDa) and widely expressed intracellular proteins. All FABPs exhibit high affinity reversible binding of saturated and unsaturated long-chain fatty acids as well as other lipids. FABPs have been considered biologically silent chaperones of fatty acids, but it has now become clear that the FABPs are central regulators of lipid metabolism, energy homeostasis and inflammation. FABPs participate in fatty acid metabolism regulating their uptake and transport but can also regulate signaling processes by distributing and/or sequestering ligands for nuclear receptors such as peroxisome proliferator activated receptors (PPARs). FABP7 (also known as brain lipid binding protein, BLBP) is expressed in neural stem cells throughout development and its expression decreases and becomes restricted to astrocytes and radial-like glial cells in the adult central nervous system. Reactive astrocytes up-regulate FABP7 expression in multiple pathological conditions. To effectively transport and donate bound ligands, FABPs display affinities in the same range or slightly weaker than those exhibited by PPARs. However, up-regulation of FABPs expression can create a “sink effect”, negatively regulating the availability of endogenous ligands for PPARs (i.e., increased intracellular levels of FABPs will result in decreased PPARs activation). PPARs govern the expression of genes involved in coordinating metabolic and inflammatory pathways in the cell. Thus, decreased PPAR activity can contribute to altered lipid-mediated signaling and NF-kB activation, two prominent features of ALS- astrocytes. Our data show for the first time that FABP7 up-regulation may be responsible for the decreased PPAR activity and concomitant increase in NF-kB activity in ALS-astrocytes. Using cell culture and mouse models we will evaluate the hypothesis that decreasing FABP7 expression should restore normal activity of these two interconnected networks and can potentially provide protection against astrocyte-mediated motor neuron death in ALS models.

NIH Research Projects · FY 2026 · 2021-07

Project Abstract Dry mouth is a significant side-effect of radiation therapy for head and neck cancer patients. Several factors contribute to dry mouth. Decreased production of saliva is called hyposalivation. Poor quality and function of saliva is called salivary dysfunction. Together, these cause xerostomia, or what a patient experiences as simply dry mouth. Xerostomia can lead to tooth decay, infections, difficulty speaking, impaired swallowing, poor nutrition, and has a significant negative effect on quality of life. Doctors recommend that patients suck on hard candy, chew gum, use saliva substitutes, and/or always carry a water bottle with them. None of these are particularly effective. Our long-term goal is to improve outcomes for patients suffering from radiation-induced dry mouth. We seek to achieve this goal by providing convincing evidence that innovative cellular therapies can safely and significantly improve salivary gland function and quality of life. The team of investigators tackling this project is uniquely suited to complete the work. Success would lead directly to the next phase of clinical testing. We have expertise in caring for head and neck cancer patients, developing bone marrow derived mesenchymal stromal cells (MSCs) as cellular therapies, and studying salivary function. The overall objective of this application is to complete a Phase 1 trial to test the safety and tolerability of IFN-g pre-licensed MSCs for treatment of radiation- induced xerostomia in head and neck cancer patients. To achieve our goals, we propose an extension of our prior funding to complete the work proposed in our prior NIH UG3/UH3 award. Due to request of the FDA to extend follow-up of patients through two years post-treatment, and delays due to manufacturing supply constraints, we are requesting additional years of funding to support completion of our trial. Our ongoing study sought to define a recommended phase 2 dose via a dose escalation trial and to confirm the safety profile, better describe the toxicity, and investigate the efficacy of MSC injection to treat radiation-induced xerostomia via a 12- patient dose-expansion cohort. We have successfully completed the dose escalation cohort and are nearing the completion of our dose-expansion cohort. We will assess the efficacy using both validated patient-reported outcome measures and through assessment of salivary production and composition. This trial is expected to provide key data used to design the next clinical trial. A phase 2/3 study that would further test the efficacy of MSCs in head and neck cancer patients. These studies will also provide important data to support future grant applications aimed at improving the salivary response through ex vivo engineering of MSCs.

NIH Research Projects · FY 2025 · 2021-07

Project Abstract: Patient-derived model systems are commonly used to study tumor biology and test novel treatments for head and neck cancer. These models are established using patient tumors sourced from surgical specimens and typically implanted into the subcutaneous tissue of the mouse. There is little data available to support the decisions we make during the initial handling of the tumor samples and, most importantly, how these decisions impact the results of subsequent studies. Our long-term goal is to improve outcomes for head and neck cancer patients using valid, predictive, and well characterized model systems. The overall objective of this application is to improve our use of these mammalian model systems by understanding the impact of choices we make when we establish them. By combining innovative approaches to study cancer evolution with rigorous assessment of tumor biology and therapy response we hope to ultimately improve the relevance of studies using these mammalian models to improve the care of human patients. Our central hypothesis is that the approach used to establish patient-derived xenografts has a critical impact on their relevance as translational models. To achieve our goals, we proposed three aims. In Aim 1, we will determine the role of heterotopic vs. orthotopic implantation on the biology of the tumor, how patient-derived animal models change with increasing passage in animals, and how these factors impact tumor evolution. In Aim 2, we will test the concordance of response between patient derived models and patients by using patient derived xenografts established as part of an ongoing (and separately funded) window-of-opportunity trial and will assess consistency in response to standard treatments over time. In Aim 3, we will use an innovative humanized mouse model developed at Wisconsin to assess the evolutionary interplay between the tumor and immune system, understand whether these novel mice replicate the tumor/immune interface seen in human cancers or in syngeneic HNC models, and investigate how well the response to immunotherapy replicates that seen in patients. In summary, these studies will provide compelling evidence for how to optimize our use of mouse models of human head and neck cancer. Completion of this project will provide robust evidence delineating and refining best practices for the translational use of patient derived xenograft animal models of head and neck cancer.

NIH Research Projects · FY 2025 · 2021-07

The Medical Scientist Training Program (MSTP) at the University of WisconsinMadison (UW-Madison) aims to train and prepare future leaders and physician-scientists in clinical medicine and biomedical research. Our program trains students across numerous fields, with a curriculum and training plan that is continuously improved through metrics, critical self-assessment, and student input. Guiding principles of our program include: (1) a rigor and caliber of both MD and PhD training equivalent to single-degree candidates; (2) continuous mentoring from program leaders, faculty, and peers; and (3) training in translational research for all students. The four program directors are all physician-scientists and each is active in research, graduate training, and clinical activities. The student government works closely with the directors on recruitment, seminars, advising, curriculum, and continuous improvement. Students begin with the preclinical phase of medical training, along with a 3-semester MSTP-specific Integrated Molecular Medicine (IMM) course series, led by the directors. IMM introduces new trainees to research methodologies, scientific writing, responsible conduct of research (RCR), rigor and reproducibility (RRT). Students then proceed through clinical clerkships in the ForWard curriculum before beginning the Ph.D. thesis. Ph.D. mentor selection is made in consultation with program leaders. Oversight of research rigor and Ph.D. mentorship is directly assured by an MSTP director on each thesis committee. An integrated Longitudinal Clinical Experience spans the Ph.D. years. After defending the Ph.D. thesis, trainees enter the final year of medical training, which includes the mentored Clinical Translational Research Elective (CTRE), custom-designed for MSTP trainees. CTRE is a 6-week preceptorship with both clinical and research facets and an additional physician-scientist faculty mentor. The integrated curriculum allows students to complete dual degree training in 7-8 years, with a minimal gap between intense research activities and postgraduate training. A majority of student theses are in the biological, chemical, population or engineering sciences, yet others select allied programs of study including clinical investigation, a program integrated with our Clinical Translational Science Award (CTSA). Additional activities foster program cohesiveness and encompass continuous training in RCR and RRT via weekly seminars, our annual retreat and yearly symposium. RELEVANCE: Trainees receive integrated training in clinical medicine and research and are awarded both M.D. and Ph.D. degrees. Through an innovative integrated physician-scientist curriculum, the graduates of our program are poised for research-intensive careers that integrate rigorous basic and translational research and clinical care.

NIH Research Projects · FY 2024 · 2021-07

ABSTRACT Venous thromboembolism is a major global health and economic burden with about 10 million cases occurring every year, and a high lifetime risk of 8% after age 45 years. Pulmonary embolism (PE) is a venous thromboembolic event associated with high morbidity and mortality, with about 20% incidence of death before diagnosis or shortly thereafter. Most recently, the COVID-19 pandemic has contributed to a marked increase in patients presenting with acute pulmonary thromboembolic disease, most likely created when the infectious vasculitis involving the endothelium creates local arterial thrombosis and subsequent lung infarction, with a superimpose hypercoagulable state that promotes clot formation. In these patients, it is increasingly being recognized that pulmonary perfusion abnormalities associated with the lung consolidations and ground-glass opacities are important predictors of poor prognosis. Currently, pulmonary CT angiography (CTA) has become the preferred method for diagnosing PE and planar lung ventilation/perfusion (V/Q) scintigraphy is used in cases when pulmonary CTA is contraindicated. A compelling unmet clinical need is to develop a method for simultaneous pulmonary CTA and parenchymal perfusion assessment without the use of two modalities like CTA and SPECT perfusion in the same patient. In this project, an imaging physics-based deep learning method will be developed to extract the previously overlooked spectral information inherently encoded in the acquired contrast enhanced CT projection data. As a result of this breakthrough, this new spectral CT imaging method, referred to as Deep-En-Chroma, will be developed and validated for perfusion defect quantification in lung parenchyma from the currently available pulmonary CTA. This will be accomplished without the need for any expensive dual energy CT (DECT) hardware upgrades that have been commercialized by major CT manufacturers. In summary, upon the completion of this project, a new functional CT imaging method will have been developed, that in addition to providing the currently available pulmonary CTA images, will also detect perfusion defects in lung parenchyma without the requirement of high-end DECT hardware.

NIH Research Projects · FY 2025 · 2021-07

Program Summary The main objectives of Graduate Training in Molecular and Cellular Pharmacology (GTMCP) at the University of Wisconsin (UW)-Madison are to provide predoctoral-level training in interdisciplinary research at the forefront of quantitative and systems pharmacology and a nucleus around which interdepartmental faculty, students, and scientists from across campus can meet and collaborate. Its overall mission is to provide a highly diverse group of trainees with the skills necessary to enter careers related to the Pharmacological Sciences in academia, industry, government, science education, and public policy. Discovering new approaches to drug delivery and developing novel drugs as therapeutics are cornerstones of the program, with a major emphasis on understanding pathways that are relevant to disease. To accomplish these goals, the curriculum focuses on delivering foundational knowledge in Pharmacology, including mechanisms of drug action, pharmacokinetics, and pharmacodynamics, stressing quantitative thinking and the value of -omic technologies. Carefully evaluated coursework centered on the importance of rigor and reproducibility, responsible conduct of research, safety within the laboratory, and grant writing promote the development of trained PhD scientists who can contribute to the biomedical research workforce. A core group of 29 dedicated faculty trainers has been assembled for this application, representing 10 departments, whose interests focus on understanding molecular, cellular, and physiological mechanisms by which drugs or natural ligands interact with cellular receptors and elicit effects in biological systems. All trainers have robust research programs and were selected based on a demonstrated commitment to mentoring graduate students in Pharmacology. Faculty members work in the interdisciplinary areas of Neuropharmacology, Cancer Pharmacology, Cardiovascular Pharmacology, Endocrine Pharmacology, and Immunopharmacology, and collaborate extensively with one another to create a highly interactive network. Each trainer has received extensive mentor training and understands the importance of strong mentor-mentee relationships in establishing an inclusive and supportive research environment. GTMCP leverages strong institutional support and substantial resources to facilitate the professional development of its trainees. Through its well-funded seminar series, all trainees are provided regular opportunities to develop excellent oral presentation skills and invite outside faculty speakers from top institutions across the country. Research retreats and symposia offer additional opportunities for students to host and interact with prominent members of the Pharmacology community and develop networking skills. GTMCP also boasts considerable trainee diversity, a high retention rate, a rapid time to degree, and an excellent record of trainee publications. Ten slots to support trainees for two years of their early graduate education are requested based on the growing demand for PhD- level scientists trained in Pharmacology and the high quality of students that apply to UW-Madison.

NIH Research Projects · FY 2025 · 2021-06

ABSTRACT This proposal presents a five-year research career development program focused on targeting donor liver- resident cells with regulatory properties to decrease rejection after transplantation. I am an Assistant Professor of Surgery at the University of Wisconsin-Madison, with previous research and clinical experience in transplant immunology and transplant surgery involving normothermic ex vivo machine perfusion (NEVLP), whereby an organ is housed under physiologic conditions. The present project will advance the field of transplant immunology by using NEVLP technology to modify the immune cells within the liver prior to transplantation. I have assembled an outstanding mentorship team of investigators with expertise in transplant immunology, dendritic cell biology, and extracellular vesicle biology. The proposed training will guide and enhance my development in core competencies, including transplant immunology, communication, biostatistics, and ethical research design that will enable me to transition to research independence as a surgeon-scientist dedicated to reducing organ rejection in the field of transplant surgery. Liver transplantation is the only treatment option for patients with end-stage liver disease; however, rejection of the transplant can decrease liver and patient survival. In addition, patients still require lifelong use of anti-rejection medications that suppress the immune system. Modification of the donor liver, and the immune cells within it, has the potential to promote acceptance of the liver and minimize the need for anti-rejection drugs. Advances in an innovative technique called normothermic ex vivo liver perfusion (NEVLP) offer a unique opportunity to benefit significantly the 25% of liver transplant recipients that develop acute rejection, as well as many more transplant recipients who would benefit from using fewer anti-rejection drugs. Recent studies have demonstrated the importance of regulatory dendritic cells (DCregs) for prolonging transplant survival. My central hypothesis is that expansion of the number of liver-resident DCregs during NEVLP will promote a regulatory environment for the organ after transplant. Using a rat model of NEVLP and liver transplantation that my research group has optimized, I expect NEVLP to expand DCregs potently, leading to an increase in immune checkpoint molecule expression and production of anti-inflammatory extracellular vesicles and cytokines that can reduce immune-mediated rejection. This innovative approach of expanding graft-resident DCregs to decrease rejection could be used in deceased donor liver transplantation as well as translated to other types of solid organ transplants. To achieve these objectives, I propose the following scientific aims: 1) Determine the dominant regulatory function of liver-resident DCregs after NEVLP, and 2) Measure the impact of expanded liver-resident DCregs generated by combination cytokine therapy during NEVLP on liver graft rejection in vitro and in vivo.

NIH Research Projects · FY 2025 · 2021-06

Broadening Participation in the Biomedical Sciences with Utility Value Interventions ABSTRACT The goal of this program of research is to broaden the participation of first-generation (FG) and underrepresented ethnic minority (URM) students in biomedical fields with utility-value interventions in gateway biology and chemistry classes. Using a theoretically grounded utility- value intervention, PI aims to close achievement gaps for FG students, those for whom neither parent obtained a 4-year college degree, and for URM students. A previously funded large-scale double-blind randomized study in introductory biology courses at the University of Wisconsin- Madison (UW) demonstrated that the utility value intervention (UVI), in which students write about the personal relevance of course material, was successful in reducing the achievement gaps for FG and URM relative to a control condition in which students summarized course content. The proposed research will (1) test whether UVI effects documented at UW can be replicated in different gateway courses and different universities, (2) test whether the UVI can be adapted for a more diverse student sample, and (3) test the long-term effects of the UVI by following students over time through graduation. PI will analyze the results of a recently completed large-scale multi-site study conducted at three sites. Two versions of the UVI and control writing assignments were tested with more than 7,000 students across 10 academic semesters of biology and chemistry in 3 different institutions: UW, University of Maryland, Baltimore County, and San Diego State University. By testing two versions of the UVI across three universities, and following students through graduation, PI can answer three critical questions. First, by testing a new prosocial version of the intervention and comparing it to the established “personal” version, as well as a control group, PI can draw new inferences about the impact of having students reflect on ways that they can use their education in biomedical fields to help others, give back to their community, or make a contribution to society. Second, because PI has collected data from large groups of students from diverse racial/ethnic, socioeconomic, and cultural backgrounds, the data provide the best opportunity to date to test intervention effects for different groups of students in gateway courses. Third, long-term follow-up of students in the multi-site project will help us understand how and why this intervention can be so powerful in broadening participation in the biomedical sciences.

NIH Research Projects · FY 2025 · 2021-06

Project Summary/Abstract The University of Wisconsin Carbone Cancer Center (UWCCC), Duke University and Memorial Sloan Kettering Cancer Center (MSKCC) seek support for establishing the analytical and clinical validity of a Circulating Tumor Cell (CTC) biomarker assay via the UH2/UH3 mechanism. This biomarker assay will evaluate a gene expression signature of treatment resistant, castration-resistant prostate cancer (CRPC). While many patients with prostate cancer benefit from Androgen Receptor Signaling Inhibitors (ARSIs), a subset of patients do not respond to this class of treatments while nearly all others develop resistance within 1-2 years. Identified mechanisms of resistance include development of Neuroendocrine Prostate Cancer (NEPC) and expression of Androgen Receptor Splicing Variants (AR-Vs). Early detection of NEPC or AR-Vs as drivers of treatment resistant prostate cancer would eliminate the need to wait for clinical manifestations of resistance, accelerating the time to administration of more suitable therapy and increasing survival. While precision medicine approaches are increasing in popularity and reliability, their ultimate capacity to improve patient care hinges on their diagnostic accuracy. Realization of a clinically relevant assay requires thorough analytical and clinical evaluation, and while many biomarker assays have successfully demonstrated analytical performance, failure to address clinical utility has left many unable to improve on existing diagnostics. By focusing our efforts on evaluation of both analytical and clinical validity, we aim to provide diagnostic accuracy in assessing an expression of NEPC and AR-Vs, building a necessary foundation for future clinical trials. To that end, we have optimized a multi-plexed gene expression assay on CTCs, that identifies these two major categories of resistance to ARSIs. This assay has shown promising initial results in a preliminary cohort of patients with aggressive CRPC. Optimization of this assay has taken into consideration the rarity of CTCs and the diversity of other blood cells in circulation; ensuring efficient RNA extraction, probe specificity, and appropriate data interpretation. The manipulation and retention of rare cells is enabled by our Exclusion-based Sample Preparation (ESP) technology, wherein centrifugation and wash steps are eliminated. This automated and commercially available platform, also called the Gilson ExtractMax, offers minimal user variability, thus maximizing precision. Our collaboration with Dr. Kaitlin Sundling at the Wisconsin State Lab of Hygiene, a CAP- approved clinical testing laboratory, provides expert oversight for planning and execution of analytical validation. In collaboration with Dr. Andrew Armstrong, Dr. Susan Halabi and Dr. Dana Rathkopf, we have assembled a team of clinical researchers and biostatisticians to rapidly validate this multi-plexed biomarker in a prospective study. This RNA-based CTC assay shows potential for identifying treatment resistant prostate cancer in preliminary studies of patients and is thus poised for success in both analytical and clinical validation.

NIH Research Projects · FY 2026 · 2021-05

Project Abstract Overview: This project aims to develop a reliable 18F-fluorodeoxyglucose (18F-FDG) PET/MRI method with novel metal artifact correction techniques to provide early identification of prosthetic complications causing persistent postsurgical pain (PPSP) following total hip arthroplasty (THA). Relevance: THA is one of the most rapidly growing procedures to treat the end-stage hip joint pain and dysfunction, and its annual cases are estimated to reach 572,000 by 2030. Unfortunately, a substantial number of patients experience PPSP after the procedure, which, without proper treatment, can significantly impair the quality of life. However, the early identification of pain generators for these patients is very difficult because the current diagnostic methods including X-ray, CT, and MRI, have limited sensitivity to pain and suffer from severe artifacts induced by metal in prostheses. Therefore, there is a pressing need for a novel diagnostic approach to accurately identify the abnormal inflammatory changes causing persistent pain to guide the appropriate treatment matched to the exact sources of pain. Approach: We propose the use of 18F-FDG PET/MRI for early identification of sources of PPSP following THA. Our previous 18F-FDG PET/MRI study of chronic pain syndromes demonstrated promising improvements in detecting sites of painful inflammation. However, the severe metal artifacts near metallic prostheses limit the application of 18F-FDG PET/MRI to THA patients. Therefore, our first aim in this project is the development of metal-aware attenuation correction for PET to enable reliable 18F-FDG PET near the metallic prosthesis. Our second aim is the development of high-resolution hip MRI at 3T with metal artifact correction to improve our ability for identifying structural causes of PPSP symptoms. Our third aim is to validate the improvements by 18F- FDG PET/MRI in detection of the pain generators compared to PET/CT and conventional MRI. This will be accomplished by correlating the pain score measurements with 18F-FDG PET/MRI abnormalities at 6 months, 12 months, and 18 months following the unilateral THA procedure. Summary: We propose to develop a novel 18F-FDG PET/MRI approach with metal artifact correction methods for early detection of periprosthetic complications causing PPSP following THA. Successful implementation of our method will enable early indication of individualized, effective treatments for THA patients with PPSP.

NIH Research Projects · FY 2025 · 2021-05

PROJECT SUMMARY / ABSTRACT Estrogen receptor-alpha (ER), a member of the nuclear receptor family of transcription factors, drives proliferation of breast cancer cells and is expressed in the majority of breast cancers. Tumors that express ER account for the greatest number of breast cancer associated mortalities. While targeting the ligand- dependent functions of receptor is a successful approach in the clinical management of breast cancer, ER can be activated by other means. This alternative activity of ER can promote ligand-independent properties and our lack of understanding of this activity creates a barrier to the clinical challenge of therapy resistance. We have found that phosphorylation of ER can modulate the regulation of multiple aspects of ER biology in tumor cells, including its fate and transcriptional function, in some cases leading to ligand-independence and resistance to therapy. We recently described a genome-wide DNA binding (i.e. cistrome) analyses of phosphorylated ER, specifically phosphorylation at Ser 118, and found that it has unique properties, including a novel association with Grainyhead-like protein 2 (GRHL2), a developmental transcription factor that has since been recognized to play a role in breast cancer. Based on these novel findings and additional preliminary data, we hypothesize that pS118 and GRHL2 identify selective activities of ER that are necessary for growth of therapy-resistant tumors. Toward addressing this hypothesis, we developed three lines of research. Aim 1 exploits our cistromic analysis of pS118ER and a unique cohort of patient tumor samples to define, for the first time, the pS118ER activity in ER+ therapy-resistant tumors. Aim 2 will test the requirement for pS118ER and GRHL2 in growth and malignant phenotypes in cells bearing ER mutations, a genetic form of therapy resistance. This aim will use newly derived CRISPR edited cell models. Aim 3 will use novel DNA technologies to interrogate mechanisms of pS118ER and GRHL2 interactions on DNA and to develop DNA-targeting selective inhibitors. Collectively, these three aims will employ patient samples, in vitro and in vivo approaches and unique technologies to interrogate how a post- translationally modified variant of ER contributes to the aberrant ER activity in recurrent tumors.

NIH Research Projects · FY 2025 · 2021-05

Project Summary/Abstract Eukaryotic genome duplication requires that each chromosomal base pair is copied efficiently, accurately and only once per cell division, a monumental demand given the millions to billions of base pairs that comprise eukaryotic genomes and the countless cell divisions required to form and sustain organisms. Severe defects in DNA replication are incompatible with life. However, mild perturbations in this process, while still capable of supporting cell division, and which can be challenging to identify using biochemical approaches, can compromise development and health over the course of multiple cell divisions. Regulation of the first step, the initiation of DNA replication that occurs at chromosomal positions called origins, is particularly critical in eukaryotic cells because their chromosomes require multiple spatially and temporally distributed origins for accurate and efficient duplication. Perturbations in origin number or distribution can promote cancer, stem cell aging, or developmental disorders. While the origin-binding proteins and molecular steps that define an origin are known, the mechanisms that regulate chromosomal origin number and distribution are unclear. A challenge is that chromatin heterogeneity exists across chromosomes as an intrinsic part of genome functional organization. Thus, the origin-binding proteins must work sufficiently enough within distinct chromatin environments to achieve a level of origin distribution that balances the competing demands for cell proliferation and genome stability. Dr. Fox's lab addresses the gaps in understanding how native chromatin structures regulate origin function by combining rigorous genetics and genomics to reveal chromatin-mediated mechanisms that impinge on the structure and function of Saccharomyces cerevisiae (yeast) origins. Emphasis is placed on the first step of origin formation, the origin licensing reaction, which occurs in G1-phase of the cell cycle that precedes the S-phase where origins perform their actual function, unwinding of the parental DNA for new DNA synthesis. Accumulating evidence reveals that the licensing step is particularly relevant to both genome stability and cell-fate decisions, but there is a paucity of molecular mechanisms regarding how it is regulated in vivo to achieve chromosomal origin distribution. Evolutionary conservation of the origin-binding proteins and multiple features of chromatin allow the Fox laboratory to leverage the experimental strengths of yeast to define fundamental mechanisms by which chromatin and the origin-binding proteins collaborate to form and distribute origins over the genome.

NIH Research Projects · FY 2025 · 2021-05

ABSTRACT Knowledge of protein motion is necessary to bridge the gap between structure and function and gain insight into the molecular mechanism of protein machines. My lab studies the function of ion channels and ion-coupled transporters, integral membrane proteins that must undergo structural transitions to regulate the flow of ions (channels) or actively pump substrates (transporters) across biological membrane barriers. A set of distinct but interrelated projects examines the mechanism of secondary active transport, promiscuous multidrug recognition, ion channel selectivity and gating, molecular basis of temperature sensing, allosteric regulation of transporter and channel activity, and how small localized interactions can regulate broader dynamics in membrane proteins. These research questions span time- and length- scales, requiring an array of experimental approaches and a well-developed set of model systems to enable hypothesis driven research. One of our primary tools is NMR spectroscopy, which can simultaneously provide structural, thermodynamic (populations), and kinetic (rates of transitions) data with site-specific resolution. NMR chemical shifts are also highly sensitive to changes in the local environment, providing a direct readout of proton binding, a process that is otherwise difficult to monitor experimentally but central to dissecting proton-coupled transport. Over the past 10 years, my lab has done the painstaking work necessary to develop three completely independent model transporter and channel systems (EmrE, NaK, Shaker-VSD) and establish experimental tools ranging from NMR and molecular biophysics to in vitro and in vivo functional assays. We are now primed to address essential research questions that probe the molecular mechanism of these specific systems but also have broader implications for understanding how protein conformational change is regulated, promiscuity versus specificity in substrate recognition, the complexity of proton-coupled transport, and molecular basis for allosteric regulation of protein function.

NIH Research Projects · FY 2025 · 2021-05

Abstract. The rate of progress in understanding the basis for reproductive health and disease is breathtaking, accelerated ever further by constant advances in cellular and molecular techniques. Nonetheless, research in traditional academic departments and research in clinical departments often does not overlap. As such, the PhD trained in a purely academic environment will remain unexposed to the clinical mindset and practices and so fail to pursue translational goals, while the clinician Fellow is well aware of the clinical problem and by definition focused on the human itself, but may be less aware of recent conceptual and methodologic advances available to investigate clinically derived research questions. As PA-18-403 RFA states, “past studies have shown that health professional trainees who train in programs with postdoctoral researchers who have intensive research backgrounds are more likely to apply for and receive subsequent research grant support”. To that end, the goal of this proposal is simple - to provide for the PhD and MD Fellow a combined and integrated immersion experience in a cutting edge cross campus research program that is in itself embedded in and focused upon a more clinical environment where health and disease is the primary consideration, and to then promote the use of nonhuman primate and human derived models in MD or PhD Fellowship projects lead by MD/DVM/PhD Faculty of combined clinical and traditional training backgrounds. The campus home for this program will be the integrated Program in Endocrinology (iPEnd), which was founded in 2016 to foster and promote collaboration focused on fetal development and the compromised adult outcomes of adverse pregnancy. We propose here that iPEnd also offers a vibrant interdisciplinary and multidisciplinary environment comprised of MD, PhD and DVM trained faculty with which both MD and PhD Postdoctoral Fellows could train together to enter the world of translational research. Such a blended training environment is very much needed if we are to maintain a future pool of interdisciplinary translational research team members intellectually and professionally ready to pursue the goals of NICHD to improve reproductive health and outcomes. Another consideration by NIH is that trainees do not go on to future independent success by simple exposure to ‘good science’ alone. Indeed, both Trainees and Trainers need support and professional education to ensure the best outcomes. To that end, our proposed training includes a deep immersion in higher level research training typical of many T32 programs at this time, but we aim to go far beyond to include the evidence based 8 core competencies for Postdoctoral trainees combined with added Mentee and Mentor training and the complimentary Professional Development Resources in order to achieve the rich blended training environment so strongly recommended by NIH. We believe iPEnd is ready to promote the concepts of the interdisciplinary and multidisciplinary ‘Translational Workforce’ through the proposed Training Program, operating within first class campus environment geared for basic but increasingly supportive of translational research. On that basis, we submit this application.

NIH Research Projects · FY 2025 · 2021-05

PROJECT SUMMARY/ABSTRACT This career development proposal resubmission is designed to provide Adrienne Johnson, PhD, the training necessary to become an independent investigator in the fields of tobacco dependence, Alzheimer’s disease and related dementias (ADRD), and dissemination and implementation (D&I) science. Dr. Johnson is trained as a clinical psychologist and has substantial experience with patient-oriented research in comorbid medical and psychiatric populations and expertise in smoking cessation within these populations. An expert mentoring team will guide her in achieving four training objectives: (1) develop a comprehensive understanding of ADRD etiological factors, prevention literature, and treatment approaches; (2) develop expertise in D&I science and its application to intervention development and testing; (3) develop expertise in public health marketing and motivational messaging; and (4) obtain training in larger scale clinical trial methodology. This training, consisting of formal coursework, guided mentoring, an apprenticeship, and participation in national scientific conferences, will allow Dr. Johnson to develop and test an intervention designed to help motivate older smokers quitting smoking. Older adult smokers are at elevated risk for cognitive decline and ADRD development and, unless they can successfully quit smoking, their prevalence will continue to rise. Unfortunately, older smokers are half as likely to attempt to quit smoking and less likely to receive evidence-based smoking treatments (EBSTs) compared to younger adults. Lower cessation efforts in older smokers may be a function of both clinician inaction and dysfunctional beliefs/motivational deficits of older smokers. The proposed work will develop and test a readily translatable Stage 1 motivational intervention for smoking cessation in older adults consisting of: (1) a novel patient-informed motivational message promoting smoking cessation, and (2) clear access routes to EBSTs within a healthcare setting. The proposed research will use three interrelated aims, occurring consecutively and building off of findings from the previous aim, to achieve this objective. Aim 1 will identify the most promising message content in terms of smoking cessation motivation and efficacy of and access to EBSTs in a healthcare setting. Aim 2 will evaluate promising motivational intervention packages using survey methodology. Finally, Aim 3 will examine the feasibility and preliminary effectiveness of a novel comprehensive motivational intervention to increase motivation to quit, quit attempts, and use of EBSTs for older adult smokers in a real-world clinical setting. Dr. Johnson will apply a widely used model of health behavior change (Health Belief Model) to guide treatment development and use a well validated D&I science framework (RE-AIM) to ensure she is building for translation. Results will inform a future R01 application aimed at implementing and evaluating this intervention in a broader context and examining the relation between smoking cessation and brain health.

NIH Research Projects · FY 2025 · 2021-04

PROJECT SUMMARY Natural killer (NK) cells provide an immediate defense against viruses and tumors by virtue of their ability to respond to infected or malignant cells without prior antigenic stimulation. This is accomplished through the integration of signals from activating and inhibitory NK cell receptors (aNKRs & iNKRs). In humans and other primate species, these include C-type lectin receptors, such as CD94/NKG2A and CD94/NKG2C, and the highly polymorphic killer-cell immunoglobulin-like receptors (KIRs), both of which interact with MHC class I ligands. These receptor-ligand interactions are fundamental to the ability of NK cells to differentiate healthy cells from unhealthy cells and provide a potential mechanism of specificity for the development of “NK cell memory”. NK cells can have a significant impact on HIV-1 infection. KIR and HLA class I polymorphisms have been identified that are associated with lower viral loads and slower courses of disease progression and certain NK cell subsets can kill HIV-infected cells in culture. Thus, NK cell-based therapies represent a promising approach for targeting HIV-infected cells and reducing the size of viral reservoirs. We hypothesize that viral peptides bound by the MHC class I ligands of aNKRs are critical to NK cell recognition and killing of HIV/SIV-infected cells and that the adoptive transfer of ex vivo activated NK cells in combination with latency reversal can deplete viral reservoirs in SIV-infected macaques on suppressive antiretroviral therapy (ART). In Aim 1, we will determine the contribution of viral peptides bound by MHC class I ligands of aNKRs to NK cell recognition of HIV- and SIV-infected cells. These studies will utilize high-throughput cellular assays to rapidly screen viral peptides for MHC class I interactions with aNKRs and to identify substitutions that disrupt these interactions. The corresponding changes will be introduced into HIV-1 and SIV to assess their impact on NK cell responses to virus-infected cells. In Aim 2, we will assess the capacity of ex vivo expanded NK cells in combination with latency reversal to deplete viral reservoirs in SIV-infected, ART-suppressed rhesus macaques. This aim will take advantage of barcoded SIV and a potent new latency reversal agent to compare with maximal sensitivity the ability of autologous versus allogeneic NK cell transfer to reduce the rate of viral reactivation after discontinuing ART. In Aim 3, we will test the hypothesis that the depletion of viral reservoirs by adaptive NK cell transfer can be enhanced by an Env-specific antibody with antibody-dependent cellular cytotoxicity against SIV-infected cells. This aim will use a similar approach as Aim 2 to determine the extent to which coupling NK cell effector function to the unparalleled specificity of antibodies can maximize reservoir depletion. These unprecedented studies will provide a better understanding of the role of viral peptides in NK cell recognition of HIV- and SIV-infected cells and an important proof-of-concept for the development of NK cell therapies to eradicate HIV-1 reservoirs in chronically infected individuals.

NIH Research Projects · FY 2026 · 2021-04

Epilepsy affects more than 2 million Americans and is the fourth most common neurological disorder. While many patients experience long-term remission, lifelong chronic epilepsy is associated with cognitive, psychiatric, and somatic comorbidities and a well-characterized neuroimaging burden. Recently, there has been much interest and concern regarding disorders of cognitive and brain aging in the general population; however, there has been little systematic study of this issue in aging persons with chronic epilepsy. We hypothesize that prolonged exposure to epilepsy and its myriad of complications accelerate brain and cognitive aging. Specific Aim 1: Characterize biomarkers suggestive of accelerated brain aging in chronic focal epilepsy using advanced PET/MR methods. We hypothesize that PET/MR biomarkers sensitive to brain aging (e.g., increased beta amyloid deposition, morphological changes, changes in functional and structural connectivity, reduced microstructural integrity, reduced metabolism (FDG-PET), and reduced vascular integrity) will be greater in a cohort of chronic focal epilepsy patients compared to age-matched controls, and thus indicative of age-accelerated brain aging. Specific Aim 2: Characterize other risk and resilience factors for accelerated brain and cognitive aging biomarkers in chronic epilepsy. We hypothesize that age-related neuroimaging biomarkers will predict the presence and severity of cognitive abnormalities in patients with chronic focal epilepsy. Furthermore, we expect risk factors for poor cognitive outcome, including vascular, socioeconomic, and lifestyle to be more prevalent in epilepsy and related to age-related cognitive and neuroimaging biomarkers. Specific Aim 3: Identify the temporal sequence of biomarkers in chronic TLE that are indicative of brain and cognitive aging allowing us to model the mechanistic cascade that leads to accelerated aging. We will provide important new mechanistic evidence characterizing the consequences of chronic TLE on brain and cognitive aging and identify the specific neuroimaging and behavioral profiles, risk and resilience factors that may be protective (or detrimental) to the aging process.

NIH Research Projects · FY 2026 · 2021-04

PROJECT SUMMARY/ABSTRACT The overall goals of our Childhood Asthma in Urban Settings (CAUSE)-Leadership Center proposal are to provide administrative leadership and support to develop and conduct collaborative research to address high priority unmet needs for childhood asthma in urban communities, including: a) developing strategies to prevent asthma, b) improving treatment and inhibiting progression, c) reducing severe exacerbations, and d) defining endotypes of respiratory health and disease. Four hypotheses are proposed to accomplish these goals. First, supplementation with immune modulating bacteria in infancy will prevent the early life perturbations in the gut microbiome that have been associated with risk for the development of allergic sensitization and asthma, and will promote airway mucosal immune development. Second, given the importance of cockroach (CR) allergy and exposure to asthma morbidity in urban children, CR immunotherapy will improve asthma control and reduce disease progression. Third, we propose that transcriptional analysis of airway cells will define T2-low mechanisms that contribute to both non-atopic and atopic asthma and provide new insights into treatment. Finally, multi-omics evaluation of airway cells and secretions obtained during severe exacerbations leading to ED visits and hospitalizations will reveal novel mechanistic pathways to inform improved treatment and prevention. We propose five protocols to test these hypotheses: 1. Urban Environment and Childhood Asthma study (URECA) 2. Effects of a Microbial Supplement (STMC-103H) on Microbial Colonization and Immune Development 3. Cockroach (CR) Immunotherapy (IT) in Urban Children with Moderate-Severe Asthma Protected by Omalizumab 4. Pathogenesis and Mechanisms of T2-low (Non-Atopic) Asthma 5. Severe Asthma Exacerbations in the Emergency Department (ED) and Hospital: Identifying Targets for Prevention and Treatment It is our expectation that our proposed CAUSE research program will provide critical information needed to recognize asthma phenotypes and endotypes in urban children, improve treatment of asthma and establish direction for prevention. Collectively, these studies will continue the rigorous programmatic approach of the NIAID Asthma Networks towards achieving the long-term goals of disease modification and prevention of disease in high-risk children of low-income families living in urban communities.