Regulation of brain angiogenesis by the tumor suppressor Reck

描述（由申请人提供）：血管向全身输送营养物质、呼吸气体、激素和免疫因子，使细胞、组织和器官茁壮成长。大脑是需要最大的血液供应来生长，功能和生存的器官。因此，出生缺陷和后天条件，影响其脉管系统往往是致残或致命的。然而，我们对控制脑血管形成的遗传机制以及发育和疾病过程中这一过程的细胞基础知之甚少。阐明脑血管发育的这些方面是一个关键的生物医学目标。在这里，我们利用斑马鱼，小鼠和培养的内皮细胞作为研究血管发育的模型的优势，以揭示肿瘤抑制因子Reck（逆转诱导富含半胱氨酸的蛋白质与Kazal基序）在脑血管形成过程中的作用。Reck是一种膜锚定蛋白，主要使金属蛋白酶失活，金属蛋白酶是在形态发生、组织修复和疾病进展（如癌症）中起核心作用的蛋白质。 Reck是斑马鱼和小鼠脑血管发育的关键，并与几种人类癌症有关，包括脑神经母细胞瘤和神经胶质瘤。Reck调节肿瘤发展的关键方面，如血管形成、侵袭和转移。在这项提案中，我们的总体目标是回答有关reck在发育和肿瘤血管生成过程中的作用的基本问题，无论是在大脑中还是在其他地方，仍然没有答案，例如：内皮细胞生物学的哪些方面受到Reck的调节，哪些组织需要Reck活性？Reck调节哪些内皮信号级联？血管发育过程中Reck活性的分子决定因素是什么？在这种情况下，哪些金属蛋白酶（MP）作为Reck的下游效应物发挥作用？ 关于Reck在脑血管生成中的作用的拟议研究将产生对Reck如何在CNS和其他地方在细胞、分子和生物化学水平上调节血管发育的第一个机制性理解。因此，我们将获得关键的见解，在脑肿瘤血管生成过程中，更广泛地说，在肿瘤发生的病理作用的Reck。这些知识将为基于调节Reck或其效应子和/或靶信号通路的活性来设计血管治疗和抗癌治疗提供必要的框架。

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.