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.

National Institute of Health (NIH)
National Heart, Lung, and Blood Institute (NHLBI)
Research Project (R01)
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Special Emphasis Panel (ZRG1-CVS-P (50))
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Tolunay, Eser
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University of Michigan Ann Arbor
Schools of Medicine
Ann Arbor
United States
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Lubeck, Beth A; Lapinski, Philip E; Oliver, Jennifer A et al. (2015) Cutting Edge: Codeletion of the Ras GTPase-Activating Proteins (RasGAPs) Neurofibromin 1 and p120 RasGAP in T Cells Results in the Development of T Cell Acute Lymphoblastic Leukemia. J Immunol 195:31-5
Lubeck, Beth A; Lapinski, Philip E; Bauler, Timothy J et al. (2014) Blood vascular abnormalities in Rasa1(R780Q) knockin mice: implications for the pathogenesis of capillary malformation-arteriovenous malformation. Am J Pathol 184:3163-9
Sevick-Muraca, Eva M; King, Philip D (2014) Lymphatic vessel abnormalities arising from disorders of Ras signal transduction. Trends Cardiovasc Med 24:121-7
Agollah, Germaine D; Gonzalez-Garay, Manuel L; Rasmussen, John C et al. (2014) Evidence for SH2 domain-containing 5'-inositol phosphatase-2 (SHIP2) contributing to a lymphatic dysfunction. PLoS One 9:e112548
Mleczko-Sanecka, Katarzyna; Roche, Franziska; da Silva, Ana Rita et al. (2014) Unbiased RNAi screen for hepcidin regulators links hepcidin suppression to proliferative Ras/RAF and nutrient-dependent mTOR signaling. Blood 123:1574-85
Burrows, Patricia E; Gonzalez-Garay, Manuel L; Rasmussen, John C et al. (2013) Lymphatic abnormalities are associated with RASA1 gene mutations in mouse and man. Proc Natl Acad Sci U S A 110:8621-6
King, Philip D; Lubeck, Beth A; Lapinski, Philip E (2013) Nonredundant functions for Ras GTPase-activating proteins in tissue homeostasis. Sci Signal 6:re1
Lapinski, Philip E; Meyer, Melissa F; Feng, Gen-Sheng et al. (2013) Deletion of SHP-2 in mesenchymal stem cells causes growth retardation, limb and chest deformity, and calvarial defects in mice. Dis Model Mech 6:1448-58
Oliver, Jennifer A; Lapinski, Philip E; Lubeck, Beth A et al. (2013) The Ras GTPase-activating protein neurofibromin 1 promotes the positive selection of thymocytes. Mol Immunol 55:292-302
Lapinski, Philip E; Kwon, Sunkuk; Lubeck, Beth A et al. (2012) RASA1 maintains the lymphatic vasculature in a quiescent functional state in mice. J Clin Invest 122:733-47

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