Exploring brain perivascular fibroblasts in health and cerebral amyloid angiopathy - PROJECT SUMMARY Maintaining a stable brain vascular network is crucial for ensuring overall brain health throughout life. Perivascular cells, like pericytes and smooth muscle cells, are crucial to maintain the integrity of the brain vasculature. Loss of pericytes and smooth muscle cells are noted in Alzheimer’s Disease (AD) and affects vascular integrity, ultimately contributing to disease pathology. Perivascular fibroblasts (PVFs) are another cell population along the brain vasculature, however their role is largely unknown. PVFs express numerous extracellular matrix proteins that are uniquely found on arterioles and venules but not capillaries. My preliminary investigations indicate that PVFs maintain vessel structural stability, particularly along arterioles, in the healthy brain. Further, I find that arterioles are more tortuous in a mouse model of cerebral amyloid angiopathy (CAA), and this is associated with a significant reduction in PVFs. CAA is a small vessel disease characterized by the accumulation of amyloid- on vessels commonly observed in AD. Arterioles and their immediate off-shoots are important major regulators of blood flow into the brain. In doing so, they undergo extensive dilation and constriction events which is likely supported in part by extracellular matrix proteins expressed by PVFs. The goal of this proposal is to determine if PVFs regulate arteriole structure and dynamics in the healthy brain. Further, my goal is to understand if CAA contributes to PVF loss, altering arteriole structure and dynamics by affecting the expression of extracellular matrix proteins, ultimately exacerbating CAA. Understanding these important aspects of the brain vasculature could ultimately provide a potential for developing therapeutics aimed at limiting AD pathology and improve vascular function. The training I will receive under the guidance of Dr. Andy Shih, who is an expert in in vivo imaging and brain vascular physiology in health and disease, will enable me to achieve the goals of this proposal. My training is further supported by my advisory committee, consisting of Drs. Steven Greenberg, Richard Daneman, and Timothy Cherry who will enhance my training by providing guidance in CAA clinical pathology, PVF pathobiology and single-cell transcriptomics, respectively. Upon completion of these studies, I will have gained extensive knowledge of in vivo imaging, complex vascular physiology and single-cell transcriptomic approaches, in addition to PVF biology in heath and CAA pathology. These foundational studies and techniques are crucial components of my proposed independent phase described in this application and will propel my future goals of running an independent research group studying small vessel diseases in the brain. Further, with the support of Dr. Shih, my advisory committee, and the faculty at Seattle Children’s Research Institute in the Center of Developmental Biology and Regenerative Medicine, I will have expanded my experience in scientific communication, grantsmanship, networking, and mentorship. By continuing to strengthen these crucial skills during my training phase I will be well poised to guide a successful research group of my own.
