RASA1-mediated control of lymphatic vessel growth and function

RASA1介导的淋巴管生长和功能控制

基本信息

批准号：
8308412
负责人：
PHILIP D KING
金额：
$ 35.33万
依托单位：
UNIVERSITY OF MICHIGAN AT ANN ARBOR
依托单位国家：
美国
项目类别：
财政年份：
2009
资助国家：
美国
起止时间：
2009-08-01 至 2014-01-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8308412
关键词：
Accounting Adult Bacterial Artificial Chromosomes Biological Biological Assay Blood Cells Cessation of life Chylothorax Chylous Ascites Clinical Dependency Development Disease Employee Strikes Endothelial Cells Etiology Event Extravasation Fibroblast Growth Factor Functional disorder Generations Genetic Goals Greater sac of peritoneum Growth Growth Factor Receptors Growth and Development function Health Human Hyperplasia In Vitro Laboratories Lead Lymph Lymphatic Lymphatic Diseases Lymphatic Endothelial Cells Lymphatic System Lymphatic vessel Lymphedema Malignant Neoplasms Mammals Mediating Modeling Molecular Molecular Genetics Monomeric GTP-Binding Proteins Mouse Strains Mus Neurofibromatosis Type 1 Protein Pleural cavity Pregnancy Ras Signaling Pathway Regulation Role Signal Transduction Signal Transduction Pathway Testing Time Tissues Transgenic Mice Vascular Diseases Vascular System Work cell type improved in vivo lymphology mouse model mutant mouse model novel ras GTPase-Activating Proteins recombinase response

项目摘要

DESCRIPTION (provided by applicant): In comparison with the blood vascular system, the molecular mechanisms involved in the growth and development of lymphatic vessels in mammals remain poorly defined. In this regard, we have recently shown that the p120 Ras GTPase-activating protein (p120 RasGAP, also known as RASA1), a prototypical negative-regulator of the Ras signal transduction pathway, is essential for normal lymphatic vessel growth and function. Using a novel conditional RASA1-deficient mouse model, we have demonstrated that systemic deletion of RASA1 from tissues of adult mice results in a generalized lymphatic disorder with leakage of lymph into the peritoneal and pleural cavities and death by chylothorax. Furthermore, we have shown that lymphatic dysfunction in this model is accompanied by a striking and extensive lymphatic vessel hyperplasia. Toward the goal of an improved understanding of molecular lymphology, it is important to elucidate the precise mechanisms by which RASA1 regulates lymphatic vessels. To this end, in Specific Aim #1 of this application, we will test the hypothesis that RASA1 controls lymphatic growth and function by acting as a negative-regulator of signal transduction initiated through one or more specific lymphatic endothelial cell (LEC) growth factor receptors. Next, in Specific Aim #2, we will test the hypothesis that the role of RASA1 in lymphatic vessels relates specifically to its ability to regulate the activation of Ras signaling pathway in LEC. Last, in Specific Aim #3, we will test the hypothesis that the lymphatic vasculature is dependent upon RASA1 throughout development, in contrast to the blood vasculature which switches from a dependency upon RASA1 in early development to a dependency upon another GAP, neurofibromin-1 (NF1), later on in development. To achieve these Specific Aims, we will utilize a variety of molecular biological, molecular genetic and cell biological approaches. In addition to leading to an increased understanding of the molecular mechanisms that regulate the lymphatic vasculature, studies may also illuminate upon means by which the growth and function of lymphatic vessels can be manipulated to clinical benefit in diseases such as lymphedema and cancer. PUBLIC HEALTH RELEVANCE: We will elucidate the molecular mechanisms by which RASA1 regulates lymphatic growth and function. Studies could illuminate upon novel means with which to manipulate the lymphatic vasculature in disease situations such as lymphedema and cancer. Studies are also of direct relevance to our understanding of the etiology of a vascular disease in humans known as CM- AVM.

描述（由申请人提供）：与血管系统相比，哺乳动物淋巴管生长和发育所涉及的分子机制仍不清楚。在这方面，我们最近发现 p120 Ras GTP 酶激活蛋白（p120 RasGAP，也称为 RASA1）是 Ras 信号转导途径的典型负调节蛋白，对于正常淋巴管的生长和功能至关重要。使用一种新的条件性 RASA1 缺陷小鼠模型，我们证明从成年小鼠组织中系统性删除 RASA1 会导致全身性淋巴疾病，导致淋巴液渗漏到腹膜和胸膜腔，并因乳糜胸而死亡。此外，我们已经表明，该模型中的淋巴功能障碍伴随着显着且广泛的淋巴管增生。为了加深对分子淋巴学的了解，阐明 RASA1 调节淋巴管的精确机制非常重要。为此，在本申请的具体目标 #1 中，我们将测试以下假设：RASA1 通过充当通过一种或多种特定淋巴管内皮细胞 (LEC) 生长因子受体启动的信号转导的负调节剂来控制淋巴管生长和功能。接下来，在具体目标 #2 中，我们将测试 RASA1 在淋巴管中的作用与其调节 LEC 中 Ras 信号通路激活的能力具体相关的假设。最后，在具体目标 #3 中，我们将测试以下假设：淋巴脉管系统在整个发育过程中依赖于 RASA1，而血管系统则从早期发育中对 RASA1 的依赖转变为对另一种 GAP（神经纤维蛋白-1）的依赖。 (NF1)，稍后开发。为了实现这些具体目标，我们将利用各种分子生物学、分子遗传学和细胞生物学方法。除了加深对调节淋巴管系统的分子机制的了解外，研究还可能阐明控制淋巴管生长和功能的方法，从而在淋巴水肿和癌症等疾病中发挥临床作用。公共健康相关性：我们将阐明 RASA1 调节淋巴管生长和功能的分子机制。研究可以阐明在淋巴水肿和癌症等疾病中操纵淋巴脉管系统的新方法。研究还与我们了解人类血管疾病（称为 CM-AVM）的病因学直接相关。