RASA1-mediated control of lymphatic vessel growth and function

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RASA 1），Ras信号转导通路的原型负调节因子，是正常淋巴管生长和功能所必需的。使用一种新的条件RASA 1缺陷小鼠模型，我们已经证明，RASA 1从成年小鼠的组织中的系统性缺失导致全身性淋巴疾病，淋巴液渗漏到腹膜和胸膜腔，并死于乳糜胸。此外，我们已经表明，在这个模型中的淋巴功能障碍伴随着一个惊人的和广泛的淋巴管增生。为了更好地理解分子淋巴学的目标，重要的是阐明RASA 1调节淋巴管的精确机制。为此，在本申请的具体目标#1中，我们将检验以下假设：RASA 1通过充当经由一种或多种特异性淋巴内皮细胞（LEC）生长因子受体启动的信号转导的负调节剂来控制淋巴生长和功能。接下来，在具体目标#2中，我们将检验RASA 1在淋巴管中的作用与其调节LEC中Ras信号通路活化的能力具体相关的假设。最后，在具体目标#3中，我们将测试淋巴管系统在整个发育过程中依赖于RASA 1的假设，而血液管系统则从早期发育中对RASA 1的依赖转变为对另一种GAP的依赖，即神经纤维蛋白-1（NF 1），在发育后期。为了实现这些特定目标，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。除了导致增加对调节淋巴管系统的分子机制的理解之外，研究还可以阐明可以操纵淋巴管的生长和功能以在诸如水肿和癌症的疾病中获得临床益处的方法。公共卫生相关性：我们将阐明RASA 1调节淋巴生长和功能的分子机制。研究可以阐明在诸如水肿和癌症等疾病情况下操纵淋巴管系统的新方法。这些研究也与我们对人类血管疾病（称为CM- AVM）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.