Diversity Supplement: Pericyte structural plasticity and cerebrovascular health

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PROJECT SUMMARY The purpose of this supplement is to increase diversity in biomedical research by supporting the professional development of Ms. Maria Sosa, a talented Latino-American post-baccalaureate student with a career goal of entering graduate school to study the neuroscience of aging and dementia. The supplement is also designed to enhance the goals of the parent R01 (R01AG062738), entitled “Pericyte structural remodeling in the adult brain and its role in maintenance of capillary function”. Briefly, the parent R01 investigates the structural remodeling of pericytes on the brain microvasculature, which allows the cells to change in size to facilitate coverage of the endothelium. It warrants detailed investigation because it may be a valuable target for mitigating the deleterious effects of pericyte loss, which is now well established as a basis of microvascular pathology in Alzheimer’s disease and related dementias (ADRD). To better understand the mechanism of pericyte remodeling, and the physiological consequence of its alteration, our approach combines high-resolution in vivo two-photon imaging of capillary hemodynamics with optical, pharmacological, and genetic manipulation of pericytes in intact microvascular networks of the cerebral cortex of both normal adult and aged mice. In the lab of Prof. Andy Shih, Maria will receive quality training on preclinical ADRD research and learn approaches to study cerebrovascular pathologies. Her work will enhance the R01 project by: (1) characterizing vascular changes in two mouse models of cerebral amyloid angiopathy (CAA) that we plan to incorporate into our studies, and (2) expanding investigations into perivascular fibroblasts (PVFs), which occupy perivascular niches like mural cells, and have emerging roles in vascular pathology during neurodegeneration. Maria will test the working hypothesis that CAA around capillaries precedes the loss of pericyte number and coverage, which in turn precedes a reduction in capillary density. Further, she will test the working hypothesis that CAA along the walls of cerebral arterioles leads to loss of perivascular fibroblasts, which precedes changes in the vascular structure, such as increased tortuosity, and loss of arteriolar smooth muscle cells. To address these hypotheses, Maria will characterize pericytes, perivascular fibroblasts, and brain vascular properties over the course of disease progression in mouse models of CAA. Throughout these studies, Maria will gain training in histological approaches, brain vascular functionality, and scientific communication in preparation for her career goals. This funding will therefore both increase inclusion and diversity as well as enhance the aims of the parent proposal.