Mayo Clinic Jacksonville

NIH Research Projects · FY 2025 · 2024-05

Community outreach and engagement (COE) has become the gold standard in addressing the burden of cancer at the community level. The National Cancer Institute (NCI) encourages all NCI-designated Cancer Centers to foster and share “COE knowledge-base, best practices, and tools” for adoption, adaptation and implementation by other NCI-designated cancer centers, the scientific community and the public at large to advance progress against the burden of cancer and cancer risk factors. Unfortunately, there have been limited nation-wide opportunities to facilitate mutual learning of COE knowledge, best practices and tools by COE administrators, COE researchers, COE professionals, cancer survivors, cancer advocates and community stakeholders. The Science of Community Outreach and Engagement (SoCOE) conference is proposed by the Alliance of COE Scientific Directors who lead COE Offices and Programs in several NCI designated Cancer Centers serving rural, underserved, understudied and under-resourced communities across the United States. The primary objective of the conference is to provide a platform for COE academic-community stakeholders to share best practices and recommendations that will address cancer prevention, early detection, care and survivorship in communities with negative health drivers. A five-year conference funding is requested to support the SoCOE conference, with the 1st conference proposed to be hosted by the Mayo Clinic Comprehensive Cancer Center and the Virginia Commonwealth University Massey Cancer Center from May 8 to 10, 2024, in Florida, United States. Subsequent conferences will focus on: Optimizing Cancer Research, Care & Outcomes for All (2025); Innovative Approaches to Contextual Differences in Health (2026); Precision Oncology/Genetics in Cancer Care (2027); and Community Outreach and Engagement: Strategies for Success (2028). Led by outstanding researchers and COE scientific directors, the SoCOE conference will foster the development of sustainable and evidence-based resources to facilitate COE in the catchment areas of Cancer Centers. Additional tangible outcomes are published meeting proceedings, collaborations among conference participants, and increased expertise among participants. We expect a minimum of 250 delegates to participate in the conference.

NIH Research Projects · FY 2026 · 2024-04

PROJECT SUMMARY Acute pancreatitis (AP) is a prevalent gastrointestinal condition that leads to a significant number of hospitalizations and high healthcare costs. With no effective therapy currently available, there is an urgent need for research to develop successful treatments. This proposal aims to investigate the roles of trypsin and coagulation in the development of acute pancreatitis and explore the hypothesis that thrombin plays a crucial role in the disease. Previous studies have shown that thrombin, a dual thrombin and trypsin inhibitor, has superior effects in preventing and treating acute pancreatitis compared to selective trypsin inhibitors. This suggests that anti- trypsin and anti-coagulation mechanisms work together to combat the disease. To investigate this further, genetic approaches will be used, including a newly engineered trypsin knockout mouse model (T2457) and a conditional thrombin knockout mouse model. The research will focus on dissecting the roles of trypsin and coagulation in acute pancreatitis initiation and progression. Additionally, the impact of thrombin on the pancreatic microenvironment will be examined using a multi-photon intravital imaging system. Thrombin inhibitors, PAR receptor inhibitors, and PAR1 knockout mice will be utilized to gain a better understanding of the coagulation pathway's influence on acute pancreatitis. In the final aim, the project will concentrate on enhancing drug delivery to the inflamed pancreas, addressing the issue of low drug concentrations in the affected tissue. Dabigatran will be used as a model drug, and proof-of-principle studies will be conducted to develop pancreatitis-specific drugs that improve drug delivery. An intravenous formulation of dabigatran will be formulated and tested for therapeutic efficacy, along with two prodrugs designed to activate locally in the pancreas. The completion of this project will significantly advance the understanding of acute pancreatitis pathophysiology and contribute to the development of targeted therapies. The knowledge gained will provide a solid foundation for future clinical trials aimed at preventing and treating acute pancreatitis. Ultimately, this research has the potential to impact patient outcomes and improve the management of this challenging condition.

NIH Research Projects · FY 2026 · 2024-04

PROJECT SUMMARY/ABSTRACT Acute pancreatitis, if it doesn’t resolve, can further develop into a chronic condition. Resulting chronic pancreatitis is characterized by presence of inflammatory macrophages, fibrosis, and loss of acinar cells. Moreover, it represents a risk factor for pancreatic cancer. The cellular and molecular mechanisms that mediate the transition from acute to chronic pancreatitis are ill-defined, and efficient therapeutic treatment methods for chronic pancreatitis are lacking. In this proposal, it is our hypothesis that Protein Kinase D1 primes acinar cells to produce factors that prevent acute pancreatitis from resolving and generates a chronic condition. We further hypothesize that the resulting chronic pancreatitis can be targeted with PKD inhibitors. To test this we will: Determine how PKD1 expression in acinar cells can generate an environment that is favorable for developing chronic pancreatitis (Specific Aim 1); and utilize our acinar cell- targeted animal models to determine the effects of PKD1 on development and resolution of chronic pancreatitis (Specific Aim 2). Successful completion of this project will define the role of activated PKD1 in altering pancreatic acinar cells in a way that they can facilitate the transition of acute pancreatitis to a chronic state. We will define how these molecular changes affect cells in the pancreatic environment and the immune landscape in the pancreas. Eventually, we will determine if inhibition of PKD1 in vivo can resolve chronic pancreatitis. This will lay the groundwork of developing targeted treatment strategies for pancreatitis based on inhibition of PKD1 or downstream signaling events.

NIH Research Projects · FY 2025 · 2023-12

PROJECT SUMMARY/ABSTRACT Pancreatic ductal adenocarcinoma (PDA) carries a dismal prognosis. Understanding the mechanisms that lead to the development of pancreatic cancer and to identify markers that distinguish between non-cancerous and cancerous lesions is the greatest hope for early detection and early treatment of patients. This proposal focusses on identifying early detection markers that would allow resection of tumors at a time point where they are still local. It is our hypothesis that pancreatic high-grade lesions significantly distinguish from low- grade lesions by expressing PADI1. We further hypothesize that PADI1 and its citrullinated substrates can be detected in pancreatic biopsy and may form a panel of markers specific for early detection of PDA. To test this we will: verify PADI1 as a specific marker for HG lesions and test its presence in liquid biopsies (Specific Aim 1); characterize citrullinated fibrinogen as a PADI1 substrate and marker for pancreatic cancer (Specific Aim 2); and identify pancreas cancer specific PADI1-citrullinated substrates (intracellular and secreted) in lesions and in liquid biopsy (Specific Aim 3). Successful completion of our project will identify secreted protein markers that are detectable in easily accessible liquid biopsy (blood serum) and distinguish between pancreatic non-cancerous lesions and PanIN3 (carcinoma in situ) and PDA lesions.

NIH Research Projects · FY 2026 · 2023-12

PROJECT SUMMARY/ABSTRACT Alzheimer disease and related dementias (ADRD) comprise a group of neurodegenerative diseases characterized by progressive decline of cognitive, behavioral, and/or motor function. These conditions place a significant burden on patients, families, and the healthcare system. Among the ADRDs is frontotemporal dementia (FTD), with approximately half of FTD cases characterized pathologically by frontotemporal lobar degeneration with TDP-43 pathology (FTLD-TDP). Single nucleotide polymorphisms (SNPs) in TMEM106B are known to alter risk of FTLD-TDP. TMEM106B is a protein localized to late endosomes and lysosomes and has been reported to play a role in endolysosomal trafficking and brain myelination. Only one TMEM106B SNP causes a coding change, altering the amino acid at position 185 from threonine to serine (T185S). The TT185 haplotype is associated with significantly increased risk of FTLD-TDP relative to SS185. The SNP is also in high linkage disequilibrium with other TMEM106B SNPs, marking the coding change as a potential mechanism behind TMEM106B’s modulation of disease risk. The coding SNP of TMEM106B has not been studied extensively, though the coding change has been reported to alter protein half-life and autophagic flux in the cell. Recently, four groups published the discovery of TMEM106B amyloid fibrils in sarkosyl-insoluble cortical lysates across a range of neurodegenerative diseases, including FTLD-TDP. In preliminary studies, we have observed that accumulation of TMEM106B fibrils is positively associated with the TT185 haplotype. We speculate that the TMEM106B risk haplotype drives fibril formation and endolysosomal dysfunction, both of which contribute to neuron loss in disease. The studies outlined in this proposal will characterize the biological consequences of TMEM106B fibril formation in the diseased human brain and investigate TMEM106B haplotype-specific differences in endolysosomal function in a new cell model system. In Aim 1, we will identify protein interactors of TMEM106B fibrils in postmortem FTLD-TDP and non-diseased brains to test the hypothesis that TMEM106B fibrils exhibit disease-specific interactions that drive neuron loss. In Aim 2, mechanistic studies will be performed in novel, isogenic iPSC-derived neuron models stably expressing TMEM106B coding variants to test the hypothesis that the TMEM106B risk haplotype impairs endolysosomal function. We will also assess mechanistic relationships between TMEM106B and top interactors identified in Aim 1, and how they may vary with TMEM106B haplotype. We anticipate that this work will help identify novel protein targets to investigate or target for therapeutic development.

NIH Research Projects · FY 2025 · 2023-09

PROJECT SUMMARY/ABSTRACT Filaments derived from transmembrane protein 106B (TMEM106B) were recently discovered to represent a novel pathological hallmark in a range of neurodegenerative disorders, including TDP-43 proteinopathies, synucleinopathies, and tauopathies. Notably, TMEM106B genetic variants are linked to risk of frontotemporal lobar degeneration with TDP-43 inclusions (FTLD-TDP), particularly cases with progranulin (GRN) and chromosome 9 open reading frame 72 (C9ORF72) mutations, and limbic-predominant age-related TDP-43 encephalopathy (LATE) neuropathologic change. TMEM106B variants also associate with cognitive decline in patients with amyotrophic lateral sclerosis. While several single nucleotide polymorphisms (SNPs) in TMEM106B have been identified and linked to disease risk, only one (rs3173615) introduces a coding change (p.T185S) and it is in high linkage disequilibrium with other risk SNPs. To investigate the intriguing idea that rs3173615 could modulate disease risk through regulation of TMEM106B deposition, we developed an antibody against the TMEM106B filament core sequence. Consistent with recent reports, we detected TMEM106B-positive filaments in the sarkosyl-insoluble fraction from FTLD-TDP and LATE patients. Remarkably, we also observed increased accumulation of insoluble TMEM106B in FTLD-TDP patients homozygous for the rs3173615 risk allele (encoding threonine at residue 185 instead of serine). Collectively, these findings support the hypothesis that TMEM106B aggregation explains the link between genetic variation at the TMEM106B locus and disease risk – and we suspect that it could also explain potential links between rs3173615, TDP-43 proteinopathy, and cognitive decline. We also speculate that differences in TMEM106B accumulation contribute to clinical and pathologic heterogeneity in both FTLD and LATE. Moreover, given that LATE is associated with greater hypometabolism on [18F] fluorodeoxyglucose PET (FDG-PET) in the frontal lobe, a region populated by TMEM106B fibrils, we predict that rs3173615 genotype will also associate with neuroimaging measures of neurodegeneration. In this project, we will investigate the impact of rs3173615 genotype on TMEM106B aggregation and assess whether it associates with TDP-43 proteinopathy and clinical outcomes. We will also explore the mechanism by which the rs3173615 coding variant affects TMEM106B fibril formation, as well as the potential functional consequences of TMEM106B genetic variation and fibril accumulation. Our approach to the latter will be two-fold: as a candidate-based approach, we will determine whether TMEM106B genetic variants impact lysosomal function in neurons, and as an unbiased approach, we will use proteomic analyses to build protein-protein interaction and co-aggregation networks from the soluble and insoluble fractions of patient brains, focusing on differences observed in carriers of the T185 allele versus carriers of the S185 protective genotype.

NIH Research Projects · FY 2025 · 2023-09

Important health disparities exist in the burden of Alzheimer’s disease and related dementias (ADRD) across US population. Compared to non-Hispanic White Americans (NHW), a higher ADRD burden is experienced by Hispanic & Latino (HL; 1.5X) and Black & African American (BA; 2X) individuals. These ADRD high-risk populations (HRP) comprise 1/3 of the US population (18.7% HL, 12.4% BA - US 2020 Census) and are projected to increase yet remain critically underrepresented in ADRD research. This underrepresentation exacerbates health disparities and challenges the development and implementation of efficacious and safe risk-reduction strategies. Genetics do not fully explain disparate ADRD risk, highlighting a fundamental knowledge gap concerning how genomic factors interact with comorbidities and lifespan exposures to social risk factors (the “exposome”) to modify ADRD risk. There is a critical need to identify clinical, social risk factors, and biological factors that contribute to disparate risk in HRP; establish the relationship between exposures underlying ADRD outcomes; use this information to mitigate disparities in ADRD burden through education and risk factor modification; and broadly disseminate this information to inform the development of effective biomarkers and therapies. The Mayo Advancing Research Engagement in ADRD Study in Jacksonville (MAREAS; Spanish for tides) will address this need. Aim 1 will advance recruitment of HRP cohorts (UH2) by developing/deploying outreach, recruitment, and engagement best practices for HRP in Jacksonville, Florida, through a bilingual (English-Spanish) research team, supported by community ambassador teams (CAT) and an external advisory board (EAB) including experts in social risk factors and ADRD research. Aim 2 will identify relevant measures of ADRD burden (UH2►UH3). Social risk factors, cognitive, clinical, and blood-based biomarker measures associated with cerebrovascular, amyloid, and tau burden, will be collected through comprehensive/culturally appropriate annual assessments and integrated with multi-omics data, structural (MR) and molecular (amyloid and tau) PET neuroimaging obtained at study entry, and every 2 years thereafter to identify modifiable dementia risk factors, blood-based biomarkers, and molecular signatures of ADRD burden. Data collection will be standardized with input from EAB members to optimize scalability and promote sample/data sharing. Aim 3 will provide meaningful individualized feedback (UH3) to participants through a Brain Health Report detailing actionable risk factors and recommendations to mitigate intraindividual ADRD burden. Aim 4 will use multi-omics measures to identify molecular signatures that interact with the exposome and associate with ADRD burden in HRP (UH3), following NIH’s findability, accessibility, interoperability, and reusability guidelines for broad data sharing. In this way, MAREAS Jax will chart the currents that drive disproportionate participation in ADRD research and disparate ADRD burden and will inform the design and implementation of strategies to shift these tides in Northeast Florida and beyond.

NIH Research Projects · FY 2024 · 2023-09

PROJECT SUMMARY/ABSTRACT Hispanics/Latinos (HL) and African Americans (AA) represent a rapidly growing proportion of the United States population (18.7% HL, 12.4% AA - US 2020 Census) who remain critically underrepresented in research of Alzheimer disease (AD) and AD-related dementia (ADRD), despite a 1.5-2-fold higher prevalence of dementia (vs non-Hispanic-white Americans). Underrepresentation in AD/ADRD research exacerbates health disparities and challenges the development and implementation of efficacious and safe risk-reduction strategies for AD/ADRD in HL/AA. Genetics do not fully explain disparate AD/ADRD risk, highlighting a fundamental knowledge gap concerning how genomic factors interact with comorbidities and lifespan exposures to Structural/Social Determinants of Health (SDoH; the “exposome”) to inform AD/ADRD risk. There is a critical need to identify clinical, SDoH, and biological factors that contribute to disparate risk in HL/AA; establish the relationship between exposures underlying AD/ADRD outcomes; use this information to mitigate disparities in AD/ADRD burden through education and risk factor modification; and broadly disseminate this information to inform the development of effective biomarkers and therapies. The Mayo Advancing Research Equity in ADRD Study in Jacksonville (MAREAS-JAX; Spanish for tides) will address this need. Aim 1 will advance recruitment of HL/AA cohorts (UH2) by developing/deploying outreach, recruitment, and engagement best practices for HL/AA in Jacksonville, Florida, through a bilingual (English-Spanish) research team, supported by community ambassador teams (CAT) and an external advisory committee (EAC) including experts in SDoH and AD/ADRD research. Aim 2 will identify relevant measures of AD/ADRD burden (UH2►UH3). SDoH, cognitive, clinical, and blood-based biomarker measures associated with cerebrovascular, amyloid, and tau burden, will be collected through comprehensive/culturally appropriate annual assessments and integrated with multi-omics data, structural (MR) and molecular (amyloid and tau) PET neuroimaging obtained at study entry, and every 2 years thereafter to identify modifiable dementia risk factors, blood-based biomarkers, and molecular signatures of AD/ADRD burden. Data collection will be standardized with input from EAC members to optimize scalability and promote sample/data sharing. Aim 3 will provide meaningful individualized feedback (UH3) to participants through a Brain Health Report detailing actionable risk factors and recommendations to mitigate intraindividual AD/ADRD burden. Aim 4 will use multi-omics measures to identify molecular targets and signatures that interact with the exposome and associate with AD/ADRD burden in HL/AA (UH3) using a systems biology approach with validated analytic pipelines and prioritizing broad data sharing following NIH’s findability, accessibility, interoperability, and reusability guidelines. In this way, MAREAS-Jax will chart the currents that drive disproportionate participation in AD/ADRD research and disparate AD/ADRD burden and will inform the design and implementation of strategies to shift these tides in Northeast Florida and beyond.

NIH Research Projects · FY 2025 · 2023-09

ABSTRACT Alzheimer's disease and related dementias (AD/ADRD) are the most common neurodegenerative brain disease and characterized by massive loss of memory and learning. AD/ADRD affects more than 6 million Americans and puts a heavy burden on caregivers in society. However, effective treatment of AD/ADRD is still lacking. While randomized clinical trials (RCT) can provide reliable evidence on the effectiveness of interventions, they also have inherent limitations including high cost and long execution time. In addition, RCTs usually are conducted on selected populations and in specialized environments with limited follow up time. Therefore, they could have limitations in generalizability to real-world clinical practice. Clinical trial simulation is becoming an effective approach to assess feasibility, investigate assumptions, and refine study protocols before conducting the actual trials. Increased availability and granularity of real-world data (RWD) such as electronic health record (EHR) and medical claims data along with advances in data science offer untapped opportunities to leverage RWD for trial simulation studies to generate real world evidence (RWE). Nevertheless, there are methodological barriers and informatics challenges in supporting RWD-based trial simulation studies, especially for AD: (1) clinical trials need to be represented using a formal and standard approach (i.e., ontologies) to capture the entire scope of a trial, especially eligibility criteria and outcome measures (i.e., both effectiveness and safety); (2) such formal and standard representation needs to be made interoperable with RWD standards (e.g., common data models) to identify study cohorts and relevant, important patient characteristics (i.e., via computable phenotypes and natural language processing [NLP] methods as rich AD-related information such as cognitive scores often exist in unstructured clinical notes); and (3) comprehensive and reusable pipelines need to be implemented that can seamlessly align with existing large-scale RWD for generating high-quality analytic-ready datasets for AD clinical trial simulation studies. To address these barriers, we propose create and pilot test the ACTS (Alzheimer's disease Clinical Trial Simulation) system, leveraging three large collections of RWD (~20 million patients from the OneFlorida network, UT Physician Clinical Data Research Warehouse, and the Optum’s Clinformatics data). Specifically, we propose to develop novel informatics approaches to represent the entirety of AD trials while considering the connection of RWD (Aim 1), to use both structured and unstructured RWD to develop robust phenotyping algorithms that will render previously incomputable AD study traits computable (Aim 2), and to develop the ACTS web application, which will provide an integrated environment for AD researchers to construct virtual AD trials using an interactive web interface and obtain analytic-ready datasets for trial simulation studies (Aim 3).

NIH Research Projects · FY 2024 · 2023-07

PROJECT SUMMARY AND ABSTRACT Significance: Glioblastoma (GBM) is an extremely devastating disease with reported median survivals ranging from 13 to 73 months and 5-year survivals of less than 20% in children and about 15 months with less than 5% 5-year survival rate for adult patients. Cancer immunotherapy using chimeric antigen receptor (CAR) modified T cells is a promising treatment, however its efficacy in GBM has been limited. Hypothesis: We hypothesize that the fierce competition for nutrients within the tumor microenvironment, especially glucose, between tumor cells and the immune system, imposes an abundant metabolic pressure to CAR T cells dampening their effector function and intratumoral infiltration, expansion, and persistence. Objective: The goal of this study is to validate a new strategy to overcome this metabolic imbalance and provide a competitive advantage to CAR T cells over tumor cells. We propose to improve CAR T cell therapy by enhancing metabolic fitness to outcompete GBM cells for nutrients like glucose. Methods: Our approach will be to directly target the first step of glucose metabolism (i.e., uptake) by permanent overexpression of GLUT1 or GLUT3 and generating the following CAR T cells: CD70CAR.G1 and CD70CAR.G3. The murine model of glioma KR158B, derived from Nf1;Trp53 mutant mouse, that we engineered to express CD70 as well as CD70 expressing human GBM patient-derived cell lines will be used for the following aims: Specific Aims 1. Investigate the phenotypic and functional characteristics of metabolically modified CD70CAR T cells, 2. Evaluate in vivo the metabolic TME of animals treated with CD70CAR.G1 or CD70CAR.G3, 3. Examine the safety and anti-tumor efficacy of CD70CAR.G1 or CD70CAR.G3.

NIH Research Projects · FY 2025 · 2023-07

ABSTRACT Ovarian cancer (OC) causes ~14,000 deaths each year in the USA. While there have been advances in treatment, progression is common and cure rates are low. In recent years, several trials have been done testing immune checkpoint blockade (ICB), either alone or in combination with other agents, largely in the setting of recurrent disease. Overall response rates have been unimpressive. Biomarkers of response to ICB therapy, such as mutational burden, neoantigen load, PD-L1 expression, and baseline T cell infiltration, are associated with response to ICB therapy in many cancers and suggest that ICB therapy requires pre-existent immunity for clinical effectiveness. Vaccines, while inefficient alone at shrinking tumor, can reliably generate the necessary pre-existing immunity, including in most OC patients. In a prior NCI-funded grant (P50- CA136393), we developed a folate receptor alpha (FR) targeting Th17-inducing vaccine that is effective at generating Th17 T cell immunity in nearly all OC patients. The premise for developing the vaccine was based on extensive work showing i) a reciprocal relationship between Th17 effectors and Tregs, ii) association of increased IL-17 expression with improved overall survival, and iii) resistance of Th17 T cells to immune suppression. A phase I clinical trial was conducted in which 19 advanced OC patients, in first remission, were vaccinated. All patients demonstrated coordinated cellular and humoral immunity. Of 18 patients evaluable for efficacy, 39% (7/18) remained recurrence-free at the time of data censoring, with a median follow-up of 49.2 months, a recurrence-free survival (RFS) superior to historical controls(<15%). Parallel murine modeling demonstrated a unique mechanism in which Th17 T cell immunity coordinates otherwise inefficient Th1, Th2 and B cell immunity through myeloid recruitment and activation of antibody-dependent mechanisms in macrophages and eosinophils. We observed that Th17 DC vaccination overcomes resistance to ICB therapy by generating tumor-specific immunity, restructuring the tumor microenvironment, and preventing adaptive resistance to ICB. Thus, we hypothesize that the combination of Th17-inducing DC vaccination and ICB therapy may be an effective therapeutic approach in patients with recurrent OC. In specific Aim 1 we will conduct a phase I/II clinical trial of the novel Th17-inducing DC vaccine in combination with pembrolizumab (provided by Merck) in 32 OC patients in the setting of early disease recurrence. Primary outcome measures will be safety and the rate of objective responses. Interrogation of baseline tumor features will be done for biomarker identification. In Specific Aim 2 we will use well validated analytical tools to examine cellular and humoral immune responses in tissue and the periphery following combination treatment to identify dominant features of the immune response induced by treatment and whether they are correlate with clinical outcome assessments. Mechanisms of resistance to therapy will be identified. If positive, a new treatment ICB treatment paradigm will be established to improve the survival of women afflicted with advanced OC.

NIH Research Projects · FY 2025 · 2023-07

PROJECT SUMMARY/ABSTRACT Chemotherapy-related cardiotoxicity leading to heart failure is a major issue in the treatment of breast cancer and lymphoma patients, who are three times more likely to get heart failure than controls. Cumulative dose of the anthracycline chemotherapy, doxorubicin, is strongly associated with increased risk of heart failure, such that patients are limited to a lifetime cumulative dose, even if the therapy is still needed. Doxorubicin is commonly used for treatment of lymphoma and high risk breast cancers, (triple negative and HER2+ breast cancer). Unfortunately, prediction of which cancer patients are at risk of heart failure is poor and current cardioprotective therapies are limited. Our published genetic studies have identified TRPC6 as a risk locus for doxorubicin-induced heart failure. Our studies of ipsc-derived cardiomyocytes and a mouse model of doxorubicin-induced cardiomyopathy showed that therapeutic inhibition of TRPC6 and TRPC6 knock-out are protective against doxorubicin-induced cardiotoxicity. Our preliminary studies and those of others suggest that inhibition of TRPC6 may also have anti-tumor properties. The overall scientific premise of this project is that genetic variants at TRPC6 and other known and novel loci, significantly increase patient risk of cardiotoxicity. Determination of these variants and better understanding of their mechanisms of action will allow individualized risk stratification and mitigation of chronic heart failure. To determine genetic risk variants of dox-related cardiotoxicity and new cardioprotective strategies for at-risk patients, we will: 1. Diversify our existing cardiotoxicity biorepository at Mayo Clinic Florida by extending to Mayo Clinic Arizona, The University of Florida Jacksonville and Moffitt Cancer Center, performing exome sequencing of these newly enrolled patients and meta-analyses of top hits with additional large and diverse datasets. 2. Define the mechanistic basis of TRPC6 gain-of-function and interaction with other doxorubicin-induced toxicity pathways. 3. Assess the efficacy and cardioprotection of TRPC6 inhibitors in a tumorigenic mouse model analogous to triple negative breast cancer.

NIH Research Projects · FY 2026 · 2023-06

Project Summary The rise in an aging population plagued by obesity and diabetes mellitus is projected to render exponential growth in diabetic kidney disease (DKD). Hence, therapeutic interventions that halt aging-related kidney changes and DKD must be rigorously pursued. Maladaptive inflammation drives DKD onset, and proinflammatory cytokines and chemokines activate macrophages leading to kidney infiltration and poor renal prognosis. Yet, inflammation remains a major unaddressed injurious pathway in DKD. We and others demonstrated that maladaptive inflammation in DKD patients and animal models is associated with increased cellular senescence and kidney dysfunction. Thus, decreasing senescence through senotherapeutics, such as, small molecule drugs or cell-derived components, may halt DKD and age-related kidney deterioration. Therefore, there is an urgent need to develop a therapeutic armamentarium targeting the multifaceted pathogenesis (inflammation and cell senescence) of DKD to extend healthy lifespan. We and others demonstrated that mesenchymal stromal cells (MSCs) suppress inflammatory responses through secretion of extracellular vesicles (EVs) containing biologically active cargo, primarily microRNAs (miRNAs), and reduce senescent burden and extend lifespan in aging mouse models. Although the therapeutic activity of MSC-EVs has previously been assessed in aging and inflammatory disease models, the effects of these biotherapeutics on inflammation and senescence in aging DKD remain unexplored. Our preliminary results indicate that MSC-EVs: (i) reduce senescence pathways, macrophage infiltration, and kidney injury in murine DKD and (ii) can be loaded with small molecule drugs for combination therapy. Additionally, our recent study demonstrated, for the first time, that senolytic drugs, dasatinib and quercetin, reduce senescent cell abundance in humans and improve kidney injury following senescent cell clearance in mouse models. We hypothesize that EVs have anti-inflammatory and senotherapeutic effects in aging DKD, that can be further enhanced by co-delivery of senolytic drugs. To address this central hypothesis, we will determine the effects of EV miRNAs on senescence and inflammation in vitro (Aim 1), assess the effects of EVs from several sources in a mouse model of aging DKD (Aim 2), and evaluate the performance of EVs as drug delivery vehicles for dasatinib and quercetin (Aim 3). To ensure the technical success of this study, we have assembled a team with complementary expertise in aging, DKD, extracellular vesicles, senolytics, and drug delivery. Novel approaches encompassing unique EV sources, EV isolation methods, and immunoprofiling technology will enhance knowledge of EV-mediated therapeutic mechanisms in DKD and may advance clinical translation of EVs as novel senotherapeutics, delivery vehicles for senolytics, and/or combination therapies to reduce inflammatory and senescence pathways in diabetic and age-related kidney dysfunction. These novel therapeutics hold potential to alter disease trajectory and extend the healthy lifespan in those with aging DKD.

NIH Research Projects · FY 2025 · 2023-03

Summary Abstract (30 lines): Existing cerebrospinal fluid (CSF) and neuroimaging measures of amyloid ß, tau and neurodegeneration (A,T,N) serve as useful diagnostic biomarkers for Alzheimer’s disease (AD), however there remains an urgent, unmet need for blood based biomarkers in AD. First, multi-omic studies discovered many perturbed biological pathways in AD, however, systematic studies for biomarkers that capture these diverse biological facets of AD are limited. Second, AD is a heterogeneous disorder but biomarkers that can distinguish the biological subtypes of AD are lacking. Third, core AD neuropathology often co-exists with other neuropathologies such as vascular disease (V). These co-morbidities and co-pathologies need to be considered in biomarker discovery. Fourth, existing biomarker studies are heavily focused on non-Hispanic Whites (NHW). Similar studies in underrepresented populations (URP) are needed. This U19, bringing together >40 experts across 13 institutions, aims to bridge these knowledge gaps for discovery and validation of Centrally-linked Longitudinal pEripheral biomARkers of AD (CLEAR-AD) in multi-ethnic populations. CLEAR-AD U19 is based on the premise that AD is a complex disorder in which many biological pathways are disrupted due to multi-omic perturbations, which can be detected in brain and reflected in blood, i.e. centrally-linked peripheral molecular signatures (CLPMS). The specific aims of CLEAR-AD U19 are: 1) To discover CLPMS of the complex and heterogeneous AD pathophysiology and its co-pathologies. 2) To identify longitudinal CLPMS that detect and predict dynamic neuroimaging, fluid biomarker, and clinical changes across AD spectrum. 3) To characterize differences and similarities in CLPMS profiles across NHW, African American (AA) and Latino American (LA) participants to uncover biomarker patterns in multi-ethnic groups. 4) To make these vast resources available to the scientific community to amplify and accelerate its impact. In this U19 managed by the Administrative Core, we will leverage NIH-funded ADNI, MCSA and ADRC cohorts of >3,700 multi-ethnic participants to generate >20,000 multi-omics measures (Omics Core) that will be processed and integrated with >48,000 harmonized AD cognitive, neuroimaging and fluid endophenotypes (Analytic Core). Using these data, we will identify brain region and cell-type specific CLPMS, which reflect biological subtypes of AD and disease stage (Project 1). We will discover longitudinal changes in CLPMS that predict cognitive and A/T/N/V progression (Project 2). We will define longitudinal cognitive and A/T/N/V changes and CLPMS in URP that are either conserved with NHW or population-specific (Project 3). This U19 will a) Identify the next generation of AD biomarkers with mechanistic insights; b) Establish a precision medicine approach for rigorous multi-omics biomarker discovery and validation in AD; c) Discover molecules that can serve as biomarkers and therapeutic targets; d) Enhance biomarker research in trial-ready multi-ethnic populations; and e) Generate and share a vast and harmonized resource of endophenotype and multi-omics data in NIH-funded cohorts.

NIH Research Projects · FY 2025 · 2023-03

PROJECT SUMMARY/ABSTRACT Maladaptive grief negatively impacts 25-40% of older adult family caregivers of persons with a serious chronic illness, with adverse health outcomes including increased morbidity and mortality, reduced independence, and diminished immune function.1-4 Losses associated with aging, such as the death of multiple close family and friends, are highly traumatic and contribute to the devastating impact of maladaptive grief among older adults.8,10 Brief, effective interventions that address maladaptive grief early in the grief trajectory are urgently needed. Accelerated Resolution Therapy (ART) is an evidence-based treatment for post-traumatic distress in civilians and veterans14-17 that may be useful in alleviating maladaptive grief prior to bereavement and could prevent prolonged, complicated grief following bereavement. We are proposing to test the efficacy of ART, a low-risk, brief therapy with a strong theoretical rationale for treatment success in maladaptive grief and supported by the promising results of our recently completed preliminary trial (R21AG056584). Additional aims of the study are to examine changes in cognitive appraisal and integration of loss following ART using a mixed methods approach and to evaluate personal, social, and psychological factors predictors of response. During the proposed double blinded, randomized, controlled two arm clinical trial, 472 older adult family caregivers from two different geographic locations will receive either ART or an educational program that is matched for time and attention. Each participant will receive four sessions of either the ART intervention or the control intervention. Data collection will occur at screening/enrollment (T1), at the end of the 4-session intervention period (T2) and at 6-months (T3) and 12-months post bereavement (T4). A subgroup of 20 participants randomly assigned to ART will participate in semi-structured interviews to enhance understanding of cognitive appraisal and integration of loss. This trial will provide critical information on the efficacy of the ART intervention as a potential first-line treatment option for pre-loss grief and preventative option for complicated grief and contribute new information about characteristics of individuals most likely to benefit from ART.

NIH Research Projects · FY 2026 · 2023-02

Alzheimer’s disease (AD) is the most common form of senile dementia without effective treatments after countless number of clinical trials for over decades. This application proposes in vitro and in vivo evaluation of targeting human tau-tubulin kinase (TTBK1), a neuron specific tau kinase involved in the phosphorylation and aggregation of microtubule-associated protein tau in human and mice and genetically associated with late- onset AD in Spanish and Chinese cohorts. TTBK1 protein expression was significantly increased in the frontal cortex of postmortem AD brains compared to the control subject, suggesting that TTBK1 may play critical roles in AD pathogenesis. Our recent neuropathological examination of postmortem brain tissues revealed abundant expression of TTBK1 in the entorhinal cortex (EC) layer II and CA1 region of the hippocampal field where early tau pathology evolves in AD. Importantly, several studies reported that CA1 neuronal loss was correlated with cognitive decline in AD, and that CA1 connectivity to medial temporal cortex was associated with reduced episodic memory with mild cognitive impairment patients as determined by functional MRI. Interestingly, we found that TTBK1 significantly reduced axonal integrity of EC pyramidal neurons in AD mouse model, mimicking the early AD pathology. Thus, suppressing initial pathological tau accumulation in the EC and their spread to CA1 region by targeting TTBK1 could halt progression of AD at the prodromal stage. There are several attempts to develop TTBK1 kinase inhibitors, which were unsuccessful due to their cross-reactivity with TTBK2, a ubiquitous tau-tubulin kinase involved in mitosis and ciliogenesis. In this proposal, we will test the therapeutic specificity and efficiency of antisense oligonucleotides (ASOs) targeting TTBK1, which have little cross-reactivity to TTBK2. The central hypothesis of our proposal is that ASO-TTBK1 reduces accumulation and spread of pathological tau in early-stage AD brains. Our exciting preliminary data have shown that ASO- TTBK1 significantly reduced the level of phosphorylated tau at pSer396, pThr231 and pThr181 in the hippocampal region in PS19 tau mice. We will examine the therapeutic effect of ASO-TTBK1 on tau pathology and cognitive function in PS19 mice and our recently developed early tau propagation model (ECII-CA1 tau mice, Aim 1). We will further validate the effect of ASO-TTBK1 on tau pathology in human induced pluripotent stem cell-derived neurons and organoids isolated from late onset AD and FTDP-17 (P301L MAPT) cases in vitro (Aim 2) and on human TTBK1 transgenic and TTBK1:APP knock-in double transgenic mice in vivo (Aim 3). Successful completion of these experiments will validate TTBK1 as a therapeutic target of tauopathy and ASO as a translatable approach for targeting TTBK1 in AD brains.

NIH Research Projects · FY 2026 · 2022-12

The goal of this project is to gain a detailed mechanistic understanding of how nuclear-import receptors (NIRs) can prevent and reverse the cytoplasmic mislocalization and accumulation of insoluble protein aggregates of the RNA-binding protein TDP-43 in the pathogenesis of common neurodegenerative disorders. TDP-43 pathology is a hallmark of frontotemporal dementia (FTD) and amyotrophic lateral sclerosis (ALS), but is also commonly found in Alzheimer’s disease (AD) and other AD-related dementias (ADRDs), marking it as a high priority target for therapy development. Our labs have discovered that 1) TDP-43 pathology is characterized by the co-aggregation of TDP-43 with FG nucleoporins (FG-Nups) in the cytoplasm, causing nucleocytoplasmic transport defects and 2) NIRs can reduce the aberrant phase transition of TDP-43 and other disease-causing RNA-binding proteins with prion-like domains. Our data demonstrate that specific NIRs can reverse the hallmarks of TDP-43 proteinopathy in cellular and animal models of FTD and ALS. Based on our findings, we propose a novel non-canonical role for NIRs as potent molecular chaperones that are recruited by FG-Nups into pathological TDP-43 aggregates, where they act to to reverse the aberrant phase transition and restore the normal nuclear localization and splicing functions of TDP-43, suggesting a promising new strategy for therapeutic intervention. To test this hypothesis, our team of experts in cellular and animal models of FTD (an ADRD) and ALS, as well as structural biology approaches, will use cutting edge in vitro and in vivo methods to gain a detailed mechanistic understanding of how NIRs restore solubility, nuclear localization and normal function of TDP-43; how NIRs reduce neurodegeneration; how NIR dysfunction contributes to human disease; and how we can use this knowledge of NIR functions to develop future therapeutic strategies for TDP-43 proteinopathies. Our specific aims are: (i) to determine how NIRs restore proper TDP-43 localization and reduce aberrant phase transition in vitro, using a combination of advanced neuronal cell culture models of FTD and ALS and biochemical characterization of TDP-43 liquid-liquid phase separation (LLPS) and fibrillization, and rational protein engineering approaches to potentiate the chaperone activity of NIRs; and (ii) to identify how NIRs reduce TDP-43-dependent neurodegeneration in cellular and animal models in vivo, employing Drosophila, organotypic slice cultures and somatic brain transgenesis in TDP-43 proteinopathy mouse models, and clarifying the nature of NIR pathology in ALS and FTD (an ADRD) patient brain tissue. Successful outcome of this project will clarify the role of NIRs in regulating TDP-43 phase transition during pathogenesis and how this activity can restore normal localization and cellular function of TDP-43. This knowledge will be critical for developing new therapeutic strategies to target aberrant phase separation in ALS, FTD, and other devastating AD-related neurodegenerative disorders with TDP-43 proteinopathy.

NIH Research Projects · FY 2026 · 2022-12

Glioblastoma multiforme (GBM) is associated with poor prognosis due to its highly invasive and drug-resistant phenotype. Recurrence is a common phenomenon in GBM patients due to the presence of chemo- and radio- resistant Brain Tumor-Initiating Cells (BTICs). Consequently, current therapies including surgery followed by radiation or chemotherapy with Temozolomide (TMZ) failed to improve patient median overall survival emphasizing the necessity of novel treatment strategies for drug-resistant GBM. Interestingly, Neuroplin-1 (NRP1) has been shown to be implicated in the drug-resistance and stemness in multiple types of cancer. Recently, we showed that depletion of NRP1 improved survival compared to that of vascular endothelial growth factor (VEGF-A) depletion in mice bearing patient-derived GBM xenografts. NRP1 depletion also improved sensitivity to TMZ and enhanced the overall survival when combined with TMZ. Our preliminary data further showed that a proprietary tumor-targeted liposomal (TTL) formulation combining a first generation small- molecule NRP1 inhibitor (EG00229; G in short) with Everolimus (E) provided significant survival advantage in TMZ resistant glioma cells as compared to that of TMZ alone. However, EG00229 is poorly water soluble, and its liposomal formulation is not stable for long term storage. Hence, we developed a new generation of small- molecule NRP1 inhibitors (NRP1i, Ni in short) with better solubility in order to create a stable liposomal formulation. The central hypothesis of our proposal is that NRP1i combined with everolimus in a single payload using TTL, either as a systemic therapy or delivered locally in a hydrogel-based system, will reduce drug- resistance and stemness and augment radiation sensitivity in GBM, leading to better therapeutic outcomes. To validate our hypothesis, we propose three major aims. In Aim 1, we will combine the most effective NRP1i with everolimus as a single payload in TTL formulation (TTL-ENi) for evaluating in vitro efficacy in inhibiting stemness and drug-resistance signaling pathways and in vivo studies using multiple therapy resistance BTICs animal models including immune-competent mice models. Further, the additive effect of radiotherapy and chemotherapy (e.g. TMZ) in combination with the TTL-ENi will be evaluated. We will also analyze the effect of our proposed therapy on the tumor immune microenvironment using two state-of-the-art techniques namely mass cytometry (CyTOF) and digital spatial profiling (DSP). In Aim 2, we will assess the efficacy of the local administration of TTL-ENi-hydrogel in a resection and recurrence model of GBM. Moreover, the additive effect of radiotherapy and chemotherapy (e.g. TMZ) in combination with the TTL-ENi-hydrogel will be evaluated. Aim 3 will focus on the comparative pharmacokinetics, pharmacodynamics, and preliminary toxicity studies of the most potent formulation for future clinical trials. We expect that a successful execution of our proposed research will lead to clinical trial in near future for a better therapeutic strategy to override the drug-resistance in GBM patients as well as patients suffering from other drug-resistant cancers.

NIH Research Projects · FY 2025 · 2022-09

PROJECT SUMMARY Alzheimer's disease (AD) is the most common form of dementia accompanied by detrimental cognitive deficits and pathological accumulation of amyloid-β (Aβ) plaques and tau-containing neurofibrillary tangles. The majority of AD cases occur late in life, and it usually develops after 65 years of age. The strongest genetic risk factor for late-onset AD (LOAD) is apolipoprotein E (APOE) genotype, with the ε4 allele increasing AD risk and the ε2 allele being protective compared with the common ε3 allele. Increasing evidence indicates that down- regulation of apoE4 protein level and/or inhibition of apoE4 aggregation not only alleviate amyloid pathology but also protect against tau-mediated neurodegeneration. In our preliminary studies, we have developed an apoE4 reporter assay with a split luciferase protein-fragment complementation, enabling us to not only monitor apoE4 protein level but also measure apoE4 self-oligomerization/aggregation by luciferase bioluminescent signals in a high-throughput screening format. Under the support of the Mayo-SBP (Sanford Burnham Prebys) Drug Discovery Collaboration Program, we performed a pilot screen of ~17,000 small molecule compounds with satisfactory performance, and discovered a novel apoE4 modulator that down-regulates apoE4 protein level and inhibits tau phosphorylation in induced pluripotent stem cells (iPSCs)-derived cerebral organoids from AD patient carrying APOE4, demonstrating that our HTS assay is robust and capable of identifying novel apoE4 modulators. Herein, we proposed a collaborative effort to identify apoE4 modulators that down-regulate apoE4 protein level and/or suppress apoE4 aggregation for AD therapy. Aim 1 will complete the apoE4 reporter high-throughput screen on a large chemical library to identify potent and specific apoE4 modulators for suppressing apoE4 level and/or aggregation. Aim 2 will examine the potency, modes of actin (MOA), and therapeutic effects of apoE4 modulators using biochemical and cell-based assays and human iPSC-derived cellular models. Aim 3 will perform SAR-by-catalog and limited chemistry on lead compounds to improve their potency and efficacy and determine the therapeutic efficacy of the most promising candidate compounds in 3-D cerebral organoid models such that our findings may have relevance in a humanized setting. Moreover, the “drug-like” and pharmacokinetics properties and brain penetration will be characterized and benchmarked to position them for future in vivo preclinical animal studies. The identified apoE4 modulators will be promising drug leads in novel therapeutic strategies for AD.

NIH Research Projects · FY 2024 · 2022-09

PROJECT SUMMARY/ABSTRACT The development of new methods for prenatal genetic editing in humans has accelerated the translation of technologies designed to disrupt disease mechanisms or remove disease-causing mutations entirely. These technologies show promise for preemptively addressing previously intractable genetic conditions. However, recent events have demonstrated considerable gaps in the governance structure surrounding human gene editing and its translation to clinical practice. Since the discovery that a scientist in China had conducted human experiments allegedly resulting in the birth of three genetically edited children, numerous calls have been made for a novel governance structure for prenatal human gene editing, frequently framed around moratoria or other forms of suppression, and several international bodies have convened. There has been strong pressure towards a values-based governance approach that moves beyond traditional technocratic considerations of safety and efficacy and takes into account collective normative deliberation about the ethics of prenatal intervention. This is challenging in the United States context, which is among the few high-income countries without centralized regulation of research on embryos and/or translational assisted reproductive technologies. As such, two important stakeholder voices have been largely left out of conversations around the future of prenatal gene editing in the US context: the patients and families that might be benefitted or harmed by the translation of prenatal gene editing and the scientists and clinicians who would be on the front lines of clinical translation were it to move forward. We propose to fill this gap by conducting empirical research with these key stakeholders that assesses potential governance approaches internationally and explores how they may be implemented in an United States context. The goal is to move past generalizations to explore the direct policy mechanisms that are feasible while incorporating the values and priorities of end users. This study consists of three aims. The first two, contemporaneous, aims will consist of qualitative research with two sets of stakeholders: patients and families affected by genetic conditions potentially addressable through prenatal gene editing and clinicians and scientists involved in relevant translational and clinical activities in this space. In Aim 1, We will begin by conducting a review of the international science policy landscape to gather policy mechanisms that have been proposed or implemented to manage emerging technologies in the reproductive science, genetics, and regenerative medicine spaces. We will identify policies that fall into a spectrum from permissive to restrictive. These policies will be shared with stakeholders during qualitative interviews to assess their concordance with stakeholder values and priorities. We will recruit a diverse cohort of clinicians and scientist leaders from 20 key professional societies and conduct qualitative interview to assess underlying normative underpinnings of proposed policy approaches, professional feasibility of proposals, and values and priorities around the potential translation of prenatal gene editing in humans. The results of this Aim will feed directly into the deliberative democracy exercises in Aim 3. In Aim 2, we will partner with Genetic Alliance, the largest patient advocacy organization for genetic conditions to recruit a panel of patient advisors from communities affected by 9 genetic conditions from across a spectrum of penetrance and severity. Together with the advisors we will connect with patient advocacy and support groups in these communities to recruit a cohort of patients and family members. Patients will be asked to share their understanding of the potential of gene editing, their aspirations or concerns about its clinical applications, their priorities and goals in research on their condition, and their views on the proposed policy approaches. In Aim 3 we will convene representatives from both groups, together with the research team and select policymakers to conduct two deliberative democracy exercises in which all stakeholders can deliberate towards a consensus on the appropriate mechanisms for optimal governance of prenatal gene editing technologies. The results of all three aims will be disseminated in the scientific, lay, and policy literatures.

NIH Research Projects · FY 2025 · 2022-09

Despite the decline in overall mortality and incidence of cancer in the US population, the burden of cancer care is still high. One key barrier experienced by those that have high burden of cancer is the lack of dedicated efforts employing scientifically rigorous approaches and implementation strategies for the enrollment in and accrual of participants in clinical trials. The Connecting Patient Populations to Clinical Trials (CP2CT) program aims to implement and evaluate multilevel outreach and education interventions that will increase the accrual of participants in clinical trials. To support the program, we are proposing to be the Data, Evaluation, and Coordination Center (DECC) to support the data and evaluation activities and coordinate a learning collaborative towards mitigating the key barriers of participating in clinical trials. Specifically, we will collaborate with the U01 program investigators and interact with involved NCI staff members and with other stakeholders, as needed, to carry out the following activities: 1) establish effective and efficient administrative processes and infrastructure through scientific leadership, organizational processes, governance structure, effective oversight and operational procedures to achieve optimal communication, collaboration, coordination, and dissemination of research, 2) facilitate and coordinate data collection and management across the program to facilitate evidence generation and rapid dissemination of methods and tools, 3) organize and facilitate collaborative efforts on program evaluation, engagement, and communication, and 4) foster a learning collaborative in leading and coordinating research across the program. We are uniquely positioned to be the DECC by leveraging our strong track record in: (i) implementing cancer research centers and consortia (e.g. Dr. Odedina is MPI on NCI CRCHD U54 CaRE2 Center and contact MPI for a newly awarded Department of Defense iCCaRE Consortium); (ii) leading statistics and data management coordinating center effort in cancer trials (e.g., Mayo is the Statistics and Data Management Center of the Alliance for Clinical Trials in Oncology (Alliance) including both interventional and NCORP grants); (ii) leading standardization and interoperability for practice and research (e.g., Mayo has been contributing to the NCI Terminology Service Development Effort and part of the data harmonization efforts in the NCATS Clinical Data to Health (CD2H)). Additionally, we have strong institutional priorities aligning with the program’s existing infrastructure and resources supporting the program’s mission.

NIH Research Projects · FY 2025 · 2022-09

PROJECT SUMMARY/ABSTRACT The goal of this project is to capture the molecular complexity of pathological tau-associated proteins in the brain of Alzheimer’s disease (AD) and related tauopathy patients via proximity-proteomics and gain a thorough mechanistic understanding of their role in the progression of tau pathology and associated neurodegeneration. Previous studies suggest a correlation of characteristic temporal and topological patterns of microtubule- associated protein tau (MAPT) aggregates with the observed clinical phenotype and the progression of the disease. Although neurofibrillary tangles (NFTs) and other forms of phospho-tau aggregates are believed to play a pivotal role in the disease process, we have a poor understanding of the composition and molecular environment of these insoluble aggregates, and how their formation, toxicity, and spread across the brain regions is regulated. A better understanding of the phospho-tau interactome in AD and primary tauopathies, and how these proteins regulate the oligomerization, pathological accumulation, and seeding of tau in affected neurons and glia is of critical importance for the identification of novel therapeutic targets. As a limitation of current technologies, the in-depth characterization of NFTs and other neuropathologic inclusions has historically been difficult to address, since these aggregates are detergent-insoluble, and thus refractory to classical affinity purification methods. To address this limitation, we have established a novel method for the proximity-labeling, purification and identification of pathological phospho-tau associated proteins from fixed human tissue followed by quantitative proteomics analysis. We hypothesize that the molecular environment of pathological tau aggregates contributes to the AD disease process and propose to use the latest cutting-edge technologies to determine and compare the phospho-tau associated proteome across different patient cohorts and disease stages, to decipher molecular signaling networks in disease development, and to functionally validate novel therapeutic targets in human AD cases, mouse models, and human organoid models. Our three specific aims are: (i) to compare tau pathology- associated proteomes across common tauopathies via proximity proteomics of phospho-tau inclusions in the brain of AD and primary tauopathy patients, (ii) to establish spatiotemporal patterns of tau pathology- associated proteomes specific for disease stages, brain regions, and brain resilience in AD patient cohorts, and (iii) to determine the functional role of tau pathology-associated proteins in neurodegenerative processes in human AD cases, mouse models, and human brain organoids. Successful completion of this project will identify novel molecular components and cellular pathways regulating the pathogenesis of AD and primary tauopathies, which may provide new therapeutic strategies for effective treatment of these devastating disorders.

NIH Research Projects · FY 2025 · 2022-09

Increasing patient participation in cancer clinical trials (CCTs) is vital to the advancement of oncology across the continuum of care. Low trust in clinical research and recruitment approaches that fail to address multilevel barriers to CCT participation are key reasons for poor study recruitment. Community health educators (CHEs) improve trust in research among many communities; yet relying exclusively on CHE availability can limit intervention reach. Virtual CHEs (vCHEs) improve scalability by extending CHE capabilities and capitalizing on remote recruitment techniques. The purpose of the current project is to increase the referral of patients to NCI-supported CCTs via a tailored, multi-level intervention. The ALEX Research Referral Portal utilizes adaptive virtual human technology that provides users with tailored CCT information. Through AI-enabled technology, human CHEs can become vCHEs to reach patients through digital outreach. Clinicians can utilize the portal to refer patients to CCTs; however, patients, families, and community members can also use the portal to easily navigate key information and make self-referrals. The ability to streamline research information from https://clinicaltrials.gov/ to patients, and then CCT referral from patient to study coordinators, is expected to improve referral to CCTs. The ALEX Research Portal will be developed with unique a multi-cancer center collaborative opportunity to provide access to patients in Florida and the nation, and in coordination with cancer centers conducting CCTs associated with national networks (ETCTN, NCTN, NCORP). Guided by the Interactive Systems Framework, this project will be conducted in three phases: establish a baseline of referrals and accrual of patients to CCTs across multiple Florida Cancer Centers (Phase 1), adapt and pilot the ALEX Research Referral Portal using a randomized controlled clinical trial (Phase 2), and scale the intervention by dissemination through national networks (Phase 3). The proposed study will result in an empirically-tested intervention that can easily be adapted and disseminated across the state and nation to overcome multi-level challenges associated with recruiting participants to CCTs.

NIH Research Projects · FY 2025 · 2022-09

PROJECT SUMMARY This is a resubmission application for a five-year mentored patient-oriented research career development award (K23). The candidate is a motivated clinical researcher at the University of North Carolina Chapel Hill (UNC) with a background in digestive disease epidemiology, a strong publication record, and an established commitment to the study of esophageal diseases, specifically Barrett’s esophagus (BE). The objective of the K23 proposal is to obtain advanced mentored training in patient-oriented research methodologies required to achieve the candidate’s long-term career goal of becoming an independently funded physician-scientist improving detection of esophageal adenocarcinoma (EAC) by implementing patient-centered and shared decision care pathways in BE. Specifically, the candidate’s proposed career development goals are: 1) to obtain training in implementation science and development of patient decision aids; 2) to gain experience in the development of patient-reported outcomes (PRO) measures; 3) to develop knowledge in conducting comparative effectiveness research using large real-world databases; and 4) to transition to independence. To achieve these career development goals, the candidate will 1) take advanced, graduate level coursework in implementation science, decision aid design, PRO measures, and comparative effectiveness research; 2) participate in scholarly activities designed to foster independence and national recognition; and 3) conduct mentored research. The candidate’s mentoring team consists of internationally recognized, independently-funded investigators with expertise in Barrett’s esophagus and gastrointestinal epidemiology (Shaheen), implementation science and decision aids (Reuland), PROs (Keefer) and comparative effectiveness (Lund). Each mentor has a track record of commitment to mentoring junior faculty. The specific aims of the research project are: 1) to develop and test a web-based, patient-directed BE screening decision aid to improve screening rates screen-eligible patients; 2) to develop a BE-specific PRO instrument using in-depth interviews for concept elicitation to generate instrument items and perform cognitive interviews to ensure content validity; 3) to evaluate the comparative effectiveness of endoscopic surveillance versus ablation for BE patients with low-grade dysplasia (LGD) using administrative claims data to aid in shared decision making. Finally, the candidate’s research and training environment at UNC, a preeminent academic research institution, is strong and well-established. For fiscal year 2020, UNC ranked sixteenth for National Institutes of Health (NIH) research funding to domestic institutions of higher education, and has access to NIH funded centers (Translational and Clinical Sciences Institute and Center for Gastrointestinal Biology and Disease) that are tailored to support the proposed studies. This collaborative environment, mentorship, didactics, and research experience will provide the candidate with the strong foundation and unique skillset to successfully achieve the proposed research and training goals. Support from the K23 is critical to achieve the candidate’s goal of transitioning to an independent physician-scientist.

NIH Research Projects · FY 2025 · 2022-08

PROJECT SUMMARY/ABSTRACT Carcinogenesis may be viewed as a multistep evolutionary process characterized by accumulation of genetic and epigenetic alterations, driven by selective pressures imposed by the microenvironment. The delineation of tumor evolution would provide invaluable insights into tumor biology and lay a foundation for the development of improved diagnostics, prognostics and targeted therapeutics. Time-series data are ideal for deriving models of dynamic progression, but this is impossible to collect in human cancer because of the need for timely surgical intervention and systemic therapy, which alter the natural history of the disease and exert selection pressures that affect tumor evolution. To overcome the human serial sampling issue, we have devised a computational strategy to understand cancer evolution by deriving pseudo time-series data from ‘static’ samples (excised tissue specimens). The design is based on the rationale that each sample can provide a snapshot of the disease process, and if the number of samples is sufficiently large we can recover a visualization of disease progression. We demonstrated the utility of the developed pipeline - referred to as CancerMapp - by applying it to the analysis of gene expression data from over 9,000 breast tissue samples. Breast cancer progression modeling identified 2 major trajectories to malignancy – an early split to basal tumors, and a continuum through luminal tumors. The computational approach and the breast cancer model concept have since been validated in independent studies, and our findings have provided the impetus for a number of investigations at our institute and by colleagues in the field. Built logically on our previous work, we now propose a large-scale interdisciplinary research plan to derive a progression model for bladder cancer (BLCA). BLCA is among the five most common malignancies worldwide. In the US alone, new cases for 2018 are estimated at 72,500 with estimated deaths at over 15,000, figures that are anticipated to increase in the near future. Classification of BLCA into multiple molecular subtypes has recently been proposed and has the potential to impact clinical management. Nonetheless, significant biologic subgroup heterogeneity remains, and more work is needed before a unified classification system can gain wide acceptance. More importantly, there is, as yet, no understanding of the inter-relationships between subtypes. Insights into how subtypes are related and how cancer evolution influences the observed changes in molecular pathologic phenotype is the next level of analysis required and is the focus of this proposal. The proposed work will inform a range of research directions that were previously unattainable. The derivation of a BLCA roadmap and the identification of pivotal molecular events that drive stepwise cancer progression will provide new insights into tumor biology and guide the development of improved cancer diagnostics, prognostics and targeted therapeutics. Annotated progression maps can also guide the design of clinical trials and animal studies to focus on pivotal points of cancer development, which may yield the best return with limited resources.