Thursday, April 18, 2024
4/18/2024
Project Abstract Alzheimer’s disease is a disease of neurodegeneration and aging that affects millions of Americans, and is expected to impact millions more without further significant breakthroughs.1 However, much of the etiology and progression of Alzheimer’s is still unclear, especially given the complex interactions of many different molecular, cellular, and environmental cues that are correlated with phenotypic outcomes. An emerging focus in Alzheimer’s study is the role of the cerebrovasculature in the initiation, progression, and exacerbation of symptomatic disease.2-4 Disruption of the blood-brain barrier, which tightly controls any exchange between systemic circulation and brain tissue, has manifested in post-mortem and in vivo studies of late-stage Alzheimer’s disease as microbleeds, dysfunctional glucose transport, and impaired efflux of toxins;5 additional animal studies have indicated that some vascular dysfunction precedes neuronal degeneration in the progression of the disease.6, 7 Thus, to understand the drivers and progression of Alzheimer’s disease in hopes of identifying therapeutic breakpoints, the role of blood-brain barrier dysfunction must be investigated. To do so, we propose using a tissue-engineered model of the blood-brain barrier with high spatiotemporal resolution to assess its dysfunction under three key categories of perturbation associated with Alzheimer’s disease. These perturbations will span cell-intrinsic mutations associated with Alzheimer’s (APP(Swe) and PSEN(M146V)), extrinsic cues of oxidative stress (hydrogen peroxide exposure), and the systemic influence of aged blood components (exposure to aged vs. young human serum). We hypothesize that this combinatorial approach will best recapitulate human BBB phenotype in Alzheimer’s, and allow for modular study of each contributor. These perturbations will be compared transcriptomically, proteomically, and functionally. Transcriptomic changes will be studied through bulk RNA-sequencing and gene set enrichment analysis to highlight similarities to published human datasets, identify hallmark pathways that are impacted by Alzheimer’s cues, and motivate functional assay design for further validation in the tissue-engineered model. Proteomic and functional assessments include changes to barrier function, cell identity, and validation of pathways implicated by transcriptomic analysis. This study will provide a deeper understanding of the role of the blood- brain barrier in Alzheimer’s progression and emphasize candidate targets for future intervention. This project and related research training will be conducted under the guidance of Dr. Peter Searson at Johns Hopkins University and the Institute for Nanobiotechnology. Skills including functional assay design, stem cell differentiation, microfabrication, and RNA-sequencing analysis will be supported by the educational resources available within the institution. Additional goals of the fellowship training period will incorporate professional development for future career success, with an emphasis on communication, mentorship, and leadership skills.
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