Blood vessels bring oxygen to every tissue in the human body. Many diseases are related to problems with the vascular system. Pericytes are special cells that stabilize growing blood vessels and maintain vascular health. Illnesses like diabetic retinopathy, Alzheimer's disease, and cancer become worse when pericytes are disrupted. This project will increase fundamental understanding of pericytes by developing experimental and computational models of their involvement in blood vessel formation and function, with a specific focus on their interactions with the protein scaffold in tissues known as the extracellular matrix. The project will test the hypothesis that defects in the production of certain components of the extracellular matrix have profoundly negative consequences for pericyte behaviors and could therefore contribute to their dysfunction in certain diseases. The educational component of this project includes working with STEM education leaders to extend the research goals for the development of activities and lessons for primary and secondary educators to use as "cross-curricular" supplemental material. Training opportunities for undergraduate and graduate students will also be incorporated, advancing the careers of students interested in gaining research experience and developing independent projects.
The project focuses on elucidating the role of the extracellular matrix (ECM) in mediating pericyte(PC)-endothelial cell (EC) interactions and their role in vascular development and maintenance of blood vessel integrity. The Research Plan is designed to test the hypothesis that proper vascular development and function depend critically on the precise regulation of 1) EC production of collagen IV, and (2) PC synthesis of vitronectin. More specifically, the Plan includes a) development of in vitro and ex vivo platforms for imaging fixed and live PCs migrating along remodeling extracellular networks, b) establishment of a primary PC cell line that has been functionally validated in addition to standard gene expression profiling, 3) establishment of a multi-scale computational modeling platform to recapitulate PC migration along developing vessels in the context of a range of collagen IV production rates from ECs and 4) use of other in vivo experimental approaches to achieve two objectives: 1) Elucidate the effect of EC-derived collagen IV on (i) PC migration and investment during vessel development and (ii) PC retention along functional vasculature and 2) Determine the role of PC-derived vitronectin in (i) vascular formation and (ii) maintaining the integrity of mature blood vessels.
This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.
