Regulation of brain angiogenesis by the tumor suppressor Reck

点击翻译按钮获取中文摘要

DESCRIPTION (provided by applicant): Blood vessels deliver nutrients, respiratory gases, hormones and immunity factors throughout the body, allowing cells, tissues and organs to thrive. The brain is the organ that requires the largest blood supply to grow, function and survive. Thus, birth defects and acquired conditions that affect its vasculature are often disabling or lethal. Yet, we know little about the genetic mechanisms that control brain vascularization and the cellular bases of this process during development and disease. Elucidating these aspects of cerebral vascular development is a key biomedical goal. Here we exploit the advantages of the zebrafish, mouse and cultured endothelial cells as models for studying vascular development to uncover the roles of the tumor suppressor Reck (reversion-inducing cysteine rich protein with Kazal motifs) during the formation of the brain vasculature. Reck is a membrane-anchored protein that primarily inactivates metalloproteinases, proteins with central roles in morphogenesis, tissue repair and progression of diseases like as cancer. Reck is pivotal for brain vascular development in both zebrafish and mouse and is implicated in several human cancers, including cerebral neuroblastomas and gliomas. Reck modulates key aspects of tumor development, such as vascularization, invasion and metastasis. In this proposal our overall goal is to answer fundamental questions about the role of reck during developmental and tumor angiogenesis, both in the brain and elsewhere, that remain unanswered, for example: What aspects of endothelial cell biology are regulated by Reck and in which tissues is Reck activity required? Which endothelial signaling cascades are modulated by Reck? What are the molecular determinants of Reck activity during vascular development and which metalloproteinases (MPs) function as Reck's downstream effectors in this context? The proposed studies about the role of Reck in cerebral angiogenesis will yield the first mechanistic understanding of how Reck regulates vascular development at the cellular, molecular and biochemical levels, both in the CNS and elsewhere. Accordingly, we will gain key insights into the pathological roles of Reck during brain tumor angiogenesis and, more broadly, during tumorigenesis. This knowledge will provide the necessary framework for designing vascular therapies and anticancer treatments based on modulating the activity of Reck or that of its effectors and/or target signaling pathways.