Vermont Center for Cardiovascular and Brain Health

点击翻译按钮获取中文摘要

Project Summary: Cerebral blood flow is precisely controlled to satisfy neuronal metabolic demands. Active neurons signal to the vasculature via multiple neurovascular coupling mechanisms to increase regional blood flow in a phenomenon known as functional hyperemia. The hyperemic response increases the frictional forces imposed by blood flow onto endothelial cells of arterioles and capillaries. We have recently demonstrated that the Piezo1 channel is a crucial mechanosensor in brain capillary endothelial cells, and that it mediates Ca2+ signals in response to mechanical stimuli. Previous research has focused on mechanisms engaged downstream of endothelial Piezo1 activation, but how endothelial cell plasma membrane fluidity controls its activity remains unknown. In response to the NIH Notice of Special Interest (NOT-GM-23-034) “Availability of Administrative Supplements to IDeA Awards to Fund Team Science Development Projects,” we provide compelling preliminary evidence that lipid domains enriched in cholesterol and phosphoinositides exist in central nervous system capillary networks. Further, we propose and provide preliminary results that lipids affect Piezo1 activity. The parent award, supported by NIGMS (P20GM135007), provides a platform to build sustainable research programs built on the exceptional potential of early career faculty to study the vital health problems facing society: cardiovascular disease, stroke and cognitive impairment. This Team Science proposal aims to lay the foundation and framework for Drs. Harraz (current Project Director, P20GM135007) and Gonzales (former Project Director, P20GM130459) to build upon their past productive collaborations and bring their expertise and techniques to synergistic work on impactful biological questions. Herein, we hypothesize that the lipids cholesterol and phosphatidylinositol-4,5- bisphosphate (PIP2) form domains in capillary networks, which determine capillary endothelial membrane fluidity and Piezo1 activity. To test this hypothesis, the proposed Team Science project will use diverse, state-of-the-art approaches, including patch-clamp electrophysiological techniques and engineered mouse models (Harraz Lab) along with high-resolution vascular imaging (Gonzales Lab) to characterize the impact of membrane lipids on endothelial Piezo1 activity. Completion of this project will foster collaboration between the two independent research teams and will support the concept that Piezo1 activity is dictated by lipid microenvironment. These studies will further establish a solid foundation that will lead to future independent funding (NIH R01 application), which will further our careers as independent scientists.