RASA1-mediated control of lymphatic vessel growth and function

描述(申请人提供)：与血管系统相比，哺乳动物淋巴管生长和发育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控因子，对正常淋巴管的生长和功能是必不可少的。利用一种新的条件性RASA1缺陷小鼠模型，我们证明了RASA1从成年小鼠组织中的系统性缺失导致了一种全身性淋巴疾病，淋巴渗入腹膜和胸腔，并由乳糜胸致死。此外，我们还表明，在这个模型中，淋巴功能障碍伴随着显著而广泛的淋巴管增生。为了更好地理解分子淋巴学，阐明RASA1调节淋巴管的精确机制是很重要的。为此，在本申请的具体目的#1中，我们将测试RASA1通过作为一个或多个特定的淋巴管内皮细胞(LEC)生长因子受体启动的信号转导的负调节因子来控制淋巴管生长和功能的假设。接下来，在特定的目标#2中，我们将检验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，在特定的目标#3中，我们将检验淋巴管系统在整个发育过程中依赖RASA1的假设，而血管系统从早期对RASA1的依赖转变为对另一个间隙--神经纤维素-1(NF1)的依赖，在发育后期。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。除了增加对调节淋巴管系统的分子机制的了解外，研究还可能阐明淋巴管的生长和功能如何被操纵以在淋巴水肿和癌症等疾病中获得临床益处。公共卫生相关性：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情况下操纵淋巴管系统的新方法。研究还与我们对一种被称为CM-AVM的人类血管疾病的病因学的理解直接相关。

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.