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.
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.
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