University Of Wisconsin-Madison

NIH Research Projects · FY 2025 · 2020-04

1 Summary: Architectures and Underpinnings of Adaptive Evolution and Reproductive Isolation 2 This research program informs foundational yet unresolved questions at the interface between genomic 3 diversity and evolutionary process. It focuses on two research themes: (1) Connecting Genomic Diversity 4 to Adaptive Evolution, and (2) Genetic Windows Into Early and Late Stage Reproductive Isolation. 5 This research fuses ambitious but cost-effective Drosophila experiments with novel approaches to the 6 analysis of large data sets. D. melanogaster offers key advantages for this work. The global expansion of this 7 species has given rise to adaptive trait differences, and early stage reproductive isolation, between populations 8 that diverged in the last ~13,000 years. The experimental efficiency of Drosophila, along with its compact and 9 well-annotated genome, and its wealth of genetic resources and transgenic tools, combine to allow these 10 evolutionary phenomena to be studied in ways that might not be practical in any other animal system. 11 This research will focus on Connecting Genomic Diversity to Adaptive Evolution in two major respects. 12 Following up on recent studies of the genetic architecture of adaptive trait evolution which showed that 13 causative variants consistently remain polymorphic, the proposed research will develop and apply population 14 genomic resources for performing genotype-phenotype association testing to identify underlying genes and 15 candidate variants within previously identified trait-associated genomic regions. Secondly, this research will 16 investigate how molecular regulatory traits provide a bridge between genomes and adaptive changes. Diverse 17 regulatory traits at chromatin, RNA, and protein levels will be assayed from the brains of flies from tropical and 18 temperate origins, and analyzed via an improved evolutionary framework. For the first time, the types of 19 regulatory traits that most frequently show the influence of adaptive evolution will be revealed. 20 The proposed work will also leverage this system to look through Genetic Windows Into Early and Late 21 Stage Reproductive Isolation. Research will build upon recent evidence of hybrid breakdown in male fertility 22 among the offspring of crosses between African and European D. melanogaster populations. By genetically 23 mapping incompatibilities using a novel framework, illuminating their biology, and identifying and testing 24 potential causative genes, this research will offer a very rare genetic perspective on the very earliest stages of 25 reproductive isolation. In contrast, D. melanogaster and D. simulans are commonly viewed as fully isolated 26 species. And yet, new population genetic results reject a simple isolation history for these taxa. Research will 27 test whether ancient genetic structure or else recent or ancient introgression best explains these observations. 28 Collectively, this research is highly consequential for fundamental evolutionary genetics. It also holds 29 substantial health relevance in terms of understanding how evolution is likely to proceed in biomedically 30 important insects such as disease vectors, and by informing the genetics human trait variation and infertility.

NIH Research Projects · FY 2026 · 2020-03

PROJECT SUMMARY Patients with early and locally advanced breast cancer (ELABC) are treated with a combination of pre- operative (neoadjuvant) therapy, surgical resection and post-operative (adjuvant) therapy. In recent years, overall survival for ELABC has improved to ~90% at 5 years. However, to achieve this goal, patients are often over-treated due to lack of effective biomarkers. For example, a majority of patients who receive adjuvant therapy are already cured after surgery and derive no further benefit. Similarly, almost a third of patients treated with neoadjuvant therapy are found to have pathological Complete Response upon surgery (no evidence of tumor upon histopathology), suggesting that the surgery could have been safely omitted. An effective biomarker for minimal residual disease (MRD) can help personalize treatment plans and reduce over- treatment, while preserving outcomes in patients with breast cancer. Recent literature shows post-operative detection of circulating tumor DNA (ctDNA) can identify recurrence, months before it is recognized on imaging. However, due to lack of sensitivity of current methods and limited blood sample volumes, ctDNA signal often drops below limit of detection. Current approaches for ctDNA analysis do not have adequate sensitivity to detect residual disease during and after completion of treatment. To address this gap, we have developed TARgeted DIgital Sequencing (TARDIS), an approach for multiplexed analysis of several patient-specific mutations in ctDNA. In this application, we propose to first analytically validate TARDIS for ctDNA detection and then clinically validate this approach as a biomarker for treatment monitoring and residual disease detection in early and locally advanced breast cancer. In the UH2 analytical validation phase, we will assess analytical sensitivity, specificity, accuracy, precision and reproducibility of TARDIS using reference material, tumor cell line dilutions and plasma samples from patients with breast cancer. In the UH3 clinical validation phase, we will measure baseline ctDNA detection rates in patients with early and locally advanced breast cancer, evaluate whether ctDNA levels after neoadjuvant treatment are predictive of pathological Complete Response and evaluate the prognostic value of ctDNA detection after surgical resection for disease-free survival. Our goal is to enable greater precision in treatment of patients with early and locally advanced breast cancer. Once validated, ctDNA analysis and monitoring will complement existing diagnostic approaches such as imaging and histopathology to help optimize management of patients with early and locally advanced breast cancer.

NIH Research Projects · FY 2026 · 2020-02

Project Summary Parasitic nematodes infect over 1.5 billion people worldwide, representing a major public health challenge addressed primarily through mass drug administration (MDA) programs. These programs rely on a small number of anthelmintic drugs with suboptimal properties and inadequate disease surveillance tools. The development of new treatments and diagnostics is critical yet progress is hindered by significant gaps in our understanding of the biological processes that enable and sustain nematode infections. Nematodes release excretory-secretory products (ESPs) that play a vital role in modulating host immunity and facilitating infection. Despite their importance, little is known about the tissue origins of ESPs or the regulatory mechanisms that control routes of secretion in human parasitic nematodes. To address this knowledge gap, we will investigate secretory mechanisms and identify regulators of secretory function in Brugia malayi, a mosquito-borne nematode responsible for human lymphatic filariasis (LF). Current LF treatments effectively clear blood-circulating microfilariae but adult worms persist after treatment, complicating disease elimination and post-drug disease monitoring efforts. A growing body of evidence implicates secretory dysregulation in the mode of action and microfilaricidal efficay of antifilarial drugs, highlighting secretory processes as potential therapeutic targets. Our overarching hypothesis is that the B. malayi secretory system can be targeted to interfere with the release of ESPs and interrupt infection. We propose three aims to pursue this hypothesis, building on preliminary leads and enabled by innovative methods to resolve the transcriptomic state of secretory tissues, measure drug effects on secretion, and profile receptors involved in secretory processes. In Aim 1, we will use transcriptomic and reverse genetic approaches to identify genes upregulated in the secretory tissues of infective stage parasites exposed to host transition cues and test whether knockdown of a prioritized set of genes alters host infectivity. In Aim 2, we will use in vitro proteomics and microscopy approaches to monitor how antifilarial drugs affect routes of ESP release in microfilariae and induce changes in the composition of the adult secreted proteome. In Aim 3, we will pharmacologically profile secretory-associated aminergic receptors and test whether ligands that act on these receptors cause secretory defects or clear parasites in a robust mouse model of infection. Completion of these aims will identify novel secretory regulators and effectors essential to host transition (Aim 1), clarify how current anthelmintics dysregulate secretory processes and alter ESP composition (Aim 2), and validate specific secretory-associated receptors that can potentially be targeted to clear patent infections (Aim 3). We expect that these fundamental insights into nematode secretory biology will be highly relevant to the development of new therapeutic and diagnostic targets in diverse nematode species.

NIH Research Projects · FY 2025 · 2020-02

PROJECT SUMMARY The emerging fungal pathogen Candida auris has produced numerous outbreaks of invasive disease in hospitals worldwide. With mortality rates as high as 60%, the continued rise of this drug-resistant pathogen is alarming. Further understanding of the unexpected virulence of C. auris is desperately needed for the design of innovative therapeutic approaches. My laboratory’s long-term goal is to find new approaches to understand, detect, and treat invasive fungal infections. The objective of this application is to delineate how C. auris evades innate immunity and to develop a novel therapeutic strategy to circumvent this mechanism. We have found that neutrophils, leukocytes critical for control of many invasive fungal infections, fail to kill C. auris. We propose that uncovering the molecular mechanism of this immune evasion will identify new drug targets. Our preliminary data provide compelling evidence for the involvement of a C. auris cell wall component. Furthermore, we have identified a subset of neutrophils with enhanced antifungal activity. We plan to capitalize on this finding to delineate the molecular aspects of a successful neutrophil response against C. auris. This will not only shed light on the virulence of C. auris, but will also establish a platform for future neutrophil-based immunotherapies. We anticipate this approach will have broad implications for the treatment of a variety of drug-resistant or treatment-refractory invasive fungal infections.

NIH Research Projects · FY 2026 · 2020-02

PROJECT SUMMARY How the intracellular membrane system of eukaryotic cells is configured and maintained is a fundamental problem in cell biology. Deficiencies in this organization often lead to disease. The overarching goal of my laboratory is to define the molecular mechanisms that regulate membrane dynamics, including vesicle biogenesis, organelle trafficking, and protein sorting in the early secretory and endocytic pathways of mammalian cells. We aim to determine how normal membrane transport contributes to cellular homeostasis and to understand the molecular basis for disease states that emerge when trafficking pathways are disrupted. Using a combination of model systems, structural biology, biochemistry, genetics, and high-resolution subcellular imaging, our studies focus on two essential trafficking pathways necessary for protein and lipid export from the endoplasmic reticulum (ER) and protein turnover within lysosomes via a multivesicular endosome (MVE) intermediate. Mutations in several factors that regulate these processes have been implicated in cancer, diabetes, immune dysfunction, and neurodegeneration. Thus, deciphering the fundamental principles underlying the regulation of ER export and MVE biogenesis should facilitate the future identification of therapeutic targets for disease intervention. One major focus of my research has been elucidating how the early secretory pathway is organized. Our findings revealed the existence of a conserved membrane interface, which links subdomains on the endoplasmic reticulum (ER) that produce COPII transport intermediates to juxtaposed ER-Golgi intermediate compartments (ERGIC). Importantly, we have also identified several regulatory factors that act at this interface to control the efficiency of secretory cargo egress from the ER. My second research focus is aimed at understanding the mechanisms that direct the formation of MVEs, which bud intralumenal vesicles (ILVs) into their interior to sequester membrane-associated cargoes from the cytoplasm. Eventual fusion of MVEs with lysosomes results in the degradation of ILVs and their associated proteins, which plays a key role in tumor suppression by governing the capture and sequestration of signaling receptors. Over the past several years, we have focused on identifying regulatory mechanisms that enable components of the endosomal sorting complex required for transport (ESCRT) machinery to efficiently sort ubiquitin-modified cargoes into ILVs. In this renewal application, we will capitalize on evolving methodologies to further establish how COPII-mediated transport and ESCRT-mediated MVE biogenesis are properly regulated. A better understanding of these processes will yield key insights into the homeostatic controls that sustain normal protein trafficking in the secretory and endocytic pathways during cell proliferation and differentiation.

NIH Research Projects · FY 2025 · 2020-01

PROJECT SUMMARY Redox reactions are among the most important synthetic methods in organic chemistry, playing a crucial role in the preparation of pharmaceuticals, natural products, and other bioactive compounds. Advances in catalytic oxidation and reduction reactions targeted in this project will have broad impact across the drug discovery and development pipeline. Many existing catalytic redox methods face challenges in their efficiency and selectivity, including chemo-, regio- and stereoselectivity, limiting their use in both small- and large-scale applications. The proposed research will further develop oxidation, reduction, and coupling methods that form carbon-carbon and carbon-heteroatom bonds. New C(sp3)–H functionalization/diversification reactions will streamline the discovery of new bioactive molecules with diverse three-dimensional architectures, addressing key challenges in medicinal chemistry and drug discovery, while others will provide the basis for streamlined process-scale synthesis of pharmaceuticals. Four complementary project directions are highlighted in this proposal. The first focuses on the synthesis and functionalization of “synthetic linchpins” derived from C(sp3)–H bonds to enable rapid access to pharmaceutically relevant compounds. New methods will be developed to access versatile synthetic linchpins, especially those that may be integrated with Ni-catalyzed cross-electrophile coupling to form C(sp3)–C(sp2) and C(sp3)–C(sp3) bonds. The second project will develop new electrosynthetic methods, including both oxidation and reduction reactions. These efforts will build upon our use of electrochemical mediators to facilitate new oxygenation, cross-electrophile coupling, deoxygenation, dehydration, radical chain, and biocatalytic reactions. We will use our expertise to develop electroanalytical methods that support optimization of catalysts and conditions for these reactions. The third project will apply chemistry developed in the first two projects to the synthesis of drug metabolites, in addition to developing new nucleophilic oxidation methods that mimic aldehyde oxidase metabolism. Development of a ‘metabolite synthesis toolbox’ will address a major bottleneck in drug development. Finally, we will develop heterogeneous catalysts for aerobic oxidation and oxidative coupling reactions that address unmet synthetic challenges, such as formation of N–N and N–O bonds, and provide opportunities for practical application in large-scale synthesis of pharmaceutical intermediates and APIs. Close interactions and collaborations with multiple academic groups and pharmaceutical companies in all phases of this project will play an important role in ensuring the broadest possible impact of our efforts.

NIH Research Projects · FY 2026 · 2020-01

Project Summary The research proposed seeks to reveal mechanisms for spatial phosphoinositide (PI) signaling in the cytosol and nucleus. These pathways have broad implications for cancer, neurodegenerative disorders, and other diseases. PI signaling generates seven distinct polyphosphoinositide (PIPn) messengers. EGF and other agonists activate the class I PI 3-kinase (PI3K)/Akt pathway on membranes that controls cell growth and other key cellular functions. In nuclei, PIPn pathways are separate from membranes, controlling stress responses that impact DNA repair, cell survival, and other critical events. The work on agonist-activated PI3K signaling is focused on the spatial and temporal activation of PI3K, which generates PIP3 to activate Akt and other pathways. The PI3K pathway plays a key role in cancer both by agonist activation and by PI3K mutations that hyperactivate the pathway independent of agonists. We show that the PI3K pathway is incorporated into an IQGAP1 complex, which uses PI to sequentially synthesize PI4P, PIP2 and PIP3, the latter activating mTORC2, PDK1 and Akt. The utilization of PI suggests that the IQGAP1 complex may function at any cytoplasmic membrane, but dogma states that PI3K signaling occurs at the plasma membrane. We have shown that agonist-stimulated PI3K signaling is endosomal and is regulated by interactions with MAP4 and PI3P that spatially targets PI3K to microtubules and endosomes, respectively. PI3K interactions with MAP4 and PI3P are required for agonist-stimulated signaling. However, the underlying mechanisms for the assembly of PI3K in these complexes is unknown. Although constitutively active PI3K mutants that hyperactivate the pathway in cancer still requires IQGAP1, MAP4 and PI3P interactions, the mechanisms by which these PI3K mutants stimulate the assembly of these complexes needs to be defined. In contrast to the cytosolic pathway, we have shown that Nuclear PI signaling is separate from membranes and is mediated by linking PIPns (likely covalently) to PIPn effector proteins (PIPylation) including p53. PIPns are linked to p53 and sequentially phosphorylated to generate a p53-PIP3 complex that activates nuclear Akt by assembly of mTORC2, PDK1 and Akt. Remarkably, wild-type (p53wt) and mutant p53 (p53mt) regulate Akt activation differently, suggesting a mechanism for its tumor suppressor and oncogenic functions, respectively. Notably, PIPns are linked to many nuclear proteins, indicating a broader “PIPylome”. Remaining questions are the chemical nature and enzymatic mechanism of the PIPn linkage, the identification of the cellular PIPylome, and the regulation of PIPylated proteins by PIPns. We have also discovered that PI transfer protein (PITP)s and PI 4-kinase II (PI4KII) are necessary for PIPylating proteins but the mechanisms are unknown. Moreover, PIPns are linked to multiple DNA repair proteins and the functional role of PIP linkage in the DNA damage response will be investigated. Significance- The scaffolded endosomal PI3K activation and PIPylation of cellular proteins are paradigm-shifting and have vast implications for biology and therapeutics.

NIH Research Projects · FY 2025 · 2019-12

Project Summary: Modern cardiovascular (CV) trials often collect data on a wide array of fatal and nonfatal events (e.g., heart failure, heart attack, stroke, chest pain, and etc.) with different implications for patient health. In recent years, new methods have started to emerge which seek to capture more events than the traditional endpoint of each patient’s first event. However, to account for the totality of a composite endpoint while differentiating the importance of its components (e.g., death vs CV hospitalization) is not easy. As it stands, investigators still lack adequate tools to measure treatment effects, design future trials, assess risk factors, and build prediction models. In this project, we address these gaps via four specific aims. In Aim 1, we consider a general class of nonparametric effect-size estimands defined though pairwise comparison (both overall and subgroup-wise), in which one component can be readily prioritized over another using a hierarchical rule of comparison. The inverse probability censoring weighting (IPCW) and augmented inverse probability weighting (AIPW) techniques are adapted to U-statistic estimators to correct for censoring bias and to improve efficiency (and thus reduce trial cost) using patient data both pre- and post-randomization. In Aim 2, we develop routines to calculate power and sample size for newly proposed methods for composite endpoints, such as the restricted mean time in favor of treatment and while-alive loss rate, under both fixed and group sequential designs. In Aim 3, we propose novel semiparametric regression models for composite endpoints following earlier work on the proportional win- fractions (PW) model. In particular, the generalized semiparametric proportional odds (GSPO) model accommodates nonproportional win fractions by extending traditional PO models to multiple events with ordered severities. In Aim 4, we extend survival trees as a predictive tool from univariate to composite endpoints. Drawing on classification trees for ordinal response, we develop time-integrated versions of the weighted Gini index and twoing approach for node-splitting, and of a generalized concordance index for cross-validative pruning, thereby accounting for both the timing and severity of the outcome events. The methods developed will be used for secondary analyses of the recently concluded INfluenza Vaccine to Effectively Stop cardio-Thoracic Events and Decompensated heart failure (INVESTED) trial (ClinicalTrials.gov: NCT02787044). Meanwhile, they will be incorporated into new and existing R-packages on the Comprehensive R Archive Network (CRAN.R-project.org) for public use by practitioners.

NIH Research Projects · FY 2026 · 2019-09

ABSTRACT Adults incarcerated in the United States are disproportionately affected by substance use disorders and chronic physical and mental conditions, and have a high risk of death after release from prison. Medicaid coverage for formerly incarcerated adults increases access to care, but is likely insufficient by itself to substantially improve outcomes without attending to the numerous social and structural barriers that make accessing care difficult. Prior research demonstrates that formerly incarcerated adults under-utilize routine, outpatient health care during the transition from prison to community living, suggesting a dire need for systems-level interventions aimed at improving engagement in primary care. In a prior study funded by NIDA, our team developed a hybrid, in-person and telephone-based nurse case management intervention that bridges the pre-release and post-release period and conducted a single-arm pilot trial in two Wisconsin state prisons. We found that the likelihood of an outpatient care visit shortly after release among those who received the intervention was nearly double the baseline rate, while being highly acceptable to prison staff. In the proposed Renewal Application, we will conduct a two-arm, randomized clinical trial among incarcerated adults with a history of substance use, that compares previously piloted transitional case management intervention, called CJC-TraC, to an enhanced usual care condition consisting of routine multi-disciplinary release planning and provision of a free cellphone at the time of release. The primary and secondary trial outcomes are attending an outpatient visit within 60-days of release for any cause and for a substance use disorder respectively. In the proposed study’s second aim, we will leverage novel linked administrative data and observational research methods to investigate care transition research questions that are policy-relevant but cannot be pursued in a randomized trial of incarcerated adults: estimating the relative effectiveness of the trial arms to usual care; assessing the generalizability of trial results to the target population; and measuring the association between post-release outpatient care use and longer-run health and criminogenic outcomes. Improving access to post-incarceration health care is a major federal policy priority. In 2023, the Centers for Medicare and Medicaid services published Section 1115 Medicaid demonstration waiver guidelines for states to provide Medicaid coverage and care transition services to incarcerated individuals during the pre-release period and post-incarceration. The waiver program represents an unprecedented opportunity to bring care transition services for incarcerated individuals to scale; however, there is limited information identifying what constitutes an effective and scalable care transition program. By testing the effect of a prison system-based intervention able to be replicated and scaled up across multiple settings, findings from this study can have a significant impact on the health of a high-priority, medically underserved population.

NIH Research Projects · FY 2024 · 2019-09

Project Summary/Abstract Cancer is the leading cause of morbidity and mortality in the US and in the world. One approach to reducing the risk and burden of cancer is to use preventive agents and interventions that are effective and safe. According to the Division of Cancer Prevention (DCP) at the National Cancer Institute (NCI), this requires the systematic development of cancer preventive agents and interventions, with three critical components; i) preclinical/toxicology studies for identification of agents, ii) early phase trials of identified agents and other promising interventions, and iii) late phase III trials of preventive agents and interventions that have successfully passed through early phase trials, in a three-legged approach. The goal of the Cancer Prevention Clinical Trials Network (CP-CTNet) is to identify safe and effective preventive agents and interventions in order to advance their further clinical development for cancer prevention. Further clinical development is to be undertaken in late phase III trials conducted by the third leg, i.e. the National Community Oncology Research Program (NCORP), supported by the DCP's Community Oncology and Prevention Trials Research Group, to ultimately reduce the risk and burden of cancer. As the second leg of this three-legged approach, the CP-CTNet will conduct early phase trials to assess the safety, tolerability, and cancer preventive potential of agents and interventions of varying classes identified by the first leg, i.e. the DCP's Cancer Preclinical Drug Development Program (PREVENT) support of preclinical/toxicology studies, many of which target molecules or processes known to be important during carcinogenesis. The CP- CTNet Sites will perform these early phase trials supported by the DCP and the CP-CTNet Data Management, Auditing, and Coordinating Center (DMACC). These trials include phase 0 (micro-dosing), phase I (dose- finding), and phase II (preliminary efficacy) clinical trials. To support these early phase trials, which will be conducted by the CP-CTNet sites alone or as cross-Network trials, the CP-CTNet DMACC will coordinate trans-Network activities and provide expertise and resources in 1) centralized data management and reporting, 2) clinical trials auditing, and 3) administrative and logistical coordination, including expertise in clinical trials methodology and biostatistics, across CP-CTNet. In addition, the CP-CTNet DMACC will provide an advisory role in early phase caner prevention trial development for all CP-CTNet trials and the primary statistical role for cross-Network trials.

NIH Research Projects · FY 2024 · 2019-09

DESCRIPTION (provided by applicant): Homeostasis is a feature of all bodily structures and represents the maintenance of stability within these structures to facilitate optimal functioning. During aging or with the development of diseases, homeostenosis or a narrowing of the functional reserves necessary to preserve homeostasis, occurs. The loss of functional reserve in one system leads to the body depleting other reserve systems to maintain function. Eventually, the continual use and depletion of multiple reserve systems leads to frailty which greatly affects the ability of the body to function and makes individuals more susceptible to negative health outcomes. Eating and drinking represent body functions vital to achieving nutritional homeostasis which is necessary for survival. Dysphagia, or swallowing impairment, is a threat to maintaining nutritional homeostasis as deficits in swallowing safety (airway invasion) and efficiency (residue) can lead to malnutrition and dehydration. The loss of functional reserves has been implicated to contribute to the development of dysphagia in diseases and in the elderly, however, the dysregulation of homeostatic mechanisms and its’ effect on optimal swallowing function is not understood. The overarching goal of this fellowship proposal is to investigate mechanisms of homeostatic dysfunction as it relates to the development of swallowing impairments. In the F99 phase of this proposed research, I will evaluate the impact of functional reserve depletion in one structure important for swallowing (the tongue) on swallowing function in individuals with ALS. Specifically, I will develop a novel lingual pressure protocol to determine patterns of lingual functional reserve decline in ALS and examine potential relationships between lingual pressure patterns and lingual reserve depletion with functional aspects of swallowing safety and efficiency. I will also evaluate whether a critical threshold of homeostenotic lingual functional reserve depletion exists wherein lingual and swallowing impairments ensue. During the K00 phase, I will move to a complementary laboratory to investigate swallowing function in the frail elderly with multiple, diminished functional reserves and evaluate the physiological differences in swallowing function that occur in the frail elderly versus normal aging. The long-term goal of the proposed work is to generate the knowledge necessary for the future development of biologically informed therapeutics to target swallowing dysfunction across various patient populations. The completion of this work will provide important insight into dysregulation of homeostatic mechanisms and functional reserve in vulnerable populations (ALS and the elderly) and will yield a novel lingual pressure testing protocol (F99 phase) and characterization of frail swallowing in the elderly (K00 phase) that will further our understanding of the role of homeostenosis on the vital functions of eating and drinking.

NIH Research Projects · FY 2024 · 2019-08

! Project summary Advances in human health rely on valid animal models of disease. Inbred or genetically engineered rodent models can answer important questions about disease pathogenesis and test promising therapies, but can sometimes fail to predict disease responses seen in humans. Spontaneously occurring diseases in companion and other domestic animals can complement the use of engineered laboratory models to understand human diseases, especially those that involve complex genetic traits, disease-modifying gene loci, environmental-gene interactions, or chronic disease progression. Veterinary clinician-scientists have expertise in these naturally occurring animal diseases, and have much to contribute to interdisciplinary research teams that are working to solve human health problems. The purpose of this proposal is to support the development of veterinary specialists into clinician-scientists capable of being productive contributors to translational research. This proposal outlines 3 initiatives: 1) targeted post-residency Translational Research Fellowships for veterinary specialists, to perform research with inter-disciplinary teams on spontaneous diseases shared by humans and animals; 2) a Translational Research Immersion Program for early career clinical faculty, to provide key training in grant writing and mentorship, and showcase successful models of interdisciplinary research collaborations; and 3) convene Translational Research Summits for established veterinary and human medical researchers working on the same diseases, to accelerate the use of spontaneous animal models to understand human disease. The long-term goals of this Translational Research Workforce Training proposal are to catalyze interdisciplinary translational research among veterinarians, basic scientists, physicians and other human health professionals. These three initiatives will provide a generalizable model to recruit clinical specialists of all backgrounds to centers of excellence within the CTSA network, provide immersion research training for clinical faculty followed by evidence-based mentoring support, and bring together clinicians and scientists from different walks of life to collaborate around shared disease interests.

NIH Research Projects · FY 2026 · 2019-08

Project Summary Dementia is a leading cause of death in the United States and is associated with loss of quality of life and independence; it cannot be prevented, or cured. Delirium is a sudden state of confusion that is associated with increased morbidity and mortality and impaired long-term cognition. Both delirium and dementia are bereft of therapies, largely due to the limited understanding of their pathogeneses. The vulnerability of people with dementia to experience delirium offers a unique opportunity to understand their overlapping pathology and to identify new therapies. It has long been thought that changes in the neurotransmitter acetylcholine cause delirium, because drugs that inhibit acetylcholine can cause a state of confusion that resembles delirium. In Aim 1, we will measure electrical activity in the brain that is affected by acetylcholine. Demonstrating that changes in this electrical activity correspond with the onset and resolution of delirium would strengthen the cholinergic deficiency theory of delirium. However, changes in acetylcholine alone do not explain the various symptoms caused by delirium or why different people develop different symptoms. In Aim 2, we will determine whether changes in the neurotransmitter noradrenaline explain these differences, clarifying the overlapping pathology of delirium and dementia. Alzheimer’s disease and related dementias accumulate abnormal tau proteins in a small region of the brain called the locus coeruleus early in the disease. The locus coeruleus controls noradrenaline signaling throughout the brain, and plays important roles in arousal and attention. When severe inflammation stresses the body, damage to the locus coeruleus may lessen the release of noradrenaline and predispose the person to hypoactive delirium. On the other hand, in the absence of early dementia pathology a robust release of noradrenaline may predispose towards hyperactive delirium. Understanding the role of noradrenaline in these different types of delirium could guide new targeted therapies. Further, noradrenaline regulates metabolism in the brain by stimulating the release of lactate from astrocytes to support nearby neurons. Some regions of the brain are less able to respond to the effects of noradrenaline, potentially making them vulnerable to metabolic insufficiency. In Aim 2, we will determine whether these brain regions are vulnerable to delirium by measuring the location and severity of slow wave electrical activity across the brain. In Aim 3, we will determine whether these brain regions are vulnerable to injury and long-term damage following surgery. Again, understanding whether metabolic insufficiency contributes to delirium and long-term injury could guide targeted preventative therapies in vulnerable patients.

NIH Research Projects · FY 2025 · 2019-07

Project Summary/Abstract Assistive technology (AT) has the potential to improve the health and function of older adults. However, multiple barriers, such as perceived stigma, financial costs, and perceived threats to privacy, impact older adult acceptance and use of AT. Studies identify that older adults from historically underrepresented (HU) groups have less access to and use of AT. In addition, older adults particularly those from HU groups, are often excluded from participating in research and in AT development. Further, AT development occurs in silos with little, if any, input from older adults and other disciplines (clinicians, social scientists, healthcare providers), thus limiting innovation and new ways of thinking about AT use and the needs of older adults. Our long-term goal is to increase the number and reach of effective AT interventions designed to improve the health and function of older adults, increase aging in place, and reduce disparities. The objective of this proposal is to create a mature and sustainable infrastructure that facilitates the formation and collaboration of transdisciplinary teams of engineers and computer scientists, healthcare providers, social scientists, and community partners to develop, test, and disseminate innovative AT interventions for older adults from diverse and historically underrepresented populations with age-related or multiple chronic conditions. To achieve this goal, we will expand the Community- Academic Aging Research Network (CAARN) infrastructure in a new direction to facilitate older adult engagement in AT and to connect engineers and computer scientists, healthcare providers, and end users to promote a better understanding of the technology needs of a diverse older adult population and create an environment for transdisciplinary engagement. We will accomplish our objective through three aims: Aim 1: To bring together multidisciplinary researchers (engineers, computer scientists,, clinicians, social scientists) and community end users to investigate the needs for and barriers to using AT from historically underrepresented communities prior to design; Aim 2: To facilitate community-academia partnerships to develop new or refine existing AT through iterative cycles of input/design/prototype testing and feedback; and Aim 3: To demonstrate preliminary feasibility, acceptability, safety, and functionality of new and/or refined AT among adopters, implementers, and end users of the technology. The result of this new infrastructure will be the development of new AT that: a) is feasible to use with broad reach and adoption; and b) is likely to be effective in promoting equitable older adult independence and health.

NIH Research Projects · FY 2025 · 2019-07

PROJECT SUMMARY/ABSTRACT The long-standing Neuroscience Training Program (NTP) at the University of Wisconsin–Madison provides multi- disciplinary, predoctoral graduate training in the neurosciences. The overarching goal of the program is to train the next generation of leading integrative neuroscientists for careers in academia, healthcare, teaching, industry, and public service. Graduate students in our program receive comprehensive, interdisciplinary research training with internationally recognized faculty whose research interests span the breadth of modern neuroscience. Indeed, students receive training in a broad range of neuroscience areas including: cellular and molecular neuroscience; membrane excitability and synaptic transmission; neural circuits; systems and computational neuroscience; perception and action; behavior, cognition, and emotion; development, plasticity, and repair; and the neurobiology of disease. The proposed renewal of the T32 training grant includes a combination of hands- on research, coursework, individual development plans (IDPs) and mentoring training, and a unique seminar course. The NTP curriculum is designed to provide rigorous training that emphasizes sound scientific reasoning, experimental design for neuroscience studies, as well as quantitative skills and statistical methodology taught by NTP Faculty Trainers using neuroscience examples selected for their pedagogical value. Importantly, training in responsible conduct of research (RCR) as well as rigor and reproducibility occurs throughout the entire training period. The NTP Faculty Trainers include 93 members drawn from 24 departments. To student training, they contribute expertise across a wide array of neuroscience subdisciplines and state-of-the-art methodologies ranging from molecular genetics/proteomics to whole brain neuroimaging. New initiatives include expanded mentorship training for our faculty and students; improved, student-tailored IDPs; and increased quantitative and computational training. Newly focused efforts related to diversity and equity will emphasize recruitment and retention of underrepresented minority (URM) students. These efforts will collectively advance the NTP’s goal of fostering an environment of interdisciplinary neuroscience training that provides students with the intellectual and experiential breadth necessary to advance biological and biomedical research as leaders in the field of neuroscience. Our program has been particularly successful in achieving its training goals. Over the past 10 years, the average time to PhD was 5.19 years, the average number of first-author papers was 2.16, and the average number of total papers was 5. Of our graduates 10-20 years post-degree, 34% hold tenure-track faculty positions. We anticipate appointing 12 new T32 trainees per year. Selection of trainees will be based principally upon prior academic and research accomplishments as well as demonstrated potential for an independent research career. Graduates will be well-equipped to carry out research aimed at understanding fundamental neurobiological processes as well as mechanisms underlying diseases and disorders of the nervous system, and to train future generations of neuroscientists.

NIH Research Projects · FY 2026 · 2019-07

The most important determinant in whether a person will develop type 2 diabetes or gestational diabetes is whether their islets of Langerhans are able to compensate for the increase demand for insulin brought about by peripheral insulin resistance. In successful compensatory islet expansion (that can mitigate the develop- ment of diabetes), islets retain their three-dimensional architecture, endocrine cell-cell communication, and in- tra-islet regulation of hormone secretion. Failure of compensatory islet expansion is a key event in the etiology of type 2 diabetes and gestational diabetes. Accordingly, abnormal islet architecture and dysregulated hor- mone secretion are hall-marks of all types of diabetes mellitus. How islets orchestrate the changes in tissue architecture and in cell-cell communication during compensatory expansion, and why they fail to do so in dia- betes, is unclear. This is important, because approaches to promoting compensatory islet expansion by focus- ing on β cell proliferation alone, without tackling other aspects of islet tissue remodeling, have not been suffi- ciently effective so far. This application focuses on the Slit-Robo signaling pathway as a critical regulatory mechanism in remodeling islet organization and intra-islet cell-cell communication, the failure of which is a lim- iting factor for compensatory islet expansion. Specific Aim 1 will test the hypothesis that down-regulation of Robo2 receptors in beta cells is essential for compensatory islet expansion. Specific Aim 2 will determine how down-regulation of Robo2 in beta cells causes alpha cells dyregulation. Specific Aim 3 will test the hypothesis that Slit-Robo mediated crosstalk between pancreatic stroma and endocrine cells is involved in compensatory islet expansion. Understanding the role of Slit-Robo signaling in regulating islet dynamics during life events could potentially be leveraged in the future to promote successful compensatory islet expansion and intra-islet control of hormone secretion in obesity, insulin resistance, and pregnancy.

NIH Research Projects · FY 2025 · 2019-05

PROJECT SUMMARY/ABSTRACT When a replication fork encounters a DNA lesion in a template strand, replication gives way to DNA repair and recombination. These encounters define an interface in DNA metabolism that can give rise to genome instability. This is ultimately manifested in tumor evolution in eukaryotes and the development of antibiotic resistance and increased pathogenicity in bacteria. In this renewal application, we are investigating perhaps the most enigmatic of repair processes, the repair of lesion-containing post-replication gaps. When a replisome encounters a template lesion, disengages, and then re-initiates upstream, the lesion is left behind in a post- replication gap. The existence of these gaps has been appreciated for over 5 decades, but progress has been limited by methodology that has been inadequate to properly explore their general importance and repair. These gaps are primary substrates for DNA synthesis by translesion DNA polymerases, recombinational DNA repair, and replicational template switching, all processes linked with genomic instability. Work in the last funding period has featured the development of a range of essential new methods, as well as conceptual advances in our understanding of how post-replication gaps are generated and processed. In E. coli, we now know that post-replication gaps are generated several times each replication cycle and that gap formation is triggered by encounters with bulky nucleotide lesions. We have laid out the pathways by which the gaps are targeted and resolved by particular DNA repair proteins. We are now in a position to provide a deep molecular understanding of these pathways. As a bonus, we have identified four potential bacterial vulnerabilities that may eventually provide pharmaceutical advances to treat antibiotic-resistand pathogens or slow the development of antibiotic resistance. We bring together world-class expertise in biochemistry, genetics, molecular biology, and biophysics. We will apply our new methods, including novel single-molecule approaches, towards detecting and quantifying gaps and further characterize the proteins acting on them. While driven by our mechanistic questions, the new methods will broadly benefit research in genomic maintenance. The six specific aims constitute a systematic attack on the problem. Aims 1-3 focus on the recombinational DNA repair of post-replication gaps by the RecFOR system. Aim 4 is an exploration of the single-stranded DNA binding protein (SSB) and how it directs the division of labor in gaps via its interactions with 20 or more different repair proteins. Aim 5 focuses on the gap-related activation of the mutagenic DNA polymerase V and its homologues, the source of most mutagenesis in any bacterial cell. Finally, aim 6 investigate an entirely new biological phenomenon, the presence of DNA sequence elements in the bacterial genome that force the formation of post-replication gaps in particular locations.

NIH Research Projects · FY 2026 · 2019-05

The overarching goal of the renewal of the Wisconsin Alzheimer’s Disease Research Center (ADRC) is to conduct breakthrough research on the pathobiology, preclinical biomarkers, early diagnosis, treatment, and prevention of Alzheimer’s disease (AD) and related dementias. This goal will be accomplished by establishing a stimulating, interdisciplinary environment for collaborative, equitable, and generalizable research that provides invaluable clinical data, ante-mortem biospecimens, and autopsy brain tissue. Funded by NIA in 2009, the Wisconsin ADRC will oversee eight well-integrated Cores and the Research Education Component that will support timely, innovative research, which will: 1) characterize preclinical biomarkers of AD and their role in predicting transition from preclinical to clinical stages of the disease; 2) investigate the neurobiology of AD; 3) identify novel vascular and genetic risk factors, linking them to the disease pathology and clinical phenotype; 4) incorporate contemporary biochemical and molecular techniques into clinical-pathologic cohort studies, including multidimensional omics and next generation sequencing; and 5) participate and facilitate the missions of other federal, state, and local agency-supported aging and dementia research programs. The overall goals of the Center will be accomplished through coordinated activities of its eight Cores and the REC. The Administrative Core will provide scientific leadership to the ADRC. The Clinical Core will perform standardized evaluations and collect UDS and additional data on all research participants. It will work closely with the Outreach, Recruitment and Engagement (ORE) and the Community Partnership (CP) Cores to enhance enrollment of participants from underrepresented groups. The Data Management and Statistical (DMS) Core will continue to meet all data management, informatics, and statistical needs and support all the PC- and web-based services and processes. The Neuropathology Core will continue to provide neuropathologic diagnoses and process, store, and distribute antemortem biospecimens and postmortem brain tissue to support novel research in AD. The ORE Core will provide a broad-range of educational and community outreach programs about AD and support the Wisconsin ADRC’ goal to recruit research volunteers, especially those from URGs into the Clinical Core and other NIA-funded initiatives, such as ACTC, ADCS, ADNI, NCRAD and GWAS studies. The CP Core will work closely with the ORE and Clinical Cores to enhance recruitment and retention of URG participants into the ADRC. The Biomarker Core will support and provide access to resources in preclinical neuroimaging and fluid biomarkers of AD. The REC will coordinate closely with the Clinical, ORE, CP, Neuropathology, and DMS Cores to provide state-of-the-art, competency-based training to learners of varied backgrounds and levels of training, including high school students, undergraduates, doctoral students, postdoctoral fellows, and early-stage faculty in all aspects of aging & dementia research. The Care Research Core will provide novel expertise and resources to conduct innovative studies that will enhance patient care and change clinical practice.

NIH Research Projects · FY 2026 · 2019-05

PROJECT SUMMARY/ABSTRACT This MIRA proposal focuses on the remarkable ability of bacteria to switch from a single cell to a group lifestyle using simple chemical signals, a process called “quorum sensing” (QS). QS has a major impact on human health, with some of the most common pathogens utilizing this signaling mechanism to regulate virulence—i.e., the ability to initiate infection—once sufficient cells have amassed to overwhelm a host. Understanding the molecular mechanisms of QS, its role in mixed microbial communities, and its impact on both acute and chronic disease remain pressing and unaddressed challenges in the field. For example, our understanding of how QS signaling molecules interact with their target protein receptors to activate or inhibit QS pathways is limited to four species in Gram-negative bacteria. We do not know how some of the most common QS signals are transported between cells. Further, with an increasing awareness of the importance of microbial communities (i.e., our “microbiomes”) to human health, it is astonishing how little we understand about the role of chemical signaling between these organisms in the maintenance (or disruption) of healthy microbial consortia. As bacteria use small molecules to regulate QS, synthetic chemists and chemical biologists are well positioned to address these questions and other related challenges at the molecular level. With support from the NIH over the past 17+ years, the PI has advanced the development of synthetic ligands that modulate QS signaling systems in Gram-negative bacteria and has shown that these ligands can strongly attenuate QS- controlled behaviors in many pathogens. This past work situates her ideally to lead this research project. The overall vision for this MIRA project is to build on the PI’s foundation of results and leadership in this area and apply a chemical approach to expand the understanding of QS across multiple scales — from individual QS signal:receptor interactions to signaling at the singular cell level to signaling within one species and on to mixed bacterial populations. We will achieve this vision through the pursuit of three broad Goals: (1) the development of new small molecules capable of strongly modulating QS in Gram-negative bacteria with high potencies and novel modes of action; (2) the application of these molecules and new chemical strategies to delineate the biochemical mechanisms of QS; and (3) characterization QS signal localization and the roles of QS in mixed microbial communities. This project will not just turn the crank for 5 years, using our current methods. We propose a swath of new experimental approaches to explore the chemistry of QS. Studies will be performed in the PI’s laboratory at the UW–Madison and with a team of committed collaborators with expertise in microbiology, biochemistry, genetics, and materials chemistry. The outcome of this project will be a drastically increased and rigorously tested understanding of QS in bacteria and its roles in biologically relevant environments, and a suite of new and freely accessible research tools for the QS field. Our findings should shape the development of new methods to treat bacterial disease and directly impact human health.

NIH Research Projects · FY 2026 · 2019-03

Project Summary The University of Wisconsin Carbone Cancer Center (UWCCC) leadership, faculty, and staff are driven by a mission to defeat cancer through rapid application of groundbreaking research, prevention, and treatment. Embedded in the UWCCC’s strategic plan are tactics for a comprehensive clinical research program with centralized support teams and disease-oriented teams (DOTs) resulting in optimized activation of trials, robust accrual, and exemplary data management. Within the NCI’s National Clinical Trials Network (NCTN), the UWCCC Lead Academic Participating Site (LAPS) multidisciplinary leadership team collaborates with key faculty to support innovative translational research for next-generation clinical trials. Since 1974, UWCCC faculty have functioned as leaders in the development of the NCI cancer cooperative group program; first within ECOG and then with RTOG, ACOSOG and GOG in the early 2000s. As the NCI transitioned the NCTN to a centralized infrastructure in 2014, the UWCCC designed a team of collaborative LAPS principal investigators by combining the existing broad scientific leadership from three of the primary cooperative groups (ECOG-ACRIN, NRG, and Alliance). This multidisciplinary approach with leaders from Surgical, Medical, Radiation, and Gynecologic Oncology has resulted in a cohesive governance structure. The overarching goal of the UWCCC LAPS is to provide scientific leadership in development and conduct of clinical trials in association with adult U.S. Network Groups as well as substantial accrual to clinical trials conducted across the entire NCTN. We will pursue this goal via the following specific aims: 1) utilize the experienced multidisciplinary oncology leadership and the established University of Wisconsin Carbone Cancer Center (UWCCC) Clinical Research Central Office for efficient and compliant conduct of NCTN genomically-directed, therapeutic, and advanced imaging trials; 2) support and develop advanced clinical and translational science within the UWCCC research infrastructure to enable development of Phase II/III clinical and advanced imaging trials within ECOG/ACRIN, Alliance, and/or NRG; and 3) provide effective senior and emerging leadership within the NCTN cooperative groups (ECOG- ACRIN, Alliance, NRG) and related NCI steering committees in order to support the development of innovative genomically-directed, advanced imaging, and therapeutic phase II/III cancer clinical trials as well as to support the NCTN goal of increasing overall accrual to clinical trials. In the six years since our last grant submission, the UWCCC LAPS team has provided support for therapeutic clinical trials, in addition to those with a focus on advanced imaging, while developing approaches to continue strengthening our Cancer Center’s infrastructure. This UG1 application seeks support for continuing the NCTN activities within the UWCCC. This partnership remains an important mechanism for providing cancer patients with novel treatment approaches, as well as a means for providing resources and support for existing and emerging leaders within the NCTN to bring innovative translational projects to Phase II/III clinical trials.

NIH Research Projects · FY 2025 · 2019-01

Botulinum Neurotoxins (BoNTs) are a large family of protein toxins that possess extreme potency and cause severe disease in humans and animals. Botulism is a neuroparalytic disease of long duration, lasting up to several months. Without proper medical care, naturally occurring botulism is lethal in up to 50% of cases, and even with supportive care and antitoxin administration, botulism is a devastating and severe disease and remains lethal in ~ 5 % of cases. While naturally occurring botulism is rare, BoNTs are classified as a Tier 1 Category A Select Agents due to their threat as potential bioterrorist weapons and severity and long duration of the disease. Conversely, BoNTs are widely used human biotherapies to treat more than 200 neuromuscular disorders, some of which are devastating without this unique treatment. BoNTs are divided immunologically into seven BoNT serotypes (A-G), which are further subdivided into subtypes. For example, there are eight subtypes of BoNT/A. Hundreds of BoNT and BoNT-like variants have been identified by sequencing efforts, but only few variants have been investigated for potency and duration of action at the protein level. Note, only two subtypes, BoNT/A1 and BoNT/B1 are currently used as therapeutics. Our recent studies have used BoNT/A subtypes to determine, for the first time, the basis for long duration of action, stable association of LC/A1 on the intracellular plasma membrane, and mechanisms for the high BoNT/A1 potency. This renewal will determine detailed molecular mechanism for the specific durations of action of BoNT serotypes that elicit natural human botulism and LC targeting of SNAP-25 on the plasma membrane. A novel mRNA-based BoNT Light Chain expression system will be used to standardize the determination of BoNT duration of action and potency. Translational studies will develop long duration variants of other BoNT serotypes as alternates for BoNT/A1 as a therapeutic agent to overcome BoNT/A specific treatment resistance. The collaborative efforts of the Pellett and Barbieri laboratories combine computational, molecular, and cellular approaches with BoNT studies by mouse bioassays and in human and rodent cell-based assays, including human motor-neurons. These studies will use native BoNTs, recombinant BoNTs produced in native expression hosts, and individual subunits to assess the two most important aspects of BoNTs, duration of action and potency. A streamlined approach will first investigate subunit domains in functional studies and select specific alterations for the more effort- and cost-intensive construction and analyses of holotoxins. Completion of these studies will provide a detailed understanding of the mechanisms underlying BoNT potency, where in addition to cell entry and catalysis, intracellular LC trafficking and membrane association are contributing factors. The molecular concepts identified in these studies can be extrapolated to other protein toxins.

NIH Research Projects · FY 2026 · 2019-01

PROJECT SUMMARY Breast cancer (BC) lethality is primarily caused by metastasis, which accounts for >90% of BC-related deaths. The epigenetic mechanisms contributing to metastasis remain largely unknown. CARM1 is overexpressed in triple-negative breast cancer (TNBC) and high level of CARM1 expression correlates with poor prognosis. We have previously shown that either CARM1 knockout or treatment with CARM1 inhibitor (CARM1i) significantly decreased the growth and invasion of TNBC in vivo. We recently identified MAP2K4, a stress-activated protein kinase family member, as a substrate of CARM1 in both BC cell lines and primary TNBC tumors. Our results showed that either mutation of the MAP2K4 single methylation site or inhibition of CARM1 affects MAP2K4 activation. MAP2K4 is known to elicit the oncogenic functions in TNBC. We postulate that MAP2K4 methylation by CARM1 potentiates the oncogenic function of MAP2K4. Moreover, loss-of-function MAP2K4 mutations have been linked to the therapeutic response to clinically investigated drugs such as PI3K inhibitors (PI3Ki). We found that CARM1i and PI3Ki synergistically inhibits proliferation and migration of TNBC cells, supporting a TNBC cell autonomous crosstalk between activated MAP2K4 and PI3K to promote tumor growth. Although CARM1i enhances the activity and tumoral infiltration of CD8+ T cells in a 4T1 syngenetic mouse model, CARM1i does not appear to synergize with the anti-PD-1 antibody. We hypothesize that combinatory CARM1 and PI3K inhibition potentiates antitumor immunity and sensitizes TNBC tumors to immune checkpoint inhibitors (ICIs). We propose three specific aims: (1) Determine if MAP2K4 methylation augments the kinase activity of MAP2K4 and enhances JNK activation and cell migration; (2) Delineate the cell autonomous transcriptional network and signaling pathways affected by dual inhibition of CARM1 and PI3K; (3) Develop combined targeted and immunotherapy regimen for treating metastasis in syngeneic mouse models. The objectives of this study are to better understand how MAP2K4 methylation by CARM1 serves as an epigenetic event that contributes to breast cancer metastasis and therapeutically target CARM1 and PI3K to sensitize tumors to ICIs for treating metastatic BC.

NIH Research Projects · FY 2025 · 2018-09

PROJECT SUMMARY/ABSTRACT - T32EY027721, R. Nickells, Program Director The objective of the Vision Research Training Program (VRTP) is to provide the next generation of vision scientists a comprehensive understanding of the basic and clinical science of the nature, prevention and treatment of diseases of the visual system, while preparing them for careers in academic research. We are applying for a renewal of the VRTP T32EY027721 training grant to help achieve this objective. The VRTP is an interdisciplinary training program in the visual sciences that crosses traditional department, school, and institute boundaries. The VRTP supports collaborative and translational research so that trainees are prepared to enter and compete within emerging, interactive research environments. The inaugural period of funding of this T32 represented the first vision-related training grant at UW-Madison and helped overcome a disbursed training structure that was defined by trainees mentored by individual faculty and which did not provide a broader context and cross collaboration among faculty from multiple disciplines. During the last funding period, the VRTP provided resources to facilitate mentor-mentee research activities while also providing a structure that facilitated learning opportunities from a wide range of scientific disciplines as well as exposure to, and interactions with, clinician scientists and clinicians to better understand translational applications of vision research and clinical management of major ocular diseases. If renewed, the VRTP will continue to provide an exceptional scientific and learning environment for trainees to interact with translational and basic scientists and clinicians. UW-Madison is an outstanding environment for the training of future vision scientists. These include a Department of Ophthalmology and Visual Sciences (DOVS) with exemplary prowess in both research and clinical activities; the McPherson Eye Research Institute (MERI); a School of Medicine and Public Health (SMPH) with renown faculty and physical facilities; an equally renowned Graduate School with Schools and Colleges containing numerous graduate programs and outstanding research mentors in the biological, engineering, and computational sciences. The VRTP is a coordinated and collaborative effort between DOVS and MERI. Eighteen faculty affiliated with DOVS and MERI currently comprise the VRTP. They are organized according to four areas of research emphasis: (a) Development and Diseases of the Anterior Segment, (b) Development and Diseases of the Posterior Segment; (c) Ocular Epidemiology and Genetics; (d) Higher Order Visual Processing. Support is being requested for 3 pre-doctoral trainees and 1 post-doctoral trainee. Pre-doctoral trainees will be supported by the training grant for 1-2 years and post-doctoral trainees for 1-3 years. Training will consist of didactic and research components. Trainees will benefit from individual development plans as well as structured career planning and counseling. Significant institutional commitment to training will help ensure the success of the program and provides instruction in the responsible conduct of research.

NIH Research Projects · FY 2026 · 2018-09

PROJECT SUMMARY/ABSTRACT The brainstem is a complex and early-developing brain region that is responsible for sensory, motor, autonomic, and critical-for-life functions. The first biology-based hypothesis of autism suggested that the brainstem's reticular formation was responsible for the behavioral features of autism. However, technological barriers have prevented the field from reliably characterizing brainstem substructures in vivo. Excitingly, recent technological advances now allow us to examine the microstructural properties of the brainstem's individual nuclei and white matter tracts using Magnetic Resonance Imaging. In our original R01, our group contributed to these technological advances through innovative development and refinement of acquisition and post-processing techniques that optimize brainstem imaging. We applied these techniques in autistic children to show how brainstem substructures relate to sensorimotor and core diagnostic features. Yet, the brainstem is highly connected, and we still do not know how the brainstem contributes to autistic whole-brain networks. Leveraging the findings of the original R01, the overall scientific premise of this renewal is that brainstem substructures, as key hubs in whole-brain networks, may hold significant insights into the neurobiological underpinnings of primary and secondary features of autism. Given the functions of the brainstem, we hypothesize that the whole-brain connections of key brainstem nuclei will explain variation in sensorimotor, autonomic, feeding, and core autism features. This hypothesis will be tested through two specific aims: 1) Determine brainstem-inclusive whole-brain network differences and markers of social and repetitive behavior features in autistic children compared to non-autistic children. 2) Identify brainstem- inclusive network associations with sensorimotor and autonomic features in autistic and non-autistic children. We will perform brainstem-inclusive whole-brain tractography across three datasets: 1) our original R01's data of brainstem-optimized imaging and measures of sensorimotor and autistic features in 74 autistic and 74 non-autistic children; 2) a new dataset with further brainstem-imaging improvements, feeding, and respiratory sinus arrhythmia measures in 74 autistic and 74 non-autistic children/youth; and 3) publicly available core diagnostic and neuroimaging data to which we will apply brainstem-optimized processing. An innovative Mahalanobis Distance measure and graph theory measures will quantify group and individual differences in brainstem-inclusive networks. Successful completion of this research will provide a quantitative characterization of brainstem-inclusive whole-brain networks that will advance the understanding of the neurobiological basis for core and co-occurring autism features. These contributions will be significant by paving the way for determining age-appropriate and biology-informed interventions for the prevalent sensorimotor, feeding, and cardiorespiratory differences of autistic individuals.

NIH Research Projects · FY 2026 · 2018-09

Abstract The overarching scientific premise of this application is to evaluate how the accumulation of social advantage and adversity over the full life course impacts risk and resilience against Alzheimer’s Disease (AD) and Related Dementias (ADRD). While there is considerable enthusiasm across the social and biological sciences regarding the sociobiological underpinnings of multifaceted diseases, including a growing research base on the social exposome and social determinants of health, evidence clearly linking *lifetime* social exposures to AD/ADRD remains limited. Existing work has been hampered by the paucity of data that covers the full life course, and relative inattention to how sex and, especially gender, may shape these processes. We address these gaps with the competing renewal application of an NIA-funded R01 (AG06073), entitled the “Wisconsin Longitudinal Study-Initial Lifetime’s Impact on ADRD (WLS-ILIAD)”, which began tracking AD and related dementia onset in 2019 among a cohort of older adults with prospectively collected data extending to their birth year. Having achieved an ~80% response rate during the current grant cycle (2018-2023), the renewed project would continue to assess for dementia as participants surpass age 85. We propose to continue the WLS-ILIAD project to build an invaluable and uniquely comprehensive dataset, which will allow us-and our broader user base-to characterize the AD biomarkers, cognitive, social, behavioral, and medical profile of participants at risk or resilient to dementia. The specific aims for this proposal include: Aim 1: We will continue to track dementia in the WLS cohort using rigorous AD biomarkers, when participants will be ~age 85-90. As before, data will be released for broad public use. Aim 2: We will add plasma AD biomarkers to the full sample (n=~5000) to examine whether core AD biomarkers predict and moderate cognitive function, AD risk, or resilience. Amyloid and tau PET brain scans, and cerebrospinal fluid (CSF) collection will be performed on 200 participants with 100 follow up visits to validate the blood-based biomarkers and identify cut points for specific blood AD biomarkers. Aim 3. Examine how accumulated social advantage and adversity influence risk and resilience against dementia onset, with attention to sex/gender differences. This aim focuses on two forms of resilience. The first is resilience to dementia. Regardless of underlying pathology, the costs attributable to dementia are high, with global health care spending on dementia projected to reach $1.6 trillion by 2050, so attention to its determinants are critical. The second type is the absence of clinical symptoms or dementia in the presence of AD pathology as established through antemortem disease biomarkers. Aim 4: Drawing on AD biomarkers collected in Aim 2, we will fold a large sample (n=468) of African American and Indigenous participants enrolled in the Wisconsin ADRC to analyze how early life advantage and adversity impact resilience in cognitive function in the presence of AD pathology. This extends the aims of the prior grant period’s attention to early life influences on dementia risk and resilience.