R-Ras signaling in vascular biology

血管生物学中的 R-Ras 信号传导

• 批准号: 8443872
• 负责人: Lawrence E Goldfinger
• 金额: $ 36.05万
• 依托单位: TEMPLE UNIV OF THE COMMONWEALTH
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-04-15 至 2015-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8443872
• 关键词: 1-Phosphatidylinositol 3-Kinase; Address; Adhesions; Adhesiveness; Affect; Apoptosis; Arterial Injury; Balloon Dilatation; Binding; Binding Sites; Biochemical; Biological; Biology; Blood Vessels; Bypass; Cardiovascular Diseases; Cell Differentiation process; Cell Proliferation; Cell physiology; Cells; Complement; Complex; Development; Family; Family member; Growth; Guanosine Triphosphate Phosphohydrolases; Human; Hyperplasia; In Vitro; Injury; Knockout Mice; Maps; Mediating; Molecular; Monomeric GTP-Binding Proteins; Mutation; Natural regeneration; Null Lymphocytes; Operative Surgical Procedures; Outcome; Pathway interactions; Physiological; Physiological Processes; Point Mutation; Process; Proteins; Proteomics; Regulation; Role; Scaffolding Protein; Signal Pathway; Signal Transduction; Site; Stents; System; Testing; Tumor Angiogenesis; Vascular Proliferation; Vascularization; angiogenesis; base; cell motility; in vivo; insight; migration; mouse model; mutant; new therapeutic target; novel; protein complex; public health relevance; ras Proteins; reconstitution; research study; response; response to injury; restenosis; scaffold; tumor; tumor growth; tumorigenesis

DESCRIPTION (provided by applicant): Support is requested to analyze the interaction between the Ras family small GTPase R- Ras and a novel effector molecule, RLIP76; the effect of this interaction on R-Ras signaling; the mechanisms by which R-Ras/RLIP76 interactions and signaling regulate vascular cell spreading, migration, proliferation and differentiation; and the roles of this signaling node in angiogenesis and injury-induced neointimal hyperplasia leading to arterial restenosis. Ras GTPases regulate cell proliferation, differentiation, apoptosis, adhesion and migration. The binding of specific effectors to activated Ras proteins propagates signaling cascades resulting in unique outcomes depending on the Ras family isotype. R-Ras in particular functions to regulate adhesiveness, motility, proliferation and differentiation of cells of the vessel wall, and to modulate these processes during angiogenesis and vascular regeneration in response to injury. Thus R-Ras signaling has unique, pleiotropic effects in vascular cells and in vascular functions, but the specific pathways involved are unknown. We identified RLIP76 in a proteomic screen for R-Ras effectors and found that RLIP76 regulates some of the unique cellular functions of R-Ras including cell signaling, spreading, migration, and angiogenesis in vitro. This is the first identification of a specific, unique effector for R-Ras with these distinct cellular functions. We hypothesize that R-Ras/RLIP76 binding controls distinct signaling pathways to mediate vascular cell functions and the unique effects of R-Ras in the vasculature. To test this hypothesis we will map the binding sites in R-Ras and RLIP76 and will identify mutations which will selectively disrupt this interaction. We will use these mutants to determine the effect of blockade of R- Ras/RLIP76 interaction on R-Ras signaling in cells of the vessel wall. We will then evaluate a putative scaffolding function for RLIP76 and will map the protein components of the RLIP76/R- Ras signaling complex in vascular cells. Next we will investigate the contributions of R- Ras/RLIP76 binding and the characterized signaling pathways to R-Ras-mediated vascular cell spreading, migration, proliferation and differentiation. Lastly, we will investigate a role for this signaling axis in R-Ras functions in vivo, namely blockade of angiogenesis, and injury-induced neointimal hyperplasia and arterial restenosis. These studies will characterize the regulation and mechanisms of novel signaling pathways that control cell signaling, migration, proliferation and vascular function. Therefore these studies will provide new insights into processes essential in physiological and pathophysiological function and may indicate new therapeutic targets in the treatment of cardiovascular disease.

描述（由申请人提供）：要求支持分析Ras家族小GTPase R- Ras与新型效应分子RLIP76之间的相互作用；这种相互作用对R-Ras信号的影响；R-Ras/RLIP76相互作用和信号传导调控血管细胞扩散、迁移、增殖和分化的机制；以及该信号节点在血管生成和损伤性内膜增生导致动脉再狭窄中的作用。Ras gtpase调节细胞增殖、分化、凋亡、粘附和迁移。特异性效应物与活化的Ras蛋白结合，传播信号级联反应，根据Ras家族同型产生独特的结果。R-Ras在调节血管壁细胞的粘附性、运动性、增殖和分化，并在损伤反应中调节血管生成和血管再生过程中这些过程。因此，R-Ras信号在血管细胞和血管功能中具有独特的多效性作用，但所涉及的具体途径尚不清楚。我们在R-Ras效应物的蛋白质组学筛选中发现了RLIP76，并发现RLIP76调节R-Ras的一些独特的细胞功能，包括细胞信号传导、扩散、迁移和体外血管生成。这是第一次鉴定出具有这些不同细胞功能的R-Ras的特定的、独特的效应物。我们假设R-Ras/RLIP76结合控制不同的信号通路来介导血管细胞功能和R-Ras在血管系统中的独特作用。为了验证这一假设，我们将绘制R-Ras和RLIP76的结合位点，并将识别有选择地破坏这种相互作用的突变。我们将使用这些突变体来确定阻断R-Ras /RLIP76相互作用对血管壁细胞中R-Ras信号传导的影响。然后，我们将评估RLIP76的假设支架功能，并绘制血管细胞中RLIP76/R- Ras信号复合物的蛋白质成分。接下来，我们将研究R-Ras /RLIP76结合及其特征信号通路在R-Ras介导的血管细胞扩散、迁移、增殖和分化中的作用。最后，我们将研究该信号轴在体内R-Ras功能中的作用，即阻断血管生成、损伤诱导的新生内膜增生和动脉再狭窄。这些研究将描述控制细胞信号传导、迁移、增殖和血管功能的新信号通路的调节和机制。因此，这些研究将为生理和病理生理功能的重要过程提供新的见解，并可能为心血管疾病的治疗提供新的治疗靶点。