Role of Syk and Rac2 in regulation of HIF1alpha and neovascularization.

Syk 和 Rac2 在 HIF1α 和新血管形成调节中的作用。

• 批准号: 7844911
• 负责人: DONALD DURDEN
• 金额: $ 23.18万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN DIEGO
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-07-06 至 2011-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7844911
• 关键词: Abbreviations; Address; Animals; Automobile Driving; Binding Sites; Biological Models; Bone Marrow; Bone Marrow Transplantation; Cell physiology; Cells; Complex; Data; Development; Diabetic Retinopathy; Disease; Endothelial Cells; Environment; Event; Fibronectins; Fluorescence; Gene Targeting; Goals; Guanosine Triphosphate Phosphohydrolases; Hematopoietic; Hypoxia; In Vitro; Injury; Integrins; Laboratories; Mediating; Molecular; Molecular Target; Mus; Myelogenous; Neoplasm Metastasis; Pathogenesis; Pathway interactions; Pattern; Play; Process; Protein Synthesis Inhibitors; Protein Tyrosine Kinase; Proteins; Receptor Protein-Tyrosine Kinases; Regulation; Research; Rheumatoid Arthritis; Role; Signal Transduction; Small Interfering RNA; System; Testing; Therapeutic; Time; Tissues; To specify; Transfection; Transgenic Mice; Tyrosine Phosphorylation Site; Vascular Endothelial Growth Factors; Vitronectin; Wound Healing; angiogenesis; base; cell motility; enhanced green fluorescent protein; genetic analysis; human SYK protein; hypoxia inducible factor 1; in vivo Model; innovation; insight; migration; mouse model; mutant; neovascularization; novel; postnatal; promoter; ras-Related G-Proteins; research study; tumor; tumor growth; tumor progression

DESCRIPTION (provided by applicant): The process of postnatal neovascularization plays a crucial role in pathogenesis of numerous diseases e.g. diabetic retinopathy, tissue remodeling upon injury, rheumatoid arthritis and tumor growth/metastasis. It has been known that endothelial cells (ECs) and its micro environment is the key for regulation of neovascularization/angiogenesis. However, the signal transduction events underlying this complex process are not well understood. The objective of this proposal is to gain insight the regulatory network in ECs for HIF11 accumulation and neovascularization. Our preliminary genetic analysis of Syk-/+ or Syk-/+; Rac2-/+ mice reveal a requirement of Syk for integrin induced activation of Rac2 and hypoxia induced stabilization of HIF11. We hypothesize that Syk-Vav1-Rac2 signaling axis exists in ECs and plays an obligate role in neovascularization via HIF11 stabilization. Preliminary data from our laboratory also suggest that specific region of Syk (Y342 and Y346 at B linker region, those are cognate binding sites for Vav and PLC3 respectively) appear to be involved in the activation of Rac2 but not Rac1 downstream of integrin signaling and migration. We propose in our Aim1 to determine Syk-Rac2 signaling axis a possible focal point for HIF11 stabilization. In Aim 2 we propose to evaluate the role of Syk-Rac2 signaling axis in postnatal neovascularization. Considering the importance of postnatal neovascularization, the identification of a novel molecular pathway, Syk-Vav1-Rac2 signaling axis, will result in the development of innovative therapeutic strategies.

描述（由申请人提供）：产后新血管形成过程在许多疾病的发病机理中起着至关重要的作用，例如糖尿病性视网膜病，损伤后的组织重塑，类风湿关节炎和肿瘤生长/转移。众所周知，内皮细胞（EC）及其微环境是调节新血管形成/血管生成的关键。但是，这一复杂过程基础的信号转导事件尚不清楚。该提案的目的是洞悉ECS中HIF11积累和新血管形成的监管网络。我们对SYK - /+或SYK-/+的初步遗传分析; RAC2 - /+小鼠揭示了SYK对整联蛋白诱导的RAC2激活和缺氧引起的HIF11稳定的要求。我们假设SYK-VAV1-RAC2信号轴存在于EC中，并且通过HIF11稳定在新血管形成中起着强大的作用。我们实验室的初步数据还表明，SYK的特定区域（B连接器区域的Y342和Y346，分别是VAV和PLC3的同源结合位点）似乎参与RAC2的激活，但不参与整联蛋白信号和迁移的RAC1。我们在AIM1中建议确定SYK-RAC2信号轴是HIF11稳定的可能焦点。在AIM 2中，我们建议评估SYK-RAC2信号轴在产后新血管形成中的作用。考虑到产后新血管化的重要性，新型分子途径SYK-VAV1-RAC2信号轴的鉴定将导致创新的治疗策略的发展。