University Of Minnesota

NIH Research Projects · FY 2026 · 2022-09

PROJECT SUMMARY/ABSTRACT The Minnesota Inclusive Neuroscience Development Scholars (MINDS) doctoral readiness program will provide two years of research experience and courses for skills development to recent baccalaureates from diverse backgrounds. This doctoral readiness program will build upon the success of our MINDS pilot program, as well as the University of Minnesota’s strength in research on the neuroscience of drug abuse. The MINDS doctoral readiness program will be affiliated with our longstanding NIDA T32 training program (DA007234), and provide participants with access to resources available through our NIDA P30 Core Center of Excellence (DA048742). Participants will be matched with one of our 22 participating faculty mentors, and conduct an independent research project that provides opportunities for technical as well as intellectual growth. The program faculty include basic researchers, technology engineers, and translational scientists to provide an exceptional breadth of scientific scope and training capacity. The scientific environment is highly cooperative, with robust extramural research support that benefits from multiple active collaborations. Strong laboratory research experience will be complemented and scaffolded by a variety of career and professional development activities, including a regular meeting of the entire MINDS program held every two weeks. These meetings and discussions will provide opportunities for skill development in communication of science, preparation for graduate program entrance, and success in navigating graduate school. Participants will enroll in a small number of graduate courses that provide strong background in neuroscience principles of drug abuse, rigorous experimental design, and the responsible conduct of research. Rigorous and effective training is supported through tailoring individual developmental plans, a highly comprehensive program for mentoring the mentors, and thorough evaluation of training outcomes. This proposal includes funds to support four new postbaccalaureate participants each year. Robust institutional matching funds will support an additional two new participants each year, with the remaining matching funds providing resources for relocation expenses, an annual symposium, and additional program expenditures. By providing training essential to the next generation of drug addiction researchers, this R25 program facilitates progress in the understanding the neuroscience of drug abuse.

NIH Research Projects · FY 2025 · 2022-09

): Deep brain stimulation (DBS) of the anterior nucleus of the thalamus (ANT) is clinically approved for treatment of epilepsy resulting in an average decrease in seizure frequency of 40%, but few patients achieve seizure freedom. Implantable neural stimulators have many parameters, such as stimulation amplitude, frequency and pulse width, which could potentially be tuned to improve efficacy. However, there is no systematic process to guide epileptologists through optimization. Stimulation of ANT in animal models has shown almost immediate changes in excitability in the loop of Papez, which we hypothesize is a biomarker that could be used to optimize stimulation parameters. Medtronic’s DBS Percept system allows for recording during stimulation and streaming the data to a computer for further analysis, which can be used in an optimization loop. Bayesian optimization (BayesOpt) is a machine learning algorithm that is widely used for efficient optimization over a bounded parameter range when acquiring data is expensive and computational time is relatively cheap. We have used BayesOpt for optimizing stimulation settings in animal models and clinical trials. Here we propose to develop an optimization platform where stimulation settings are programmed by a physician using recommended settings from a BayesOpt algorithm to minimize power measured from the patient’s thalamus in the clinic using Percept. Three aims are proposed to develop, test, and validate this approach in an exploratory clinical trial. Aim 1: Develop and test BayesOpt clinical interface with hardware in the loop system. Aim 2: Apply BayesOpt to 20 epilepsy patients treated with the Percept system in a clinical setting to optimize stimulation settings to minimize thalamic activity. Aim 3: Validate optimized settings at home by programming patients with optimized setting and their physician selected setting to test if seizure frequency or power spectral density is significantly lower in the optimized setting. The outcome of this clinical trial will be to establish safety and feasibility of optimization and validation. If successful, this study will be used to power a phase II efficacy trial. The broader impact of this work is that this platform could be used to tune the Percept system, based on different biomarkers, in other diseases, such as Parkinson’s disease, pain, and depression.

NIH Research Projects · FY 2025 · 2022-09

SUMMARY In the US, certain groups of older adults with varied social needs are disproportionately at risk for Alzheimer’s disease and related dementias (AD/ADRD) and more likely to rely on long-term services and supports (LTSS). Without training in responsive care of the LTSS workforce, these residents are vulnerable to receiving inappropriate and/or inferior care contributing to poorer quality of life and health outcomes. To address this, some states have recently mandated training of the LTSS workforce in the responsive care of these groups. There are two major barriers to this approach being successful. First, we lack research on LTSS policies affecting these groups in states where responsive care training is not mandated. Such research would inform whether such state legislation is needed. Second, there are no scalable, sustainable, evidence-based training programs to train the LTSS workforce in the appropriate care of these groups with varied social needs. This application is focused on the Training to Serve curriculum, which has trained over 12,000 LTSS workers in 12 states. This acceptable, feasible, and promising curriculum employs a multilevel approach to train management and frontline LTSS staff in responsive care for groups at heightened risk of AD/ADRD. But, it has not been rigorously evaluated and relies solely on in person instruction. This mixed methods and comparative effectiveness study has three specific aims. In Aim 1, we will conduct a comprehensive policy analysis of 362 nursing homes and 362 assisted living facilities in Minnesota to assess the number and proportion of agencies that have explicit affirmative policies in human resources, marketing, training, governance; anti-discrimination policies guiding culturally responsive care, and data collection relevant to these groups. These findings will inform Aim 2 curriculum. In Aim 2, to make Training to Serve more scalable nationally and with high fidelity, we will design and develop an asynchronous online version and pilot it with 30 LTSS management and 30 staff. In Aim 3, to assess the effects of training, we will conduct a 3-arm, management/staff stratified, group randomized, controlled trial of the in-person training versus an online curriculum versus a waitlist control group (in 62 LTSS agencies, with 310 management and 450 staff per arm). At the individual level, we will assess management and staff knowledge, attitudes, and skills providing care to these groups. At the agency level, at 3-6 months’ follow-up, we predict agencies who receive training will have more explicit policies, more welcoming environments, more relevant data collection at intake, and staff with significantly greater knowledge, comfort, and skills in providing responsive care.

NIH Research Projects · FY 2026 · 2022-09

Project Summary/Abstract Using a unique longitudinal data set and linear growth modeling analytic techniques, the proposed research will examine relations between early and life course trajectories of adversity and adult biobehavioral markers of aging. Animal and human studies suggest that early exposure to adversity may negatively impact developing biological systems altering long term structural and functional trajectories, and accelerating aging processes. The proposed research will examine this neurotoxicity hypothesis in relation to brain neurobiology (structure, function, connectivity) and related cognitive and epigenetic markers sensitive to adversity and aging. The research will also examine the role of protective social relationships (especially positive early caregiving) in moderating the adversity-related effects. Based in the Minnesota Longitudinal Study of Risk and Adaptation (Sroufe et al., 2005) and drawing on methodology from the Human Connectome Project in Aging (HCP-A; Bookheimer et al., 2019), the study addresses significant gaps in both neurobiological and behavioral investigations of the origins of adult aging processes and the effects of adversity on development. Unlike concurrent and retrospective studies of risk and protective influences on aging, the proposed study employs a prospective multilevel design with a sample of individuals assessed from birth to middle adulthood. The proposed assessments of neurobiological and cognitive functioning will contribute to an understanding of the impact of exposure to adversity on adult brain health (structure, function, connectivity) and age-related cognition. Specifically, we will examine the timing and chronicity (onset and trajectory) of adversity in relation to adult outcomes. Genetic data will permit analyses of associations between adversity, epigenetic variation (i.e., telomere length, DNA methylation age), and concurrent neural and cognitive functioning. The proposed work will address critical research, policy, and practice questions regarding the effects of adverse experience on the human brain, the cognitive and biological correlates of neurobiological change, and the potential moderating influence of early caregiving experience on these relations, generating testable research hypotheses and contributing to the development of targeted prevention and intervention efforts.

NIH Research Projects · FY 2025 · 2022-09

Project Summary/Abstract With stagnant cure rates, there is a severe unmet need for strategies to improve oral and all other types of aerodigestive cancer survival. There are no robust chemoprevention drugs or other treatments for high risk oral precancerous conditions or field carcinogenesis despite 40 years of clinical trial research. High risk oral precancerous conditions (such as leukoplakia) represent a standard target for chemoprevention interventions. Type II anti-diabetic agents, including pioglitazone and metformin, are promising cancer prevention drugs for oral cavity preneoplasia that we have used in NCI sponsored clinical trials. They have adequate safety and moderate efficacy in human trials, however, individually are likely not sufficient to advance to large scale clinical trials. These agents have differing mechanisms of action which each attack different events in oral carcinogenesis. In this project, we propose to conduct a phase IIa 12 week clinical trial with combination BID pioglitazone-metformin (15mg-500mg) in oral preneoplasia patients. We have assembled a consortium of clinics in Minneapolis/St. Paul MN for efficient accrual to this trial. We will examine pharmacodynamic endpoints in specimens based on both the mechanisms of the agents and how they may affect T cell subsets before and after treatment. Further, we will also analyze leukoplakia specimens and adjacent normal mucosa specimens by RNA-Seq before and after treatment, which will shed light on effects of the drugs as well as any putative “off target” effects. At the completion of this project, we will have a better understanding of pioglitazone and metformin effects on oral carcinogenesis, as well as, an early stage clinical trial which could be expanded to larger randomized trials with a promising cancer prevention strategy for oral preneoplasia or other tobacco-associated malignancies.

NIH Research Projects · FY 2025 · 2022-09

Project Summary Peroxisomal ABC transporters like ABCD1, ABCD2, and ABCD3 shuttle very long chain fatty acids (VLCFAs), branched chain fatty acids (BCFAs), and bile acid precursors into peroxisomes. Their functional impairment leads to severe neurological and metabolic pathologies stemming from disrupted phospholipid and fatty acid metabolism, including X-linked Adrenoleukodystrophy (X-ALD), both the most common leukodystrophy and most common peroxisomal disorder that is caused by mutations in ABCD1 and for which no cure exists, and bile acid synthesis defects and liver disease stemming from impaired ABCD3 function. While additional roles for ABCD transporters in a wider array of disease pathways continue to be uncovered, the underlying mechanisms governing their substrate recognition, transport, and transport regulation remain poorly understood. The long- term objectives of this project are to gain insight into peroxisomal ABCD transporter function and regulation in molecular detail. We will use a combination of biochemical and cell biological tools, high resolution structural analysis by cryo-electron microscopy, and continuous wave electron paramagnetic resonance (CW-EPR) spectroscopy to reveal the functionally relevant structural features and conformational states used by ABCD transporters in fatty acid translocation, how they may be altered by ABCD1 mutation in X-ALD, and how ABCD1 is mechanistically distinct from ABCD2 and ABCD3 despite their functional overlap. Specific Aim 1 deals with the development and utilization of in vitro assays for determining substrate specificity profiles and transport properties of ABCD1, ABCD2, and ABCD3. Specific Aim 2 deals with obtaining high resolution structural information of ABCD1, ABCD2, and ABCD3 in functionally relevant states in a physiological lipid environment through cryo-EM analysis. Specific Aim 3 deals obtaining information on the structural dynamics of ABCD1 through CW-EPR studies. Our results will provide fundamental insights into peroxisomal ABC transporter functioning that can be exploited for ABCD1 targeted diagnostic and therapeutic tools to improve X-ALD patient outcomes, provide a framework for the design and development of chemical probes to study ABCD family function, and generate reliable in vitro and in silico tools to accelerate drug development/discovery efforts targeting them.

NIH Research Projects · FY 2024 · 2022-09

PROJECT SUMMARY/ABSTRACT This project proposes to develop methods for automated, real-time, single-voxel magnetic resonance spectroscopy (MRS) in brain tumors, integrate these methods with a clinical MRI system, evaluate their performance, and distribute them as open-source tools to the research community. MRS can provide metabolic information noninvasively for assessment of tumor phenotype and therapeutic response. Single-voxel MRS methods provide the best quality and most reliable data, but require the scanner operator to have a high skill level and expertise to produce good quality results. The need for this expert involvement in both acquisition and processing remains a critical barrier to the translation of MRS methods to clinical research sites without spectroscopy experts and to clinical practice. The first part of this project is to develop a method for 3D voxel placement using image guidance, integrate this method with a clinical MR system, and evaluate its performance. In the second part, we will automate our advanced MRS methods. In the third part, we will create real-time, automatic quantification tool specific to the obtained MRS data that will provide clinically interpretable results. We identified collaborators, the brain cancer researchers and clinicians, who will be early adopters and beta-testers of our tools. Successful completion of this project will improve data robustness and quality, eliminating the need for the expert interaction at the time of the scan and enabling adoption of MRS in multi- site clinical trials and clinical practice.

NIH Research Projects · FY 2026 · 2022-09

PROJECT SUMMARY Alzheimer's disease (AD) and related dementia (AD/ADRD) is a multifactorial and heterogeneous disorder. Most current studies focus on drug interventions for AD/ADRD and currently none of pharmacological intervention (PI) discovery research has been translated into effective treatments. However, increasing evidence demonstrates that non-pharmacological interventions (NPI), such as sleep, diet, dietary supplements, aerobic exercise, aromatherapy, light therapy, cognitive training, are potentially modifiable and thus offer alternative opportunities for AD/ADRD prevention. Thus, the objective of this project is to develop translational informatics approaches to aggregate, standardize and discover the effects of drug and NPI candidates on AD/ADRD using multi-modal data resources (i.e., biomedical literature, EHR, clinical trials) followed by animal model validation. To achieve our goal, we propose the following aims: 1) constructing a comprehensive Pharmacological And Non- Pharmacological Interventions for Alzheimer's Disease Knowledge Graph (PANIA-KG) from biomedical literature and other knowledge bases; 2) detecting, understanding, and visualization of drug repurposing signals of PIs, NPIs, and their synergistical effects for AD/ADRD using the PANIA-KG; 3) re-ranking and validating individual and synergistical drug repurposing signals using multimodal data sources and animal models. The successful completion of this project will deliver a comprehensive NPI knowledge graph, novel informatics approaches, ranked list of drug and NPI candidates, and validated synergistic intervention using multi-modal data sources. The generated approaches, PANIA-KG and ranked lists can further our clinical investigations and clinical trial design which focuses on synergistic effects of drug and NPIs for AD/ADRD.

NIH Research Projects · FY 2025 · 2022-09

Project Summary/Abstract A leading cause of death worldwide, heart failure is often linked to deficits in energy production in mitochondria. Mitochondrial uptake of cytosolic Ca2+ plays a critical role in matching energy production to demand by stimulating ATP production. However, mitochondrial Ca2+ in excess can lead to permeability transition pore opening and potentially cell death. Animal models of heart failure more closely akin to heart failure with reduced ejection fraction (HFrEF) are linked to increased mitochondrial Ca2+ in some studies and decreased mitochondrial Ca2+ in others; even less is known regarding the role of mitochondrial Ca2+ in heart failure with preserved ejection fraction (HFpEF). With the long-term goal of helping to develop therapies to limit or restore mitochondrial Ca2+ when appropriate to improve clinical outcomes in HFrEF and HFpEF, this application will map out the contribution of increased and decreased mitochondrial Ca2+ to cardiac dysfunction in homeostasis and in mouse models of pressure overload and high fat/high sucrose diet with L-NAME. Tamoxifen-inducible cardiac-specific deletion of Micu1, the gene encoding the “gatekeeper” of mitochondrial Ca2+ uniporter complex (mtCU), will be used to induce mitochondrial Ca2+ overload. In the same manner, deletion of Emre, the gene encoding the essential regulator of the mtCU, will be used to eliminate mtCU activity and lower mitochondrial Ca2+. The overall objective in this application is to systematically compare the effects of increased and decreased mitochondrial Ca2+ on measures of cardiac health – mitochondrial function, tissue histology, contractility before and after stimulation – in homeostasis and in two different types of induced heart failure. The central hypothesis is that elevated mtCa2+ impairs heart function in homeostasis and in HFrEF, whereas lowered mtCa2+ has negative effects in energetically demanding states and in HFpEF. The rationale is that based on the literature and our preliminary data, pressure overload forces the heart to work harder, elevating mitochondrial Ca2+, while some indications suggest that mice fed the high fat/high sucrose diet with L-NAME have lower mitochondrial Ca2+. Hence, in the former conditions, increased mitochondrial Ca2+ is detrimental, and in the latter, decreased mitochondrial Ca2+ is detrimental. The central hypothesis will be tested by pursuing two specific aims: 1) Assess how elevated and reduced mitochondrial Ca2+ impact cardiac homeostasis; and 2) Assess how elevated and reduced mitochondrial Ca2+ impact HFrEF and HFpEF- MetS. This research is conceptually innovative in using genetic manipulation to modulate mitochondrial Ca2+, and in directly comparing elevated and reduced mitochondrial Ca2+ in models approximating HFrEF and HFpEF. The outcomes of this research are expected to be significant by establishing a new paradigm regarding mitochondrial Ca2+ in HFrEF and HFpEF, with the potential to inform future therapeutic strategies.

NIH Research Projects · FY 2024 · 2022-09

PROJECT SUMMARY This Mentored Clinical Scientist Research Career Development Award (K08) proposal describes a three-year career development and training plan for Dr. Forum Kamdar, a heart failure cardiovascular physician-scientist at the University of Minnesota. Her long-term goal is to be an independent physician-scientist making significant contributions in the field of neuromuscular cardiomyopathy. Her career development training plan encompasses the following: (1) protected research time, (2) focused formal coursework and hands-on laboratory training in cardiac tissue engineering and extracellular matrix dynamics, (3) rigorous training in the Responsible Conduct of Research (4) a structured mentoring program with a multidisciplinary team of experienced scientists and physician-scientists, and (5) focused research experience in basic science through the study of Duchenne muscular dystrophy (DMD) cardiomyopathy utilizing cardiac tissue engineering to develop a DMD human chambered muscle pump (hChaMP) culminating in the successful application for independent research funding. DMD is the most common and deadly muscular dystrophy, and DMD-associated cardiomyopathy is ubiquitous and significantly reduces survival in DMD patients. There are currently no effective treatment methods available for DMD cardiomyopathy, and mechanisms defining DMD cardiomyopathy progression are not well understood. The dystrophin glycoprotein complex (DGC) is a key component of cardiac mechanotransduction (MT) and the loss of dystrophin in DMD results in loss of sarcolemmal integrity, which is a critical early event that ultimately results in DMD cardiomyopathy. She and others have demonstrated that increased stress also exacerbates the DMD phenotype, however a 3D model with progressive loading would allow for improved understanding of DMD cardiomyopathy. The overall objective of the proposed research is to determine how progressive loading impacts DMD cardiomyopathy disease progression and the impact of partial restoration of dystrophin using a 3D DMD human chambered muscle pump (hChaMP). In Aim 1, Dr. Kamdar will evaluate the impact of altered MT on DMD cardiomyopathy disease progression using a DMD hChaMP model system with increasing load. Next, in Aim 2, she will determine the impact of dystrophin gene correction on cardiac remodeling mechanisms dictating disease onset in DMD cardiomyopathy using dystrophin exon skipping. This research will provide novel insights into DMD disease progression and ECM changes which will lay the foundation of her long term goal to identify therapies to prevent or ameliorate DMD cardiomyopathy. In summary, a comprehensive career development plan, in the context of a well-defined training, research and mentorship structure, will allow Dr. Kamdar to emerge as a highly successful, independent physician-scientist in DMD cardiomyopathy.

NIH Research Projects · FY 2025 · 2022-09

This application is proposing to continue and expand the collaboration between the Koob lab at the University of Minnesota and the MODEL-AD Center. We have developed Gene Replacement (GR) approaches that allow us to replace mouse genes with their full human orthologue alleles. The GR targets for this project include many of the human genes most central to the etiology of AD, including APP, PSEN1, PSEN2, and MAPT, as well as genes that play pivotal roles in modulating AD risk, including the APOE gene cluster, the TREM2 gene cluster, the critical region of the MS4A gene cluster, and INPP5D. A set of models will be generated for each GR target genomic region, consisting of a control line with a wt human genomic sequence, and at least one matching line with either a pathogenic mutation or risk variant in that same human genomic sequence. Basic QC evaluations of each GR allele will be performed at the University of Minnesota, and MODEL-AD will then validate them by confirming that each variant line exhibits the expected AD-related endophenotypes. The human alleles that pass the QC and endophenotype validations will then be incorporated into base AD models with additional AD alleles, with the ultimate goal of recreating the human genetics and pathophysiology of AD as closely as is possible in a mouse. JAX will distribute all mouse lines generated by this project without restrictions.

NIH Research Projects · FY 2025 · 2022-09

PROJECT SUMMARY/ABSTRACT Pathological changes in the human metabolome are ubiquitous and fundamental to the pathogenesis of all brain disorders including cancer, dementia, and psychiatric disorders. This project proposes to develop a non-invasive magnetic resonance imaging tool to interrogate human brain metabolism in an unprecedented way using the world’s first ultra-high field 10.5 T whole-body human MRI scanner and a novel dynamic deuterium to proton exchange (2H-to-1H) MRS approach. Two complimentary strategies, single-voxel spectroscopy (SVS) and MR spectroscopic imaging (MRSI) will be developed in parallel. 2H-to-1H MRS will be able to quantify and image concentrations and metabolic fluxes in the human brain in vivo through the entire metabolic pathway from a single scan. In the first part of this project, we will utilize state-of-the-art MR-compatible sensors and calibration scans to accurately characterize spatial field inhomogeneities and monitor scanner- and subject-dependent temporal instabilities at 10.5 T. In the second part, we will develop and validate a novel dynamic 1H-SVS technique at 10.5 T with the focus on maximizing the range of reproducibly detectable metabolites by targeting a single accurately defined brain region. In the third part, we will establish a new highly accurate and robust dynamic 1H-MRSI method for 10.5 T, which will trade-off the ability to interrogate a broad range of metabolites for the ability to image some of them over the entire brain. In the final part, we will proof the feasibility of measuring human brain metabolism in vivo non-invasively via dynamic 2H-to-1H MRS at 10.5 T and 7 T using 2H-labled glucose and estimate experimental and physiologic variability. We will compare the performance of our novel tool to deuterium metabolic imaging. Successful completion of this project will provide a powerful tool for neuroscience and metabolic research.

NIH Research Projects · FY 2025 · 2022-09

Project Summary/Abstract Cardiogenic shock is a devastating problem that has had a relatively stagnant in-hospital mortality around 30-40% in the last decade. Consequently, an array of mechanical support strategies has emerged to mitigate the multi-organ hypoperfusion. Among them, percutaneous veno-arterial extracorporeal membrane oxygenation (VA-ECMO) is increasingly being used to treat cardiogenic shock due to its capacity to be instituted rapidly in the cardiac catheterization laboratory and provide large volume complete hemodynamic and respiratory support. However, this strategy has notable disadvantages, namely high cost associated with its programmatic development and the potential for introducing iatrogenic complications in a very sick population. Prior invasive hemodynamic data from animal models have suggested that there is deterioration of LV performance due to increased stroke work within minutes of the commencement of VA-ECMO hemodynamic support. There is also observational clinical data showing that LV distension may worsen with VA-ECMO support. Conversely, human data from our group’s prior experience have suggested that VA-ECMO support in patients with minimal pulsatility after out-of-hospital cardiac arrest can dramatically improve cardiac recovery and rates of neurologically favorable survival. These conflicting data have led to the emergence of diverse management strategies including VA-ECMO in patients with cardiogenic shock either due to AMI or cardiac arrest. In the context of the rapidly increasing usage of VA-ECMO usage there is a critical need to identify the manner in which VA-ECMO affects cardiac hemodynamics in the setting of cardiogenic shock. To that goal we will pursue the following specific aims: 1. Define the LV pressure volume area (PVA) and stroke work at different levels of VA-ECMO support in patients cannulated for CS. 2. Define the temporal changes of LV stroke work with prolonged VA-ECMO support over the course of the hospitalization. The temporal recovery patterns will be associated with clinical hard endpoints of decannulation or transition to permanent cardiac assist devices/transplant or death. 3.Validate the accuracy of non-invasive reconstruction of PV-loops compared to invasively collected data to help establish an easier way to assess LV stroke work for every day practice. The expected outcome of this research proposal is to define the physiologic effect of VA-ECMO support on the left ventricle energetics and provide objective scientific clinical proof derived from a high mortality and morbidity patient population. Additionally, we expect that our data will be useful to establish normative hemodynamic and imaging principles and strategies for assessing patients on VA-ECMO.

NIH Research Projects · FY 2025 · 2022-09

Abstract Facioscapulohumeral muscular dystrophy (FSHD), is one of the most prevalent neuromuscular genetic disorders, and it is caused by a loss of epigenetic repression of the D4Z4 repeats at chromosome 4 that then leads to loss of silencing of DUX4. One of the most mysterious aspects of FSHD is the timing and the extent of the DUX4 expression. Levels of DUX4 in the affected muscles are either extremely low and/or transient as attempts to date have failed to detect the protein in situ. Evidence of DUX4 expression is indirect, based on elevated DUX4 target genes in MRI-guided biopsies from FSHD patients. We developed an FSHD mouse model (iDUX4pA;HSA) that allows conditional expression of DUX4 in muscle fibers, and which upon low level long-term expression shows hallmarks of FSHD disease pathology. Because it is inducible and reversible, the iDUX4pA;HSA mouse model provides a unique opportunity for exploring the hypothesis that DUX4 is only required to prime muscle for later pathology. Our initial experiments indicate that transient DUX4 expression is sufficient to induce long-term abnormalities in muscle tissue including an increased frequency of FAPs, an excess of the fibrotic extracellular matrix, and the inability of the muscle to completely recover after injury. The research proposed in this application aims to explore the long-lasting effect of transient DUX4 expression on muscle physiology and histology, cellular alterations, and epigenetic state of the genome in the muscle of FSHD mouse models. They will test the hypothesis that the echo of DUX4 expression, independent of DUX4 expression itself, can contribute to muscle pathology.

NIH Research Projects · FY 2025 · 2022-09

Scientific Abstract Malignant germ cell tumors (GCTs) in children and adults are hypothesized to occur as a result of events in utero. The high heritability of adult testicular GCT (TGCT) suggests a genetic etiology, and recent genomewide association studies support this through the discovery of multiple susceptibility loci. We recently confirmed a subset of these loci as susceptibility variants for pediatric GCT. While 5-year relative survival rates are very high overall for GCTs, mainly due to the effectiveness of cisplatin chemotherapy, approximately 20% of patients will display resistance to chemotherapy or relapse following treatment. Clinical risk stratification to identify patients with poor prognosis is still very crude and further molecular analysis, including analysis of tumor epigenetics, may help to tailor treatment. Our recently completed Children’s Oncology Group (COG) case- parent triad study of GCT was the first large study to collect germline DNA samples from pediatric and adolescent GCT cases, tumor specimens and outcomes data. The research proposed in this application will allow us to extend the scope of our ongoing study by evaluating tumor DNA methylation as a prognostic factor for GCT and by expanding our analyses of germline genetic variation to include the sex chromosomes. Our overarching goal for the proposed study is to evaluate the contribution of genetics and epigenetics in pediatric GCT risk and outcomes. Our hypothesis is that DNA methylation patterns will predict GCT cases who are likely to have poor outcomes. Further, we hypothesize that common and moderately rare variants on the sex chromosomes increase risk for GCT. To evaluate these hypotheses, we will combine data from our ongoing COG case-parent triad study of pediatric GCT (N=867 cases and 1,517 parent controls) with GCT cases and controls obtained from the state biobank programs in California, Michigan and Washington (N=1,601 cases and 1,601 controls). Our primary aims will be to: 1) Identify methylation patterns that predict poor outcomes, including disease relapse and death, and 2) Discover single nucleotide polymorphisms (SNPs) and copy number variants (CNVs) on the sex chromosomes that contribute to GCT risk in children and adolescents. We will also evaluate the contribution of rare genetic variants in GCT through the use of aggregate burden tests in an exploratory aim. Methylation will be evaluated using the Illumina EPIC methylation array in 500 GCT tumor samples. Germline genetic analyses will be conducted using existing GWAS data generated on the Illumina Human CoreExome array. The contribution of rare variants will be assessed through analysis of whole exome sequencing data generated through the Gabriella Miller Kids First Pediatric Research Program (N=250 trios) and Exome content available for the entire dataset (N=2,468 cases). Little is known about the etiology of pediatric GCT; analysis of germline genetic variation will shed light on disease biology. Identification of methylation patterns associated with poor prognosis could improve the existing clinical risk stratification and suggest new avenues for treatment. Finally, this will be the first study of GCT susceptibility in any age group to include individuals of non-European ancestry.

NIH Research Projects · FY 2025 · 2022-09

Summary A social gradient in health and aging is well established in humans; the greater the social connectedness and socioeconomic status (SES), the lower the burden of a plethora of diseases and mortality rate. Consistently, lack of social support and low SES are among the major negative determinants of health, increasing the prevalence and/or anticipating the onset of diseases. Unfortunately, diseases often only manifest at old age when therapeutic options and biological flexibility are limited. Additionally, the causal role of social context on aging is difficult to ascertain, requiring an experimental design in which social factors can be randomized to infer causation, which is unethical and often not feasible in humans. The evolutionary conserved role of social determinants of health and aging (SDoHA) and the ability to conduct randomized experimental designs in social mammals, offer the opportunity to reverse-translate observations made in humans to other animals. In particular, the use of laboratory mice has several advantages to study the effect of social factors on aging, including: their comparatively short lifespan when compared to other mammals enabling the completion of longevity studies in a reasonable timeframe; the ability to conduct intent-to-treat randomization designs of socio-behavioral variables; they are amenable to sophisticated genetic manipulations. However, the role of SDoHA is often neglected in biomedical aging research using mice, thus missing critical components of human aging. The objectives of this project are to: (i) develop rigorous socio-behavioral models suitable for aging studies in male and female mice; (ii) develop innovative assessment tools and a “comprehensive aging index” summarizing the global impairment in behavior, physical functions and physiology, and a that can predict functional impairment and longevity, (iii) identify social factors affecting individual variability in aging processes, and finally (iv) identify socio-behavioral intervention strategies to increase resilience. The R61 – development, proof-of-concept phase has 2 Aims. Aim 1 will identify social factors affecting the pace of aging by using a randomized design that manipulates social connectedness, social stability and social stress. We will also develop quantitative assessment tools relevant for aging research. Aim 2 will develop a “comprehensive aging index”, an algorithm which is based on quantifiable behavioral, physical and physiological changes over the lifecourse. The R33 – implementation phase has 2 Aims. Aim 3 will determine whether social rank, social instability and/or social deprivation affect lifespan in male and female mice and will implement the algorithm to predict longevity based on data collected during the lifecourse. Aim 4 will implement behavioral strategies designed to increase resilience, including social rank reversal, social integration and cognitive stimulation/environmental enrichment. At its completion, this project will develop novel experimental paradigms and assessment tools with far reaching impact to the field. It will also generate an unprecedented new knowledge on how social factors affect health trajectories and aging, and which aging process is amenable to intervention versus those that are not amenable to intervention.

NIH Research Projects · FY 2025 · 2022-09

ABSTRACT Angiotensin-converting enzyme (ACE) plays a well-established role in regulating blood pressure in the periphery. ACE is also expressed in the brain, with high levels in the striatonigral pathway formed by medium spiny projection neurons that express the Drd1 dopamine receptor (D1-MSNs). We have found that ACE degrades an unconventional enkephalin heptapeptide, Met-enkephalin-Arg-Phe (MERF), in the nucleus accumbens of mice. Captopril, a prototypical ACE inhibitor used to manage hypertension, enhances extracellular levels of MERF in the nucleus accumbens. The resulting enhancement of mu opioid receptor activation by MERF causes a cell type-specific long-term depression of glutamate release onto D1-MSNs. This mechanism of action has great therapeutic potential, as our preliminary data indicate the decrease in excitatory drive to D1-MSNs can diminish the rewarding effects of fentanyl. However, neither captopril nor modern ACE inhibitors routinely used in the clinic have been optimized to regulate endogenous opioid signaling. For example, MERF may be specifically degraded by the catalytic N-domain of ACE, whereas most clinically-approved ACE inhibitors have greater selectivity for the catalytic C-domain of ACE. There is thus a need to identify optimal chemical entities that inhibit MERF degradation by ACE in brain tissue. The goal of this project is to identify new compounds that inhibit ACE and regulate endogenous opioid signaling in the nucleus accumbens. In AIM 1, we will screen a selected library of ~2,000 small molecules for domain-selective inhibition of recombinant ACE protein. This will include candidate molecules drawn from rationally selected libraries using a pharmacophore-based approach, as well as molecules with diverse chemical scaffolds identified through a virtual screen. In AIM 2, we will validate the domain selectivity and efficacy of lead compounds on MERF degradation in nucleus accumbens tissue. This will include direct measurement of extracellular MERF using liquid chromatography- tandem mass spectrometry, as well as whole-cell voltage-clamp recordings to measure functional effects on excitatory input to D1-MSNs. These experiments will include knockout mice to test the necessity of each catalytic domain of ACE in MERF degradation, as well as the involvement of mu opioid receptor signaling in physiological changes. In AIM 3, we will evaluate the ability of lead compounds to attenuate fentanyl reward and reinforcement. This will include measurement of fentanyl-conditioned place preference and intravenous self- administration of fentanyl. At the conclusion of these experiments, we expect to identify chemical motifs that may serve as leads to generate novel ACE inhibitors that block MERF degradation in the nucleus accumbens. We may observe a double-dissociation between catalytic domains of ACE that degrade angiotensin (C-domain) and MERF (N-domain), raising the exciting possibility of selectively manipulating endogenous opioid signaling in the brain while avoiding cardiovascular side-effects in the periphery. Our results may also reveal that central ACE inhibition can boost endogenous opioid signaling for clinical benefit, while mitigating risk of abuse/addiction.

NIH Research Projects · FY 2025 · 2022-08

Project Summary/Abstract Visual Snow Syndrome (VSS) is a serious but poorly understood visual disorder characterized by the persistent perception of specks flickering across the entire visual field, akin to television snow. VSS has an estimated prevalence of 1.4-3.3% and is often accompanied by additional symptoms such as prominent afterimages (palinopsia), poor night vision, entoptic phenomena, and photophobia (light sensitivity). These symptoms make tasks like reading and driving particularly difficult. While previous research has focused on identifying the common symptoms and comorbidities, effective treatments have not been identified, the mechanisms underlying the disorder are still unknown, and quantitative assessments of visual perception remain sparse. The proposed research seeks to address these knowledge gaps by measuring differences in visual performance and associated neural processing with a series of well-established psychophysical and imaging paradigms. To provide quantitative measures of perception and visual processing in VSS, we will assess (1) contrast sensitivity, (2) spatial context, and (3) temporal context perception in people with VSS compared to normally sighted controls through a series of fundamental psychophysical and high field (7T) functional magnetic resonance imaging (fMRI) experiments. These experiments will help us understand how people with VSS perceive and process contrast, which is an important measure of visual function that is related to performance on every-day visual tasks. Additionally, the proposed research will address how both spatial and temporal context are altered in VSS—previous but sparse research suggests that both spatial and temporal context may be altered in VSS, but further evidence with both larger numbers of participants and robust measures of neural activity are required to investigate potential differences in visual context processing. Critically, we will also provide high resolution 7T fMRI measures of cortical responses during visual tasks to investigate potential differences in gain control throughout the visual system. The proposed assessment of visual perception and accompanying measurements of neural processing in VSS are necessary to better characterize this disorder, and will help formulate hypotheses about mechanisms underlying VSS.

NIH Research Projects · FY 2025 · 2022-08

Abstract Hepatocellular carcinoma (HCC) ranks the third in cancer-related mortality because of ineffective therapy. Intratumoral accumulation of regulatory T-cells (Tregs), which suppresses antitumor immunity, has been identified in HCC. Despite the extensive research of microRNAs in HCC, their roles in regulating immunosuppression are poorly described. Aberrant activation of AKT (v-akt murine thymoma viral oncogene homolog 1) and Nras (neuroblastoma ras viral oncogene homolog) (Ras) was observed in Kupffer cells (KCs) and hepatocytes (HCs) in 74% of HCC patients. Hydrodynamic injection (HDI) of activated forms of AKT and Nras (AKT/Ras) into mice triggered the development of lethal HCC within 6-8 weeks. MiRNA profiling revealed that miR-15a and miR-16- 1 cluster (miR-15a/16) was reduced in KCs from HCC tumors of AKT/Ras mice and patients. KC-specific expression of miR-15a/16 fully prevented growth of aggressive HCC in AKT/Ras mice, while 100% of AKT/Ras mice died from lethal tumor burden within 6-8 weeks post-injection. KC-specific expression of miR-15a/16 also led to a significant regression of HCC tumors in AKT/Ras mice bearing tumors. Mechanistically, AKT/Ras reprogrammed the transcriptome of KCs toward M2 polarization of KCs and drove a significant increase in serum C-C motif chemokine 22 (CCL22) and mRNA levels of Ccl22 in KCs of AKT/Ras mice. In contrast, miR-15a/16 reversed this process and inhibited CCL22 overproduction by directly targeting NF-κB that activates transcription of Ccl22. CCL22 recruits Tregs via CCR4 (C-C chemokine receptor type 4). Indeed, additional treatment of CCL22 recovered immunosuppression and growth of HCC that was fully prevented by miR-15a/16 in AKT/Ras mice. We hypothesize that AKT/Ras-educated KCs initiate hepatic recruitment of Tregs by overproducing CCL22, thereby promoting HCC development; while KC-specific expression of miR-15a/16 suppresses hepatic recruitment of Tregs and HCC development by attenuating CCL22 production. The objective of this project is to elucidate the role of AKT/Ras-educated KCs in promoting immune suppression that promotes growth of HCC, while miR-15a/16 reverses this process by inhibiting NF-κB signaling in KCs. The long-time goal is to develop KCs as a therapeutic target and miR-15a/16 as a novel immunotherapy against HCC. Three specific aims are designed to test our hypothesis. Specifically, we will (1) unravel the mechanism(s) by which AKT/Ras-educated KCs promote immunosuppression and HCC development. (2) establish the mechanism(s) by which miR-15a/16 drives antitumor immunity; and (3) evaluate the therapeutic potential of miR-15a/16 against HCC with divergent backgrounds. The combination of strong preliminary data and a logical and rationally based experimental design make this project highly feasible. We expect that this study will provide a novel insight into the immunosuppression mechanisms in HCC and facilitate the design of KCs as a novel therapeutic target and miR-15a/16 as a rational immunotherapy against HCC.

NIH Research Projects · FY 2025 · 2022-08

PROJECT SUMMARY/ABSTRACT Globally, acute lymphoblastic leukemia (ALL) is the most common cancer in children 0-14 years of age, with an estimated 74,000 incident cases each year. Nearly 1,500,000 years of life are lost due to the disease annually; and because of their large, young populations, the burden of ALL is centered within south, southeast, and east Asia; the middle east and north Africa; and sub-Saharan Africa. These trends highlight the need for research addressing risk for ALL in global populations where the need is greatest. Incidence of ALL also shows distinct patterns by ancestry. In the United States, risk is highest in Latinos, followed by European and Asian/Pacific Islander children, while African-American children have by far the lowest rates. There is reason to believe these patterns may be based at least partially on genetics. For instance, incidence of childhood ALL among diaspora populations in the United States largely recapitulates international patterns of incidence. The germline genetic architecture of ALL risk revealed to date suggests that ALL has a stronger risk component accounted for by common polymorphic variants than is found in adult cancers, with genomewide association studies (GWAS) having identified over 15 common variants associated with B-cell precursor ALL (B-ALL, comprising ~85% of ALL cases), which together describe nearly a 10-fold difference in risk between the lowest and highest ends of distribution of polygenic risk score. However, these studies have largely examined European genomes. The Childhood Cancer and Leukemia International Consortium (CLIC) is ideally suited to understanding the genomic architecture of ALL risk in children of many ancestries. CLIC’s collective genomic datasets comprise ~12,000 children with ALL from five continents, making them both the largest and most diverse such datasets worldwide. Moreover, most of CLIC’s genomic data is embedded within epidemiologic studies, unlike the purely clinical studies to date. With this resource, which more than doubles the sample size over previous GWAS, we propose to: 1) estimate heritability of ALL using SNP-based methods in diverse populations including Africans/African- Americans (AFR), admixed Americans (i.e. Latinos; AMR), East Asians (EAS), Europeans (EUR), Middle Eastern/North Africans (MENA), South Asians (SAS), and Southeast Asians (SEA); 2) conduct comprehensive genomewide and local discovery for variants associated with ALL; and 3) create population-specific polygenic risk scores and examine their relationship to harmonized epidemiologic data within CLIC. At the conclusion of this study, CLIC will have articulated a far more comprehensive genetic epidemiology of ALL than exists today in populations that represent most of the children on earth; and, for the first time, will simultaneously consider non-genetic risk factors. We further will have prioritized candidate variants for functional validation and built a robust infrastructure for future analyses of CLIC’s genomic datasets.

NIH Research Projects · FY 2026 · 2022-08

PROJECT SUMMARY Recent studies have demonstrated that the adaptive immune response plays an important role Alzheimer’s disease (AD) progression by promoting a pro-inflammatory state in the brain. This inflammatory process involves T cell and microglial cell activation. Such inflammatory processes are typically suppressed by a subset of T cells called regulatory T cells (Tregs). Significantly, Treg dysfunction is associated with AD in humans and in mouse models of AD. In addition to decreased Tregs in AD cases, studies have demonstrated that systemic depletion of Tregs exacerbates early AD pathology, while an increase in Tregs attenuates early AD pathology in transgenic mouse models of AD. However, these previous studies come with important caveats. First, all studies involving Treg depletion focused on studies in young mice at early stages of AD pathology, which may not be a clinically relevant time-point. Second, studies using FOXP3-DTR mice and diphtheria toxin to selectively deplete Tregs deplete Tregs everywhere and induce body-wide inflammation. This makes it difficult to assess whether worse outcomes observed in AD upon “Treg depletion” are specific to an effect of Tregs in the brain or due to massive systemic inflammation. Moreover, the types of Tregs that accumulate during AD progression, and their functional role in disease progression, particularly in brain, are also unknown. Thus, major gaps in our knowledge are (i) what types of Tregs are found in the brain during steady-state and in Alzheimer’s disease and, (ii) what role Tregs or distinct subsets of Tregs play in ameliorating AD. Our preliminary studies demonstrate that Tregs in tissues are quite diverse and that distinct Treg subsets occupy inflamed tissues with different kinetics. Most notably, we identified a novel population of Tregs, called ISG-Tregs, that accumulate in tissues with IFN-driven inflammation. Previous studies of AD demonstrate that type I IFN is a characteristic of AD, that it exacerbates neurological damage in AD models, and plays an important role in initiating neuroinflammation and promoting AD progression. Thus, ISG-Tregs may play a critical role in AD progression. The goal of this proposal is to identify the subsets of Tregs present in the brain, and identify where those subsets are located within the brain, during AD progression, and establish murine models to directly test the function of Tregs and Treg subsets in AD. We will use scRNA-Seq and spatial proteomic/transcriptomic approaches to characterize Tregs during AD progression. Using a novel Treg reporter/deleter mouse strain that we developed we will also develop new mouse models that will allow us to study the function of brain Tregs, or select brain Treg subsets, on AD progression. We will also provide important information regarding the pathological role of Treg at different stages of AD in vivo. These studies will allow us to characterize the types of Tregs present in AD, establish their localization in the brain during disease progression, and develop models that will allow us to establish their functional role in ameliorating or exacerbating Alzheimer’s disease in the future. Such information will prove critical for better implementation of Treg-based therapies to improve outcomes in Alzheimer’s disease.

NIH Research Projects · FY 2025 · 2022-08

Project Abstract Black immigrants are poised to make up a significant portion of the Black older adult population and similar to U.S. born Black older adults, are at risk of poor health outcomes related to dementia. However, few efforts have culturally adapted dementia care and caregiving interventions for racial/ethnic minority populations. Existing adaptations have not been systematically conducted or documented, and have not focused on Black immigrants. The objective of this K01 award is to acquire targeted training in the cultural adaptation and feasibility testing of behavioral interventions for racial/ethnic minority older adults. The candidate’s training goals are to: 1) Build expertise in dementia, cognitive impairment, and long- term care for Black immigrant older adults; 2) Expand skills in the development, delivery, and implementation of culturally relevant behavioral interventions for Black immigrants; 3) Design and conduct a feasibility study with community dwelling older adults; 4) Apply advanced statistical methods to analyze paired, longitudinal, pre-and post-test, and clinical trial data; and 5) Obtain the experience necessary to advance as a well-rounded successful independent scientist (e.g. grant writing expertise, increased first-author peer-reviewed publications, mentorship of junior scholars etc.). Mentored research training will occur in the context of a dedicated project with these specific aims:1) Explore the experiences and care strategies used by Black immigrant older adults with dementia and their informal caregivers. 2) Guided by the Ecological Validity Model, use the knowledge gained from Aim 1 to culturally adapt the evidenced-based Active Caregiving: Empowering Skills (ACES) for Black immigrant older adults with dementia and their informal caregivers. 3) Determine the feasibility and acceptability of the culturally adapted ACES intervention with Black immigrant older adults with dementia and their informal caregivers. The candidate’s mentoring team has extensive expertise in these areas and will offer mentoring, consultation, hands-on training, networking/collaborations and resources to facilitate the candidate’s career development. The 2020 NIA Dementia Care Summit Gaps and Opportunities highlights the need for research that explores differences in the effects of social and cultural determinants of dementia care and caregiving. Completion of this research and training meets this research need and will enable the candidate to become a successful independent scientist with substantive expertise in dementia care and cultural adaptation of interventions for racial/ethnic minority community-dwelling older adults. This is an important step towards improving health outcomes and eliminating health inequities for these populations.

NIH Research Projects · FY 2025 · 2022-08

Abstract Parkinson’s disease, dementia with Lewy bodies, and related synucleinopathies have a long prodromal stage, lasting years to decades, during which neurodegeneration progresses insidiously across the nervous system. Compensatory neuroplastic changes in structural and functional connectivity are thought to occur during the prodromal stage that mask the expression of motor and non-motor signs, which could markedly delay diagnosis during a critical therapeutic window. Alternatively, neuroplastic changes in structure and function may contribute to the emergence and/or exacerbation of motor and non-motor signs. Currently, little is known about the temporal evolution of structural and functional adaptations, the state of cortical neuroplasticity, and how these factors contribute to the masking and/or emergence of motor and cognitive signs during prodromal disease. This project will study the progression of disease in people with isolated rapid eye movement (REM) behavior sleep disorder (iRBD), a sleep disturbance characterized by elevated muscle activity during REM sleep, in conjunction with dream enactment. IRBD is recognized as a prodromal stage of synucleinopathy since more than 70% of people with this disorder eventually develop Parkinson’s disease, dementia with Lewy bodies, or multiple system atrophy. The goal of this project is to characterize the temporal evolution of neuroplastic changes in the structure and function of the brain in people with iRBD and to identify factors contributing to the masking and/or emergence of motor and cognitive signs. Aim 1 will use ultra-high field MRI at 7T to obtain measures of structural (diffusion tensor) and functional (rest-state) connectivity of prefrontal and sensorimotor pathways, their progression over two years, and their relationships to measures of motor and cognitive function. Aim 2 will use paired associative stimulation (peripheral nerve stimulation paired with transcranial magnetic stimulation) to examine the state and progression of long-term potentiation (LTP)-like plasticity in motor cortical pathways and its relationship to measures of motor function. Similarly, Aim 3 will use paired associative stimulation to examine the state and progression of LTP-like plasticity in prefrontal cortex and its relationship to measures of cognitive function and gait. Aim 4 will look at the relationships between the level of REM sleep muscle activity, the state of structural and functional connectivity, and cortical neuroplasticity and the progression of motor and cognitive signs. This project will provide unique insight into the temporal evolution of neuroplastic changes in the brain during prodromal disease in people at high risk of developing parkinsonism, dementia with Lewy bodies, or related synucleinopathies.

NIH Research Projects · FY 2026 · 2022-08

PROJECT SUMMARY/ABSTRACT Great advances are underway in the field of dementia. Symptomatic Alzheimer’s’ disease (AD) can be diagnosed with a simple blood test. The number of new dementia patients per capita is shrinking in parallel to public health campaigns to improve brain health. New drugs are emerging that promise to effectively prevent or treat dementing illness. While these breakthroughs in dementia diagnostics, prevention and treatment are cause for celebration, hardly anything is known about whether these advances will translate to Native American (NA) communities, where very little is known about dementia from a biomedical perspective. For instance, only two NA at the time of this writing have available blood test data in the AD Neuroimaging Initiative, the largest AD biobank in the United States. Approximately 200 NA have been included in the largest AD consortium in the country out of over 40,000 participants. This lack of knowledge regarding dementia in NA is problematic and portends a widening of already severe health disparities. The current study’s central hypothesis is that American Indians have unique dementia risk factors and a differential effect of APOE ε4 – the most significant genetic risk factor for AD. These factors will change the epidemiology of dementia and preclude a “one size fits all” AD blood test using APOE ε4, The first goal of the current project is to determine what types of dementia exist among NA Tribal Nations, which is currently unknown but is a first-step to designing and implementing effective brain health policy. The second goal involves measuring the ancestry- dependent effect of APOE on AD risk and AD biology in NA. AD blood tests utilize the APOE gene along with direct quantification of the toxic proteins associated with AD to determine a positive or negative result. If inherited from a European ancestor, having an APOE ε4 allele increases the chances of AD and also increases the probability of a positive AD blood test result. But if a patient inherits their APOE ε4 gene from an African ancestor, there is an attenuated impact on accumulation of toxic proteins that define AD. The same neutral relationship between APOE ε4 and AD likely applies to NA – preliminary data from our group and others suggest that inheriting an APOE ε4 gene from a NA ancestor similarly does not increase the risk of AD. If an NA individual undergoes an AD blood test and carries an APOE ε4 allele, will they receive a life-changing but false diagnosis for a devastating condition? Our study thus will measure the relationship between APOE and AD risk/biology in NA. As APOE is also a centerpiece of personalized medicine, risk/benefit discussions for anti-amyloid therapy, trial eligibility, and the target of genetically guided therapies, this study will provide critical knowledge about the applicability of APOE based medical advances to NA. This is the first study to our knowledge that attempts to bring American Indian dementia care into the 21st century and provide a foundation for this understudied group to benefit from the latest advances in diagnosis, prevention treatment of dementia.

NIH Research Projects · FY 2025 · 2022-08

Abstract Recently, NCI called for research to effectively study small or rare populations relevant to cancer research. Sexual and gender minorities (SGM) are small populations at disproportionate risk for cancer but who have been under-researched in cancer studies. The principal challenge common across lesbian, gay, bisexual, and transgender populations is to develop effective methods to identify and recruit patients and survivors who are SGM into NCI cancer studies. Two technical advances have transformative potential to advance research on health disparities in SGM cancer patients. First, online recruitment has yielded large SGM samples in other areas of research (e.g., HIV primary prevention), but using online methods to recruit SGM cancer patients has not been rigorously studied. Second, cancer clinics have begun to include sexual orientation and gender identity (SOGI) data in the electronic medical record, but we need to test protocols on how to recruit SGM cancer patients using this data source. This application is based upon our recent success in overcoming challenges to recruit over 400 gay and bisexual prostate cancer patients into an R01 intervention trial of tailored rehabilitation for this population. We will replicate and expand upon these clinic-based and online methods to study how to recruit three small SGM populations – (1) sexual minority cisgender men, (2) sexual minority cisgender women, and (3) transgender and gender non-binary cancer patients - into cancer research studies. We have three specific aims. In Aim 1, we will document, in depth, SGM’s attitudes towards participating in NIH cancer research, identifying the facilitators and barriers that each group reports influences their willingness to participate. We will also investigate any impact poor cancer care and discrimination has on research participation. We will investigate these in cisgender SM men, cisgender SM women and gender minority cancer patients (n=15 per group) and compare experiences within these small populations and between SGM and a cisgender, heterosexual patient comparison group. In Aim 2, we will test the effectiveness, efficiency, cost, and workload in using two clinic SOGI-based strategies and three online strategies to recruit SGM small populations (150 each) compared to recruiting a sample of cisgender, heterosexual cancer patients. We predict size of the small population will negatively correlate with work, cost, and time involved, but positively correlate with yield. In Aim 3, we will conduct an online quantitative survey of willingness to participate in cancer research with 450 SGM cancer patients (150 per group) versus a cisgender heterosexual group (150 men and 150 women). Key measures assess facilitators and barriers to participation in NIH cancer research. To advance measures, we will assess performance of each group on five validated cancer scales to compare cancer care experience, discrimination in treatment, and outcomes. Finally, we will integrate and triangulate findings and assess intersectionality with race/ethnicity. This study will establish what recruitment strategies are effective across SGM populations, and which may be specific to each subgroup.