Regulation of brain angiogenesis by the tumor suppressor Reck

肿瘤抑制因子 Reck 对脑血管生成的调节

基本信息

批准号：
9130431
负责人：
Jesús Torres-Vázquez
金额：
$ 42.38万
依托单位：
NEW YORK UNIVERSITY SCHOOL OF MEDICINE
依托单位国家：
美国
项目类别：
财政年份：
2015
资助国家：
美国
起止时间：
2015-09-01 至 2017-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9130431
关键词：
Adhesions Affect Arteries Base of the Brain Basement membrane Binding Biochemical Biological Assay Biological Models Blast Cell Blood - brain barrier anatomy Blood Vessels Brain Brain Neoplasms Cell Culture Techniques Cell Transplantation Cell Transplants Cell membrane Cells Cellular biology Central Artery Cerebral Neuroblastoma Cerebrum Chimera organism Complex Congenital Abnormality Data Defect Development Disease Disease Progression ECM receptor Embryo Emigrations Endothelial Cells Endothelium Environment Extracellular Matrix Genes Genetic Glioma Glycoproteins Goals Growth Factor Health Hormones Human Hyperactive behavior Hyperplasia Image Immunity Immunofluorescence Immunologic Impairment In Situ Hybridization In Vitro Knowledge Letters Life Ligands Link Malignant Neoplasms Matrix Metalloproteinases Mediating Membrane Metalloproteases Mining Molecular Morphogenesis Mus Neoplasm Metastasis Nutrient Organ Pathology Peptide Hydrolases Polysaccharides Process Proteins Proteoglycan RNA Regulation Reporter Role Shapes Signal Pathway Signal Transduction Specificity Study models Techniques Testing Therapeutic Time Tissues To specify Transplantation Tumor Angiogenesis Tumor Suppressor Proteins Umbilical vein Vascular Endothelial Growth Factor Receptor-2 Vascular Endothelial Growth Factors Vascular blood supply Vascularization Veins Zebrafish angiogenesis anticancer treatment base cDNA Expression cysteine rich protein design dimer extracellular gain of function hindbrain inhibitor/antagonist insight interstitial knock-down migration mind control mutant novel receptor research study respiratory gas tissue repair tumor tumorigenesis vascular abnormality

项目摘要

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.

描述（由申请人提供）：血管将营养物质、呼吸气体、激素和免疫因子输送到全身，使细胞、组织和器官蓬勃发展。大脑是需要最大血液供应才能生长、发挥功能和生存的器官。因此，出生缺陷和影响其脉管系统的后天条件通常会导致残疾或致命。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、小鼠和培养内皮细胞作为研究血管发育模型的优势，揭示肿瘤抑制因子 Reck（具有 Kazal 基序的富含半胱氨酸的逆转蛋白）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、组织修复和癌症等疾病进展中发挥核心作用的蛋白质。 Reck 对斑马鱼和小鼠的脑血管发育至关重要，并且与多种人类癌症有关，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，例如血管形成、侵袭和转移。在本提案中，我们的总体目标是回答有关 reck 在大脑和其他部位的发育和肿瘤血管生成过程中的作用的基本问题，这些问题仍未得到解答，例如：内皮细胞生物学的哪些方面受到 Reck 的调节以及在哪些组织中是否需要 Reck 活动？ 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) 充当 Reck 的下游效应子？关于 Reck 在脑血管生成中的作用的拟议研究将首次对 Reck 如何在细胞、分子和生化水平上调节中枢神经系统和其他部位的血管发育产生机制理解。因此，我们将深入了解 Reck 在脑肿瘤血管生成过程中以及更广泛的肿瘤发生过程中的病理作用。这些知识将为设计基于调节 Reck 或其效应器和/或目标信号通路的活性的血管疗法和抗癌疗法提供必要的框架。