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）：血管在整个体内提供营养，呼吸气，激素和免疫因子，使细胞，组织和器官繁殖。大脑是需要最大的血液供应才能生长，功能和生存的器官。因此，影响其脉管系统的出生缺陷和获得的条件通常是致命或致命的。然而，我们对控制脑血管形成的遗传机制以及在发育和疾病期间的细胞基础的遗传机制知之甚少。阐明脑血管发育的这些方面是关键的生物医学目标。在这里，我们利用了斑马鱼，小鼠和培养的内皮细胞的优势，作为研究血管发育的模型，以发现脑血管形成过程中肿瘤抑制Reck（用Kazal诱导富含半胱氨酸的蛋白质富含Cysosteine富含半胱氨酸的蛋白质）的作用。 RECK是一种由膜锚定的蛋白质，主要使金属蛋白酶，蛋白质，在形态发生，组织修复和癌症等疾病的进展中具有中心作用。 RECK对于斑马鱼和小鼠的脑血管发育至关重要，并且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调节了肿瘤发育的关键方面，例如血管化，侵袭和转移。在此提案中，我们的总体目标是回答有关RECK在发育和肿瘤血管生成中的作用的基本问题，无论是在大脑还是其他地方，尚未得到答复的：哪些内皮信号传导级联反应由RECK调节？在这种情况下，血管发育过程中RECK活动的分子决定因素是什么？在这种情况下，哪种金属蛋白酶（MPS）起着Reck的下游效应子的作用？提出的关于RECK在脑血管生成中的作用的研究将对CNS和其他地方的细胞，分子和生化水平的细胞，分子和生化水平的血管发育产生首次机械理解。因此，我们将在脑肿瘤血管生成期间以及更广泛的肿瘤发生过程中对RECK的病理作用进行关键见解。这些知识将为设计血管疗法和抗癌治疗方法提供必要的框架，以调节RECK的活性或其效应子和/或目标信号通路的活性。