University Of Minnesota

NIH Research Projects · FY 2025 · 2021-09

Project Summary/Abstract This proposal seeks continued funding to expand and improve IPUMS CPS, an essential data resource for research on population health and child well-being in the United States. IPUMS CPS streamlines access and reduces technical barriers to analyzing data from the Current Population Survey (CPS), the nation's most comprehensive source of data on the economic and social well-being of U.S. individuals and families, including women of reproductive age and children. IPUMS CPS enables rigorous and reproducible research on population dynamics and the social and economic contexts in which health inequities are created and reinforced, enabling public policy based on sound scientific evidence. Building on an impressive record of accomplishments since 2016, the project will undertake new initiatives to ensure broad access, timely delivery, and innovative use of CPS data for population dynamics and population health research. The project has five specific aims: (1) Database expansion to add more than eight million person records by incorporating 65 new files that will be released between 2021 and 2026, including all CPS monthly and supplement data; (2) Data and metadata improvement to enhance research opportunities, reproducibility, and rigor; (3) Data access improvements to allow users to specify the combinations of CPS data they want linked and the formats in which they will receive the data; (4) Data processing tool enhancement to reduce the time to deliver new data to the research community and reduce the costs of maintaining the infrastructure over the long run; (5) Expand and support the research community through targeted, thoughtful outreach, and active user support and training. CPS data are indispensable for analyzing demographic topics identified in the core mission of the NICHD Population Dynamics Branch, including fertility, migration, population distribution, nuptiality, family demography, population growth and decline, and the causes and consequences of demographic change. They also contain rich measures of the most important non-clinical determinants of health and health inequities. The CPS is vital for evaluating the consequences of social safety net policies for children, individuals, and families; the impact of labor market disruption on marital transitions; and the implications of marital dissolution for economic well-being. With data on entire households, analyses of individual-, couple-, family-, and household-level dynamics are possible. Timely, user-friendly CPS data on the economic and social well-being of the U.S. population has never been more urgently needed.

NIH Research Projects · FY 2025 · 2021-09

Project Summary The COVID-19 pandemic and the co-occurring period of racial trauma has upended family environments and exacted a toll on parents (mothers in particular), racial and ethnic minorities, and sexual minorities. Understanding how parents functioned during this time is crucial to identifying mechanisms linking race, gender, and sexual identity marginalization to disparities in parental well-being with critical implications for child health. Leveraging novel population-based survey and time diary data collected this past year from the National Couples’ Health and Time Study (NCHAT), we will identify mechanisms underlying gender, racial and ethnic minority, and sexual minority disparities in parenting stress and parental well-being during COVID and this period of intense racial trauma. NCHAT (N = 3,642) is a population-representative study of individuals between 20 and 60 living in same and different-gender couples in the U.S. with oversamples of Black, Latinx, and Asian families and sexual minorities. The study includes 41% of partners as well. The analytic sample for this study focuses on the 35% of the sample that had children under 18 (n = 1,274 main respondents; n = 567 partners). This project has four specific aims: Aim 1. Determine gender, racial and ethnic minority, and sexual minority disparities in parenting stress and well-being and parent-child relationship quality and test marginalization, socioeconomic status, and adverse childhood experiences as mediators; Aim 2. Evaluate COVID and racial trauma stress, psychological distress, and couple relationship functioning as moderators of parenting stress and well-being and parent-child relationship quality disparities; Aim 3. Identify dyadic stress processes in the associations between COVID and racial trauma stress, psychological distress, and relationship functioning and parenting; Aim 4. Examine community disruptions and context as moderators of parenting stress and well-being and parent-child relationship quality disparities. Further, the NCHAT data, the contextual data produced for this project on structural racism, sexism, and heterosexism, and NCHAT survey items for harmonization will be shared with the Social, Behavioral, and Economic Research on COVID-19 Consortium Coordination Center (SBECCC) and the wider health research community, leveraging the exceptional resources of the Institute for Social Research and Data Innovation (ISRDI), home to the IPUMS data projects. Forty percent of NCHAT main respondents identify racial and ethnic minorities, and 45% identify as sexual minorities. Data such as these are crucial to the success and inclusiveness of the SBECCC. This study aligns with the U01’s intention to fund “research to understand the health impacts of coronavirus mitigation strategies and the mechanisms that may convey risk and resilience, particularly in underserved and vulnerable populations, [that] will help improve long-term responses to the pandemic and prepare more effectively for the next public health emergency.” Importantly, understanding family experiences and strategies at this historical moment can inform interventions to address health detriments and build resiliency for the future of families.

NIH Research Projects · FY 2025 · 2021-09

Neurostimulation, including invasive methods like deep brain stimulation (DBS), is an increasingly important approach to treating mental illness. It offers the possibility of directly targeting the circuit dysfunctions that produce mental disorders. The clinical use of brain stimulation, and DBS in particular, has been limited by a lack of mechanistic understanding. We do not know why/how stimulating a specific region or pathway leads to symptom improvement. This limits our ability to correctly “dose” stimulation, or to verify biological target engagement. Further, mechanisms are difficult to dissect in humans, because (A) we cannot easily capture stimulation’s effects on brain circuits and (B) human patients cannot tolerate the many repeated experiments needed to map stimulation parameter space. Detailed network/mechanism mapping is possible in animals, but common animal models of psychiatric illness are not strong mirrors of human disease. This project attempts to overcome those barriers by modeling psychiatric DBS’ mechanisms through the lens of cognitive function – behaviors that can be more rigorously measured in both humans and animals. Specifically, we recently showed that DBS of the ventral internal capsule/ventral striatum (VCVS), acts in part by improving patients’ executive function. In two human studies, we showed that VCVS DBS augments cognitive control – the ability to withhold a habitual/default response in favor of a more goal-aligned option. Further, this augmentation translates across species. We applied DBS-like stimulation to a rat homologue of VCVS, during a cognitive control task similar to our human paradigm. We saw improvements that very closely tracked our human results. We now propose to use that reverse-translational model to identify which cellular/circuit elements and neural activity variables mediate this behavioral improvement. A dominant theory argues that DBS in psychiatry works through white matter, e.g. by retrograde modulation of PFC through cortico-thalamic axons in VCVS. Our data suggest, however, that changes in local striatal activity are also important. We will replace electrical DBS with population-restricted optogenetic stimulation, mapping the contributions of individual cortico-thalamic circuits (Aim 1) and striatal sub-regions (Aim 2). During those manipulations, we will record spikes and LFP, at multiple sites within the cortico-striatal cognitive control circuitry. We will identify which variables are most strongly changed by DBS-like stimulation and correlate with behavior change (Aim 3). Success would identify putative mechanisms of a promising neurostimulation therapy, with near-term clinical implications. Technologies already exist to steer the DBS electric field to target specific axons/nuclei, and to titrate stimulation based on physiologic measures. The PI is a DBS psychiatrist, and could use those approaches in his own clinical program to target the mechanisms we identify.

NIH Research Projects · FY 2025 · 2021-09

The overall goal of the University of Minnesota (UMN) Udall Center is to develop novel, circuit based deep brain stimulation (DBS) therapies for Parkinson’s disease (PD) based on an understanding of the changes in pathophysiological activity patterns that occur in basal ganglia thalamocortical-brainstem (BGTC-B) pathways. Project 1 (human) will characterize the role of oscillatory activity, coupling and connectivity across the broader BGTC network, including the subthalamic nucleus (STN), globus pallidus internus (GPi), sensory, motor, premotor and dorsolateral prefrontal cortices. These recordings will be performed at rest and during cognitive- motor tasks, with and without therapeutic interventions (DBS, L-dopa, DBS+L-dopa). It will also clarify the relative effect of stimulation in different functional subregions of the STN and GPi on motor and cognitive function. Project 2 (human) will explore the mechanisms and effects of pallidal DBS on levodopa resistant motor signs using MRI-derived computational models and fMRI to examine the pathways mediating these changes. It will use new sensing technology (Percept) to identify and correlate the physiological changes in the GP to worsening of, or improvement in, gait dysfunction. Project 3 (non-human primate) will examine the electrophysiological changes in pallido↔peduncular, pallido→intralaminar, and pallido→habenular activity that are related to cognitive-motor symptoms providing further network-level insights into cognitive motor gait impairments, task shifting difficulties, and loss of motivation, which will complement the results from the human studies in Projects 1 and 2. All center components have synergistic interactions with the Catalyst Project, which will support research efforts of a promising Early Stage Investigator who will use a novel closed-loop DBS approach to probe circuit dynamics in PD patients and their relationship to PD motor signs. The Imaging Core will acquire state- of-the-art, high-field structural MRI as well as rest and task-based fMRI for PD patients in Projects 1 and 2 (using 7T scanner) and structural MRI for the NHPs in Project 3 (using the first of its kind 10.5T scanner).The Clinical Core will obtain clinical and quantitative motor and neuropsychological assessments that will be correlated to physiological data obtained acutely in the operating room, subacutely in patients with externalized DBS leads and electrocorticography arrays, and chronically through postoperative recordings using Percept. The Biostatistics Core will provide overall data management, quality control, statistical and machine learning analysis and data entry into the NINDS Data Management Resource. The Administrative Core will orchestrate all aspects of the UMN Udall Center, implement and support patient education and public outreach efforts, and develop and monitor individualized career enhancement plans for the next generation of PD researchers. Together, these approaches will provide critical data towards the development and translation of novel patient- specific DBS therapies.

NIH Research Projects · FY 2024 · 2021-09

PROJECT SUMMARY The innermost compartments of the testes’ seminiferous tubules are shielded from the general circulation by the molecular and cellular anatomy of Sertoli cells that form a highly effective blood-tissue barrier. The BTB presents a hurdle to scientific efforts aimed at developing male-directed contraceptives or fertility-enhancing therapeutics that target developing sperm cells uniquely locatedwithin the “adluminal” compartment of seminiferous tubules. Additionally, the adluminal compartment of seminiferous tubules is an “immune privileged site”, providing a safe harbor where pathogens escape both host immunity and anti-pathogenic therapeutics. Thus, developing this specialized tool will provide unique resources needed for institutions to improve the effectiveness of drugs targeting a broad spectrum of human health issues. Our central hypothesis is based on the premise that novel methods for sampling tissues and fluids located behind the BTB will be of great benefit to de-risk drug discovery programs focused on developing therapeutics directed at viral diseases, cancer, parasites and contraception. Our long-term research goals are to expedite the development of pharmaceuticals that will be effective against targets located within the adluminal compartment of the testes. Our objective for the R61 phase of this project is to develop and validate procedures by which we can sample and analyze fluid from the rat’s rete testis, behind its BTB. Sampling fluid from behind the rat BTB will allow researchers to verify how effectively their test drugs are able to cross the BTB and interact with targets located in the testes’ pharmacologically privileged sites. Furthermore, we will identify and validate molecular reference standards that will be used to compare relative abilities of test compounds to cross the BTB. Finally, we will determine the feasibility of adapting the rat procedure to a mouse system. Our objective for the R33 phase of this project is to identify unique chemical structures and/or scaffolds that will penetrate the BTB and to also establish and validate a robust sampling method in the mouse since it is the predominant species used for efficacy models ranging from fertility/contraception, infectious disease and cancer. Although similar in structure and function, rat and mouse BTB can differ significantly in a host of factors such as transporter and macromolecule composition.

NIH Research Projects · FY 2025 · 2021-09

PROJECT SUMMARY Pancreatic ductal adenocarcinoma (PDA) is a highly lethal malignancy with a 5-year overall survival of <10%. Lethality is due to late diagnosis, early metastasis and therapeutic resistance. A hallmark characteristic of PDA is the robust fibroinflammatory and suppressive tumor microenvironment that compresses blood vessels and restricts drug access. This tumor microenvironment is also believed to interfere with immunotherapies, which are transforming the standard of care for many other cancer indications. Tumor-antigen specific T cells are responsible for mediating the therapeutic effects of immunotherapy. While much has been learned about suppressive cells within the pancreatic tumor microenvironment, factors that impact the differentiation program of antigen-specific T cells and their antitumor activity is markedly understudied in this disease. We created a novel engineered T cell therapy that shows marked anti-tumor and anti-stromal activity in an aggressive and difficult to treat genetically engineered PDA animal model that recapitulates many aspects of the human disease, including response to immunotherapy. T cells engineered to express a tumor-reactive T cell receptor specific to mesothelin, which is highly expressed by tumor cells yet poorly expressed by normal cells, is safe, destroys the stroma, alters myeloid cell composition, induces objective responses, and significantly prolongs animal survival. Notably, engineered T cells preferentially accumulate in primary tumors and metastasis, challenging the dogma that PDA is immune privileged. Based on this efficacy, candidate T cell receptors specific to mesothelin for use in patients have been identified leading to a Phase 1 clinical trial. However, despite engineered T cell persistence and significant antitumor activity in vivo, a principle obstacle to cure is the progressive loss of engineered T cell function within the suppressive pancreatic tumor microenvironment. While T cell functionality and differentiation are well-studied in other cancer indications, little is understood regarding how the pancreatic tumor microenvironment impacts tumor antigen-specific T cells. Here, we incorporate innovative tools we have developed to identify mechanistically how engineered T cells mediate stromal remodeling, how the tumor adapts and evades anti-tumor T cells, and then use this knowledge to develop a cutting edge engineered T cell therapy for patient treatment with strategic advancements as compared to most cell engineering approaches. Our Specific Aims are to: (1) Identify how engineered T cells mediate stromal remodeling, (2) Identify the contribution of TCR affinity and the tumor microenvironment on T cell differentiation and functionality, and (3) Test the safety and efficacy of a novel cell engineering approach for targeting solid tumors. Our studies will identify characteristics of T cells and the tumor microenvironment that produce durable antitumor responses during immunotherapy to create safe and durable clinical opportunities for pancreatic cancer patient treatment.

NIH Research Projects · FY 2025 · 2021-09

ABSTRACT A key limitation to effective immunotherapy is the physical access of immune cells to the cancer cells. We propose to develop a multiscale tumor simulator to predict tumor dynamics based on immune and cancer cell migration and net proliferation as measured quantitatively from live cell microscopy. The tumor simulator will be developed by biomedical engineers working in close collaboration with immunologists and genetic engineers who are developing immunotherapies for pancreatic ductal adenocarcinoma and glioblastoma. The tumor simulator will be a computational platform that will help guide immunotherapy development and so will evolve to become an immunotherapy simulator. In addition, we will integrate state- of-the-art genome engineering and microenvironmental engineering to bring a full suite of engineering approaches to bear on the simulator development. Together, the simulator will be used to make quantitative, testable predictions that are then tested experimentally using pharmacological and genetic perturbations. By iterative model development we will test our central hypothesis that immune cell proximity is a major determinant of effective anti-tumoral immune response, and limiting to effective immunotherapy of solid tumors. Altogether, our Program Project will develop a comprehensive biophysics-based simulator to predict tumor progression and accelerate immunotherapy development.

NIH Research Projects · FY 2025 · 2021-09

Summary In response to PAR-19-269, “Cognitive Systems Analysis of Alzheimer's Disease Genetic and Phenotypic Data”, we propose developing and applying more powerful and robust machine learning methods for causal and integrative analysis, especially deep learning approaches for instrumental variable analysis, to identify causal risk/protective factors for Alzheimer's disease (AD) in the post-GWAS era by leveraging published large-scale GWAS, whole-genome sequencing (WGS) and other omic and neuroimaging data. Our main motivation is to ex- tend an emerging and increasingly influential approach of integrating GWAS with gene expression data, called transcriptome-wide association studies (TWAS), aiming to improve over the current practice of GWAS by not only increasing statistical power, but also identifying (putative) causal genes, thus gaining insights into the genetic basis of common diseases and complex traits. The statistical principle underlying TWAS is the (two-sample) two-stage least squares (2SLS) for linear models in the framework of instrumental variable (IV) analysis for causal inference. In practice, however, TWAS may fail to identify true causal genes while giving false positives due to the violation of its modeling assumptions, e.g., due to non-linear effects of IVs or gene expression, or due to invalid IVs (in the presence of horizontal pleiotropy of SNPs). First, we propose developing linear models and neural network models incorporating a large number of functional annotations on the genome (e.g. various types of functional genomic and epigenetic data from the ENCODE and Roadmap Epigenomics projects) as prior knowledge to improve im- puting/predicting gene expression (or other molecular or imaging endophenotypes or complex traits/diseases) via SNPs, corresponding to the first stage of 2SLS. Second, we propose neural networks as more flexible non-linear models for the second stage of 2SLS in the presence of invalid IVs, which may be the SNPs having direct (or horizontal pleiotropic) effects on the outcome as expected from the wide-spread pleiotropy. Then we combine the approaches in the above two stages to form a more flexible and robust neural network approach as an extension of 2SLS for causal inference. Third, we consider inferring causal directions between two traits, e.g. a gene's expres- sion and AD, allowing non-linear relationships between SNPs and traits and between the two traits. This is critical in reducing false positives, e.g. due to reverse causation, but has been largely under-studied. Fourth, we apply the new (and existing) methods to transcriptomic, proteomic, neuroimaging and AD GWAS/WGS data to identify (pu- tative) causal genes, proteins and brain regions of interest (ROIs) for AD, while building the corresponding genetic prediction models for endophenotypes and AD risk. Finally, we will develop and disseminate publicly available software implementing the proposed analysis methods, e.g. as Python programs or R packages, to facilitate the wide use by the scientific community.

NIH Research Projects · FY 2025 · 2021-09

PROJECT SUMMARY/ABSTRACT The long-term goal of this research is to define the mechanisms of action of a successful cell transplantation therapy for chronic spinal cord injury (SCI) and to translate this knowledge from bench to bedside for patients. Human SCI currently has no effective treatment, and any new treatments would have a significant impact on public health. The overall objective of this proposal is to determine whether transplantation of regionally specific bioprinted spinal neural progenitor cells (sNPCs) in combination with a 3D printed scaffold can result in the formation of functional neuronal networks within the injured adult rat spinal cord. We have three specific aims. The first aim is to optimize the biomaterial and design of the 3D printed scaffold, as well as the cell-laden bioink utilized in bioprinting. The second aim is to determine the optimal cell configuration of two types of regionally specific sNPCs within the scaffold to form functional neuronal networks. The third aim is to test our scaffold in a rat model of transection injury to determine whether our cells can provide a relay system across the site of injury, and whether this will result in functional recovery. We will perform detailed functional, histological, and electrophysiological analyses to elucidate the mechanisms of our combinatorial treatment. The scientific premise is that there is a synergistic relationship in providing the substrate (cells) for a relay system across the injury site and optimizing this with a conduit (scaffold), providing an effective relay for neuronal signaling leading to functional recovery.

NIH Research Projects · FY 2026 · 2021-09

PROJECT ABSTRACT While cigarette smoking and smokeless tobacco use has declined among American youth over time, use of electronic cigarettes – or vaping – among youth has increased tremendously. The recent vaping-related acute lung injuries and deaths as well as the first animal studies linking vaping to cancer have highlighted the need to respond to e-cigarette use among youth. In Aim 1, the project will assess the relationship between spatial density and proximity of tobacco/e-cigarette retailers around schools and county-level youth e-cigarette use and marketing exposure in Florida, overall and by county-level sociodemographic characteristics and racial/ethnic segregation. In Aim 2, it will qualitatively explore where, how, why, and from whom youth access e-cigarettes, interactions with tobacco/e-cigarette retailers, exposure to e-cigarette marketing, and combined substance use, as well as whether these factors differ across neighborhood sociodemographic characteristics using participatory mapping and focus groups. Finally, in Aim 3, I will leverage a natural experiment in tobacco regulation across three Florida counties to assess whether T21+TRL is more effective in reducing youth ENDS use and marketing exposure than T21 alone using quasi-experimental methods – comparative interrupted time series and difference-in-differences analysis. Dr. Zinzi Bailey is an Assistant Scientist in the Jay Weiss Institute for Health Equity at the Sylvester Comprehensive Cancer Center at the University of Miami Miller School of Medicine. As a Black woman in academia where Black women are underrepresented, Dr. Bailey seeks a K01 Mentored Research Scientist Development Award to Promote Diversity to gain the skills, experience, and preliminary data needed for an independent, policy-focused research program in translational cancer disparities research. Dr. Bailey will integrate her background in social epidemiology and tobacco smoking behavior with methods and theories that capture the socio-ecological complexity of tobacco regulation and its potential impact across communities. To achieve this goal, Dr. Bailey proposes to gain the training and experience in policy analysis using quasi- experimental designs, geographic information systems, and participatory research through mentorship, coursework, workshops/seminars, and scientific meetings. Her career development objectives include (1) obtaining training in quasi-experimental designs for policy analysis, (2) advancing my expertise in assessing local, state, and federal tobacco policies and regulations, (3) receiving formal policy-relevant training in geographic information systems (GIS) and spatial econometrics, and (4) developing methodological training on qualitative, participatory methods. This study will lay the groundwork for a tobacco regulation-oriented research program that blends multiple methods of policy analysis to guide the translation of disparities-focused research to evidence-based policy.

NIH Research Projects · FY 2025 · 2021-09

Project Summary/Abstract Children with developmental language disorder (DLD) demonstrate language deficits in comparison to unaffected peers from similar language-learning environments. Because of the diversity in children’s language-learning environments, the linguistic characteristics of DLD differ across children. However, affected children may share common underlying deficits in cognitive processing skills such as processing speed, working memory, and sustained selective attention. This project systematically examines the cognitive processing profiles of individual children with DLD from different language-learning environments to identify common patterns of deficit and utilize them to identify DLD. We include children aged 5- to 7-years from three different language groups (English only, Spanish-English, and Vietnamese-English); within each of these three groups, both children with typical development (n = 60 per group; n = 180 total) and children with DLD (n = 20 per group; n = 60 total) are represented. Participants will complete assessments of processing speed, working memory, and sustained selective attention in the visual and auditory modalities using nonlinguistic stimuli to avoid bias based on linguistic experience (for bilingual children) or linguistic deficits (for children with DLD). The project will establish the reliability and validity of each assessment task to ensure suitability for clinical use (Aim 1). Cluster analyses will determine common profiles of cognitive processing skill and whether these profiles differ for children with and without DLD (Aim 2). Diagnostic accuracy analyses will be conducted to determine whether nonlinguistic cognitive processing tasks can identify children with DLD within a diverse group of language learners (Aim 3). This project will advance understanding of the underlying cognitive mechanisms that contribute to DLD by examining commonalities across children learning language in diverse circumstances. It will also establish a novel and universal approach to DLD identification that will reduce disparities across children.

NIH Research Projects · FY 2025 · 2021-09

PROJECT SUMMARY To ensure that emerging technologies grow without causing illness or injury to workers and the public, a professional workforce must be prepared with the ability to anticipate, recognize, evaluate, and control exposures to hazardous materials in emerging technology workplaces. Therefore, the University of Minnesota, the University of Iowa, and University of Utah have formed the Interdisciplinary Training, Education and Research Activities for Assessing And Controlling Contaminants From Emerging Technologies (INTERACCT) Program. The objectives of the INTERACCT Program for this funding period are (i) to develop a comprehensive web-based curriculum on occupational hygiene, with emphasis on applications to worker health and safety in emerging technologies. To accomplish this objective, we will develop three online core courses for education and training in chemical hazard recognition, exposure assessment, and risk assessment. In the cores, we will demonstrate concepts with examples and illustrations drawn from the following emerging technologies: nanotechnology, additive manufacturing and novel drug delivery. Each core in the curriculum will be comprised of 10-15 web-based modules; each module, in turn, will include a carefully-constructed set of short narrated screencasts, animations, exercises, and activities. (ii) to build research in industrial hygiene skills. To accomplish this objective, we will provide interdisciplinary research experience opportunities to graduate students. (iii) To produce graduates with high levels of technical, scientific and proessional competency. To accomplish this objective, Instructors will use the curriculum to create academic and continuing education courses that develop the skills of industrial hygiene students; students in other health, science, engineering, and technology disciplines; and professionals who require continuing education on the health and safety of emerging technologies. The program is innovative because it provides flexible, online education materials that instructors can first use to train themselves, and then to train others, on topics that fit the needs of their organizations. All materials will be freely available on the web, ensuring that the INTERACCT Program has a regional, national, and global reach.

NIH Research Projects · FY 2025 · 2021-08

Antiretroviral therapy (ART) is recommended for all people living with HIV (PLWH) – regardless of their CD4 cell count – to improve survival and reduce transmission. This “treat-all” approach benefits PLWH overall, but also confers a risk of unmasking immune reconstitution inflammatory syndrome (IRIS) and death, particularly for the 30-40% of people who present with advanced HIV disease (CD4 count <200 cells/µL) worldwide. In 2017, the World Health Organization (WHO) recommended that persons with advanced HIV disease be screened for opportunistic infections (OIs) and given prophylaxis for tuberculosis (TB) and cryptococcal antigen (CrAg). However, because this screening and prophylaxis package has never been validated in a clinical trial, it is not consistently implemented in sub-Saharan Africa. Compounding the problem, funding for CD4 testing has been reduced by stakeholders as CD4 testing is no longer needed for ART initiation. Consequently, identification of persons with advanced HIV disease via CD4 testing and OI screening and prophylaxis often does not occur in reality. As a result, early mortality after ART initiation remains high. Subsequent to the release of the initial 2017 WHO recommendations for OI screening and prophylaxis, several novel point-of-care diagnostics and treatments for OIs have emerged: ● Visitect point-of-care CD4 assay provides a visual result of CD4 count >200 of <200 cells/µL, with a sensitivity of 92% and specificity of 89% in venous blood; ● Semi-quantitative CrAg lateral flow assay (CrAg-SQ LFA) can detect persons with CrAg titers who likely have disseminated infection and are at risk of meningitis/death despite standard of care antifungal therapy; ● Fujifilm SILVAMP TB LAM, a new point-of-care TB urinary test, has 70% sensitivity and 91% specificity; ● Isoniazid (INH) + Rifapentine given for one month for latent TB treatment is non-inferior to 9 months of INH. The objective of this proposal is to improve survival in persons with advanced HIV disease. We will implement a 2x2 factorial, cluster-randomized trial in 24 Ugandan clinics to: (Aim 1) determine the survival benefit of a novel point-of-care CD4 test compared with standard flow cytometry CD4 testing in persons with advanced HIV disease; and (Aim 2) determine the survival benefit of an enhanced diagnostic OI screening and prophylaxis strategy in persons with advanced HIV disease. The enhanced OI screening and prophylaxis strategy will include point-of-care FujiFilm TB LAM, CrAg-SQ LFA, with enhanced prophylaxis for TB (1 month of INH + rifapentine), and referral of plasma CrAg+ with high titers to hospital. Survival and retention-in-care will be assessed at 6 months. Lastly, (Aim 3) we will evaluate the cost and cost-effectiveness of the CD4 testing strategies (described in Aim 1) and OI screening and prophylaxis strategies (described in Aim 2). Findings from this trial will have the potential to impact international HIV treatment guidelines on optimal management of persons with advanced HIV disease in order to reduce HIV-related mortality globally.

NIH Research Projects · FY 2024 · 2021-08

PROJECT SUMMARY Surgical technical skills directly impact patient outcomes. There remains a need for objective, accurate, and inexpensive methods to measure such skills in a manner that can scale to the large number of surgical residents and practitioners. The long term goal of this research program is to improve surgical training and assessment by establishing more scientifically-rigorous foundations for accurate, objective evaluation of surgical technical skills and their relationship to surgical outcomes. The overall objective of this research proposal is to determine the biases, limitations, and absolute accuracy inherent in the putative gold standard of surgical technical skill evaluation—review of video footage by a panel of human raters—across representative procedures in three surgical specialties: urology, gynecology, and orthopedic surgery. The central hypothesis is that both expert and non-expert raters are subject to unconscious bias and limitations in their capacity to evaluate surgical technical skills objectively and accurately. This will have positive impact on advancing the science and improving the practice of surgical skill evaluation for surgical residency programs. The research will answer the following questions, at least for representative procedures from urology (robotic prostatectomy), gynecology (robotic hysterectomy), and orthopedic surgery (hip fracture fixation and pedicle screw placement). 1. What is the magnitude of identity bias (gender, ethnicity, etc.) in the evaluation of surgical technical skills? a. How do ratings change from the control condition (identity-blind) to identity-visible for gender, race, age, or perceived reputation? b. How does this bias change across skill levels? (e.g. preliminary evidence shows that perceived females are docked more severely than males among novice skill levels, but less so at proficient levels). c. How much do faculty semester evaluations of resident technical skill (current widespread practice) differ from identity-blind skill evaluation (anonymized review of video)? Especially across gender? 2. What is the optimal user interface and conditions for identity-blind web-enabled review of surgical video that maximize skill discrimination and minimize reviewer resource cost? 3. What is the absolute accuracy of human raters? i.e., how imperfect is the gold-standard of technical skill evaluation

NIH Research Projects · FY 2025 · 2021-08

PROJECT SUMMARY/ABSTRACT – University of Minnesota The Collaborative Pediatric Critical Care Research Network (CPCCRN) has been critical in building the knowledge base of pediatric critical care medicine. The overall aim of this site proposal is for the University of Minnesota Masonic Children's Hospital (UMMCH), under the leadership of Site Principal Investigator, Marie Steiner, MD, MS, to join this expanded iteration of CPCCRN. UMMCH is a free-standing, quaternary care, academic children’s hospital located in Minneapolis, MN, serving children and families across a diverse range of racial, ethnic, and socioeconomic backgrounds. It has a 24-bed mixed medical/surgical and cardiac pediatric intensive care unit and offers the full spectrum of pediatric and surgical subspecialty services. UMMCH has a strong history of clinical research and innovation in conjunction with the resources of the University of Minnesota, the state’s land grant university. Pediatric critical care research includes numerous completed and ongoing studies championed by multiple faculty, including the Co-Investigators for this grant. With increasing support from internal and external grants and the development of the Pediatric Device Innovation Center, the Division was third in the Department in launching new studies in 2019, behind Hematology/Oncology and HSCT. Children's Minnesota (Children’s) will serve as our Ancillary Site under the leadership of Alberto Orioles, MD. Children’s is a not-for-profit, freestanding children’s hospital also located in Minneapolis, with a long-standing history of participation in critical care research, including several CPCCRN studies. Together, UMMCH and Children's will provide access to 55 pediatric ICU beds and over 3500 annual admissions, which captures the majority of critically ill children throughout the Upper Midwest and will facilitate participation in large clinical trials. The proposed “Personalized Immunomodulation in Sepsis-Induced Multiple Organ Dysfunction Syndrome (MODS)” trial addresses the hypothesis that immunosuppressed children will benefit from administration of granulocyte macrophage-colony stimulating factor and that children with hyperinflammation will benefit from targeted anti-inflammatory therapy. Benefit will be evaluated in terms of recovery from MODS, as well as short- and long-term health-related quality of life measures. This partnership has the knowledge and skills to successfully complete this trial, including sample collection and processing for immunophenotyping and collection of short- and long-term outcomes. Drs. Steiner and Orioles have the full support of their respective institutions to participate in CPCCRN and to prioritize patient recruitment and accrual to its studies. The institutions are strongly committed to collaboration with CPCCRN sites and the Data Coordinating Center to conduct the proposed and future research. Our clinical center and ancillary site will provide local mentorship for our highly talented young faculty and will support their participation in the central CPCCRN mentoring activities that are described in Section B.3 of the required CPCCRN Network Organizational Structure attachment to the Overall Component of this PL1 application.

NIH Research Projects · FY 2024 · 2021-08

Abstract Over the last decade Chimeric Antigen Receptor based T cell therapy (CAR-T) has developed into an effective immunotherapy for some cancers. However, CAR-T cell therapies have several shortcomings and clinical success has primarily been limited to hematological cancers. Challenges of CAR-T cell therapy include tumor immune evasion through loss of target antigen expression by tumor cells and inhibition of CAR-T cell function by tumor expressed inhibitory molecules. Natural killer (NK) cells present an alternative to T cells that could be more effective due to their ability to perform both antigen dependent and independent killing. NK cells have demonstrated antigen specific killing when engineered to express T cell CARs and NK cells also mediate the direct killing of transformed cells with reduced or absent MHC expression. In fact, NK cells carry out antibody dependent cell mediated cytotoxicity (ACDD) of cells that bind antibodies via the NK cell CD16A receptor. Due to the multiple modalities for cancer cell killing, there is an increased interest in NK cells for cancer immunotherapy. As NK cells are not associated with graft versus host disease, neurotoxicity, long-term autoimmunity, nor cytokine release syndrome, they are more suited for use in allogeneic settings than T cells and have significant clinical potential for use as off-the-shelf products. However, previous publications and clinical trials have demonstrated that the use of unmanipulated NK cells to treat cancer is minimally effective, likely due to limited engraftment, little in vivo expansion, and suppression by the tumor microenvironment. NK cells activated and expanded with feeder cells expressing membrane bound interleukin-21 (mbIL-21) have shown promising results clinically with high-risk myeloid malignancies and preclinically in several solid tumor models. Therefore, we hypothesize that activated/expanded NK cells that have be genetically edited can be used to successfully treat osteosarcoma, a disease for which patient outcome has not improved in over thirty years. Our proposed objectives are to evaluate the baseline response of rested- and activated-NK cells against various osteosarcoma cell lines, knockout negative regulators of NK cell function (specifically, c-CBL, IL-1R8, and SMAD3), and implement a specific CAR that optimally activates NK cell antigen-specific killing. Genetically engineered NK cells will be evaluated for enhanced therapeutic efficacy and safety in osteosarcoma models. Our preliminary data strongly supports the hypothesis that NK cell-based cancer immunotherapy can be fully realized using activated, genome engineered NK cells.

NIH Research Projects · FY 2025 · 2021-08

Project Summary / Abstract Dr. Mahsa Abassi is an Assistant Professor of Medicine in the Division of Infectious Diseases at the University of Minnesota. Over the past six years, she has been engaged in clinical research, focusing on HIV- related neuroinfections in Uganda. Her long-term objective is to become an independent clinical researcher with an emphasis on improving outcomes in neuroinfections. Her career development plan proposes mentored training in: 1) neurologic techniques (EEGs, neuroradiology, and neurocognitive assessment), 2) laboratory techniques related to metabolomics applications, and 4) biostatistics with an emphasis of analyzing metabolites in biologic samples. Research: Cryptococcal meningitis accounts for 15% of HIV/AIDS-related deaths globally and is the most common cause of adult meningitis in Africa. Altered mental status (ranging from delirium to coma) at the time of cryptococcal meningitis diagnosis is consistently an independent predictor of increased mortality. Despite repeated studies confirming this strong association between altered mental status and death, there is a fundamental lack of understanding into the exact neurological abnormalities leading to acute altered mental status, its contributions to increased mortality, and the best practices for management. The objective of this proposal is to identify the neurological abnormalities that contribute to altered mental status and to understand how this contributes to increased cryptococcal mortality. The overarching hypothesis is that cryptococcal meningitis with its increased intracranial pressure leads to cerebral hypoxia, abnormal electrical activity, and biochemical changes in the central nervous system (CNS) that can be detected through brain metabolite CSF analysis and enhanced clinical monitoring with cerebral oximetry and EEGs. This proposal aims to: 1) determine if HIV-infected persons with cryptococcal meningitis presenting with altered mental status (Glasgow Coma Scale (GCS) <15) at diagnosis have measurable underlying neurological abnormalities and impairments in cerebral energy metabolism (i.e. insufficient oxidative metabolism) as compared to persons with normal mental status (GCS=15); and 2) determine if implementation of standardized clinical interventions can reverse neurological abnormalities and improve cerebral energy metabolism within 3 days of diagnosis, and reduce 30-day mortality in HIV-infected persons with cryptococcal meningitis presenting with altered mental status (GCS<15). Results of the above aims will shed light into previously unknown pathophysiologic mechanisms that lead to altered mental status in cryptococcal meningitis. The training in neuroinfections, metabolomics applications, and biostatistics that Dr. Abassi will obtain will inform future proposals dedicated to understanding the neuropathology of various neuroinfections and finding evidence- based interventions dedicated to improving survival.

NIH Research Projects · FY 2025 · 2021-08

PROJECT SUMMARY/ABSTRACT This K23 application proposes a career development plan to help Dr. Emily Kringle establish an independent research program that focuses on optimizing health among adults with stroke-related disability and other neurological disabilities. She will train under the mentorship of a transdisciplinary group of senior scientists with research expertise in behavioral clinical trials, stakeholder-engaged intervention development, qualitative research methods, and interpersonal theories and methods. She will continue working with her current T32 mentors, Drs. Jun Ma and Megan Lewis, both of whom have extensive experience mentoring trainees. This will be complemented by content and mentoring expertise from Drs. Bethany Barone Gibbs, Elizabeth Skidmore, and Dilip Pandey. Collectively, this team will provide an outstanding training environment that will allow Dr. Kringle to fill critical gaps in her knowledge and skill set relating to the study of lifestyles interventions and interpersonal social dynamics that influence post-stroke sedentary behavior and quality of life. Her training goals are to develop skills in (1) design and analyses of conventional and contemporary behavioral clinical trials, (2) qualitative analyses of stakeholder engagement data, (3) theory, measurement, and analyses of interpersonal (dyadic) influences on post-stroke health behaviors, and (4) professional skills in interdisciplinary team science and scientific leadership. Achieving these goals will strengthen her scholarly activities, establish important collaborations, and acquire critical data that will ensure her successful transition to independence. To this end, Dr. Kringle’s proposed research plan that builds directly on her prior work developing the Activating Behavior for Lasting Engagement (ABLE) intervention. ABLE uses behavioral activation to reduce post-stroke sedentary behavior. Reducing sedentary behavior is particularly important for promoting health in the context of stroke-related disability. Even if impairments (motor, cognitive, sensory) fully resolve, stroke survivors do not automatically re-engage in non-sedentary activities as impairments diminish. Further, residual impairments, social influences (protective care providers), and environmental factors (transportation, accessibility) create barriers to engagement in personally meaningful non-sedentary daily activities. The purpose of this proposal is to adapt ABLE to telehealth (teleABLE), targeting the first year post-stroke, and evaluate its acceptability, fidelity, and potential effects in a pilot randomized clinical trial. We will also explore factors that are potential moderators or theoretically driven mediators of intervention outcomes. Embedded within this trial is data collection from stroke survivors’ social support person to explore interpersonal (dyadic) influences on post- stroke sedentary behavior. Findings from this study, in combination with the career development plan, will enable Dr. Kringle to launch an independent program of research that aims to 1) develop interventions that reduce post-stroke sedentary behavior to enhance health and quality of life, and 2) elucidate the role of interpersonal social dynamics in health behaviors and quality of life among adults with stroke-related disability.

NIH Research Projects · FY 2024 · 2021-08

Project Summary/Abstract This proposal aims to examine four interrelated pathways by which psychosocial and socioeconomic stressors may lead to poorer bladder health (lower urinary tract symptoms [LUTS] and impact of symptoms) among women and men across the life course: affective, cognitive, behavioral, and physiological pathways. The proposed work leverages data and intellectual resources from two NIH initiatives, the 30+ year Coronary Artery Risk Development in Adults (CARDIA) cohort study, initiated in 1985, and the Prevention of Lower Urinary Tract Symptoms (PLUS) Research Consortium, initiated in 2015. LUTS, including overactive bladder (OAB) and urinary incontinence (UI), affect the lives of millions of women and men. Prevention of LUTS has been hindered by a lack of epidemiologic research utilizing life course data. In addition, little research has incorporated the concept of well-being and examined factors that promote and maintain bladder health, defined by the PLUS Research Consortium as “a state of complete physical, mental, and social well-being…that permits daily activities, adapts to short-term physical and environmental stressors, and allows optimal well- being (e.g., travel, exercise, social, occupational, or other activities).” The proposed research, which extends beyond PLUS Research Consortium activities, utilizes existing CARDIA data from women and men with bladder health and LUTS and invites a subsample of CARDIA participants recruited from the Year 35 examination (ages 53-65; funded for 2021-22) to complete a new clinical examination. Analyses will strengthen the evidence base for individual pathways that may promote bladder health or LUTS. It is hypothesized that poorer bladder health/LUTS status will be observed as a result of (1) depressive symptoms (affect), (2) impaired cognition, (3) behavioral factors (poor diet, physical inactivity, smoking), and (4) physiological factors (weight gain, central adiposity, hyperglycemia, hypertension, inflammatory biomarkers, and pelvic floor muscle weakness). Analyses will also establish the evidence base for psychosocial and socioeconomic stressors. It is hypothesized that stressors (adverse childhood family environment, stressful life events, job strain, caregiving stress, chronic burden, discrimination, financial hardship, low subjective social standing) will be associated with poorer bladder health/LUTS status. Finally, analyses will examine whether individual pathways mediate proposed associations between stressors and poor bladder health/LUTS status, and whether resources for support weaken hypothesized effects. There is a clear need to develop new approaches to improve both prevention and early treatment of LUTS. Our findings may inform “upstream” approaches (e.g., amelioration of specific stressors shown to serve as risk factors, enhancement of social support and ties shown to serve as a protective factors), as well as “downstream” approaches (e.g., treatment of depressive symptoms; cognitive training exercises; weight loss; behavior modification, including pelvic floor exercises).

NIH Research Projects · FY 2024 · 2021-08

PROJECT SUMMARY Approximately 20% of adolescents in the US have obesity, which is significant because of its many health consequences, including cardiometabolic disease leading to premature death. Treatment of obesity is particularly important for adolescents because obesity in this age group also increases the risk for lower income and lower educational attainment in adulthood. The cornerstone of all forms of obesity treatment is behavioral modification strategies that support daily dietary and physical activity change. Self-monitoring is a powerful behavioral tool that is grounded in Social Cognitive Theory. This theory states that greater self- awareness through proximate self-measurement improves self-efficacy, self-control, and self-reinforcement. Self-monitoring of weight through daily self-weighing (SW) at home has been found to be effective and safe for weight loss and maintenance in adults, particularly when there is external accountability for the home weights. Daily SW at home with accountability to clinic represents a scalable intervention that can be feasibly implemented into the clinical care for adolescents with obesity. However, daily SW at home has not been prospectively assessed in adolescent patients with obesity who are seeking obesity treatment. The objective of this proposal is to evaluate the feasibility, acceptability, safety, and estimate the effect on weight of daily SW at home, integrated with the electronic health record (EHR) and clinical care of adolescents with obesity. I will: 1) Use mixed methods to determine adolescent and parent perspectives on daily weighing on smart scales connected to the EHR as a tool for adolescents with obesity who are seeking weight loss treatment; 2) Determine clinician and clinic staff perspectives on daily weighing on connected to the EHR; and 3) Conduct a randomized, clinic-based pilot study to compare the feasibility, acceptability, safety, and estimate the effect size of three conditions in a weight management clinic for adolescents with obesity: a) usual care, b) usual care + daily SW at home on a simple scale, and c) usual care + daily SW at home on a smart scale that is connected to clinic (with individualized feedback to the patient). I will prospectively and serially assess mood, body image, stress, weight management practices, and disordered eating behaviors. This project will generate critical preliminary data to inform the design of a larger study (R01) that fully evaluates safety and efficacy of daily SW at home, with and without regular external accountability from clinic, in adolescents with obesity. Completing this K23 training program will allow me to establish skills in mixed methods, epidemiologic methods and intervention design, and foundational skills in implementation of digital technology, as well as lay the groundwork for leading novel and high-impact obesity studies. The multidisciplinary mentorship during this career development award will prepare me to become an independent, extramurally-funded clinician scientist who investigates clinic-based interventions for obesity treatment.

NIH Research Projects · FY 2025 · 2021-08

Summary Muscular dystrophies are genetically and clinically heterogeneous disorders characterized by progressive weakness and degeneration of the skeletal muscles that control movement. The most common, Duchenne Muscular Dystrophy (DMD), is caused by genetic and biochemical defects of the dystrophin-glycoprotein complex (DGC). These alterations lead to cell membrane damage and death of muscle cells, resulting in chronic tissue degeneration and impaired muscle contractility. Although no effective treatment is available at present, one attractive therapeutic approach is to use cell-based therapies to promote muscle regeneration. There has been tremendous excitement for the therapeutic potential of induced pluripotent stem (iPS) cells in treating genetic diseases since these cells have virtually unlimited proliferation potential, and can differentiate into all cell types. We have pioneered a method to generate engraftable skeletal myogenic progenitors from pluripotent stem cells through conditional expression of Pax3 or Pax7. This approach results in highly efficient generation of therapeutic myogenic progenitors, which when transplanted into dystrophic mice locally or systemically produce large quantities of functional skeletal muscle tissue that incorporates normally into the host muscle. Importantly, a fraction of transplanted cells remains mononuclear, and displays key features of skeletal muscle stem cells, including satellite cell localization, response to re-injury, and contribution to muscle regeneration in secondary transplantation assays. Based on these encouraging findings, we have begun the manufacturing of these cells under cGMP compatible conditions and performed preclinical studies in murine recipients. The results from these studies are promising but before moving this therapy towards clinical translation, it would be ideal to assess scalability, delivery, distribution, safety, and engraftment in larger animal models. Therefore, here we propose preclinical studies to investigate these parameters using non-human primates (NHP) as recipients. It will also be critical to understand the impact of HLA mismatch on muscle engraftment, and NHP represent the ideal system to properly address this question. The transplantation of NHP iPS cell-derived myogenic progenitors into NHP recipients will provide critical knowledge for understanding tolerance in the allogeneic setting. This aspect, which has important implications for regenerative medicine, has been mostly overlooked in the pluripotent stem cell field. These are all critical prerequisites to advance this therapy towards successful clinical translation.

NIH Research Projects · FY 2025 · 2021-08

Pain associated with primary and metastatic bone tumors is often severe and difficult to manage. Opioids are first-line treatment for severe cancer pain, but their side effects, including tolerance, addiction and respiratory depression, limit their use. The search for opioid alternatives with high analgesic efficacy and low adverse effects has yielded limited success. Long-term goal is to identify novel, effective, and safe alternatives to opioids for pain treatment. This project is focused on Resolvin D1 (RvD1), an endogenous derivative of -3 polyunsaturated fatty acids, as a possible therapeutic for cancer pain. Using a mouse model of bone cancer pain. Preliminary data show that systemic administration of RvD1 decreased cancer-evoked hyperalgesia, attenuated sensitization of nociceptors and nociceptive dorsal horn neurons, and reduced descending facilitation while increasing descending inhibition of nociceptive transmission from the rostral ventromedial medulla (RVM). RvD1 did not impair motor function and did not produce place preference, suggesting it is not addictive. The overall objective in this proposal is to determine peripheral and central underlying mechanisms of RvD1 exerts analgesia. The central hypothesis is that systemic administration of RvD1 inhibits enzymes involved in the biosynthesis of pronociceptive prostaglandins (PGs) and the hydrolysis of antinociceptive endocannabinoids (eCBs) that reduce sensitization of nociceptive neurons and inhibit descending facilitation. Preliminary data suggest that increased PGs and decreased eCBs in the DRG, spinal cord and RVM contribute to neuronal sensitization and pain during cancer. Because RvD1 increased eCBs, role of different types of cannabinoid receptors in RvD1 produced antinociception will be elucidated. The central hypothesis will be tested in three specific aims. 1) Identify molecular mechanisms of RvD1 antinociception in the peripheral and central nervous system; 2) Determine functional effects of RvD1 on nociceptive primary afferent and spinal neurons during cancer-induced bone pain; and 3) Determine functional effects of RvD1 on descending facilitation and inhibition from the RVM. For the first aim biochemical and molecular approaches will be used to determine changes in prostaglandin and endocannabinoid signaling during the development of cancer- pain and the effects of Resolvin D1. The second aim will investigate the effects of Resolvin D1 on sensitization of nociceptors and dorsal horn neurons using in vivo electrophysiological and in vitro [Ca2+]i-imaging approaches. The third aim will evaluate the effects of RvD1 on descending facilitation and inhibition by determining if RvD1 reduces activity of ON cells and increases activity of OFF cells in the RVM and how it affect nociceptive transmission in spinal dorsal horn neurons. The proposed research is innovative because it will uncover novel mechanisms by which RvD1 reduces cancer pain. This project is significant because it will provide a mechanistic-based justification for RvD1 as a safe and effective approach to manage cancer pain.

NIH Research Projects · FY 2025 · 2021-08

PROJECT SUMMARY/ABSTRACT Ovarian cancer is the 5th leading cause of cancer deaths in women in the U.S. Earlier detection is the key to increased survival for women with ovarian cancer, yet a screening tool that is both sensitive and specific enough for use in the general population has yet to be developed. In contrast, screening for cervical cancer by Pap tests has been routinely performed for over 50 years. In the liquid-based Pap test, cells are collected from the cervical opening and placed into an alcohol-based fixative and then examined for abnormal cells. Since ovarian cancer cells have been observed in Pap tests, ovarian cancer peptide biomarkers may also be present; yet Pap samples have not been rigorously examined for diagnostic peptides. Our central hypothesis is that proteins shed by ovarian cancer cells can be detected in the Pap test fixative and on cervical-vaginal swabs by Mass Spectrometry (MS)-based proteomics. The Pap test fixative and swabs are ideal for biomarker discovery since they are derived from a site proximal to the ovarian cancer (i.e. proteins may be secreted or shed from the tumor and flow through the fallopian tube into the uterus and out the cervical opening). Recently, ovarian cancer precursor lesions have been identified in the fimbria of the fallopian tube, strengthening the hypothesis that ovarian cancer proteins will be found in the lower genital tract, perhaps even at early stages. In preliminary studies, candidate biomarkers were successfully identified by MS-based proteomics in Pap test fixatives from women with ovarian cancer, and the levels of biomarker peptides were quantified in cases vs. benign and healthy controls, demonstrating the feasibility of this approach. The long- term goal of this project is to develop a noninvasive screening test that can be incorporated into a routine Pap test or a self-administered home test, so that women can be screened simultaneously for cervical and ovarian cancer. The objective of this study is to verify ovarian cancer biomarker peptides identified in Pap test samples and extend the results to cervical swabs, using our collection of biospecimens from over 600 patients and controls. Aim #1 will build on our preliminary studies to prioritize ovarian cancer biomarker candidates found in liquid-based Pap test samples by performing Tandem Mass Tag™ 11-plex isobaric labeling, 2D LC-MS/MS, and bioinformatics integration. In Aim #2, the most robust candidate biomarkers will be quantified by developing a targeted Selected Reaction Monitoring (SRM)-MS assay coupled with a multi-protein classifier, which will then be used to test hundreds of Pap test samples from women with ovarian cancer, other gynecologic cancers, and benign gynecologic conditions, as well as healthy women. In Aim #3, proteins eluted from cervical swabs will be tested to determine whether they are also detected by our SRM-MS assay. Results from this study may be extended to the early detection of ovarian cancer in women in high risk groups and eventually for screening the general population, thereby shifting the paradigm for how women are screened for ovarian cancer and improving survival rates for the >22,000 women diagnosed with ovarian cancer each year.

NIH Research Projects · FY 2025 · 2021-08

ABSTRACT Antiseizure medications are one of the most commonly prescribed teratogens. In pregnant women with epilepsy, continuation of antiseizure medications and dose increases are often necessary to prevent seizure worsening, but need to be balanced against the fetal risks of in utero exposure, such as congenital malformations and adverse neurodevelopmental outcomes. Additionally, breastfeeding introduces another route of drug exposure to the infant and can affect child development. Although measurement of drug concentration in plasma is thought to reflect drug concentrations at the site of action in the mother, it is more difficult to translate the overall exposure to the fetus or determine the full extent of the exposure to the child through breastfeeding. Physiological-based pharmacokinetic (PBPK) methods will be used to advance a precision medicine approach to characterize drug concentration-time profiles at the tissue level allowing evaluation of target doses needed to achieve optimal drug exposure in women with epilepsy, taking into account drug exposure to the fetus during pregnancy and to the breastfeeding infant. Information from both basic science and clinical studies will be used to develop, evaluate, and validate PBPK models. This grant will use previously collected data and new measures from existing samples in the clinical study MONEAD, animal data, in vitro studies, and a new external validation cohort with sampling at critical timepoints (not previously obtained) to determine the mechanistic basis of alterations in antiseizure medication concentrations during pregnancy and lactation. These data can then be combined with outcome data in other clinical studies to expand our knowledge of drug response and safety in women and children during two very vulnerable times, pregnancy and lactation.

NIH Research Projects · FY 2025 · 2021-08

PROJECT SUMMARY/ABSTRACT The goal of this proposal is to characterize the evolution of changes in neuronal activity and connectivity that occur within and across nodal points in the basal ganglia thalamocortical (BGTC) circuit using a progressive nonhuman primate (NHP) model of Parkinson’s disease (PD). Simultaneous recordings from populations of neurons as well as local field potential (LFP) activity will be made from the basal ganglia, motor and sensory thalamus, primary motor (MC) and sensory cortex (S1) as well as dorsal premotor (PMd), supplementary motor area (SMA) and dorsolateral prefrontal (DLPFC) cortices in the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) progressive model of PD. Data will be collected during both rest and movement, on and off L-dopa and on L-dopa during drug-induced dyskinesia. A within-subject design will be used as animals progress from the normal to mild, moderate and severe conditions of parkinsonism. Specific Aim 1 will characterize changes in coupling and connectivity that occur between the subthalamic nucleus, internal and external segments of the globus pallidus, motor thalamus (ventralis anterior (VA), ventralis lateralis, pars oralis (VLo), ventralis posterior lateralis, pars oralis (VPLo), and cortical areas involved in the planning, preparation and execution of movement (PMd, DLPFC, SMA, and MC). Specific Aim 2 will examine the effect of dopaminergic therapy (L-dopa) on subcortical↔cortical connectivity and the relationship of these changes to improvement in motor signs and the development of L-dopa induced dyskinesia (LID). Specific Aim 3 will characterize the changes and contribution of altered sensorimotor processing in thalamo↔cortical and cortical↔cortical circuits (MC-S1). This proposal will define the relationship between changes in synchronized oscillatory activity in, and effective connectivity between, subcortical↔cortical and cortical↔cortical regions of the broader BGTC network to parkinsonian motor signs as they develop, progress in severity, and improve with L-dopa. It will also characterize the role of changes in different frequency spectrums to the preparation, planning and execution of movement, as well as the contribution of sensory dysfunction in thalamocortical circuits to the motor dysfunction observed in PD. A better understanding of the role of individual motor circuits and the types of physiological changes that occur within these circuits and how they relate to the development of individual motor signs will provide the rationale for the development of new targets and neuromodulation therapies directed at restoring a more normal pattern of activity in the BGTC circuit.