TNF receptor-2 signaling in arteriogenesis/angiogenesis

动脉生成/血管生成中的 TNF 受体 2 信号传导

• 批准号: 7390637
• 负责人: WANG MIN
• 金额: $ 41.34万
• 依托单位: YALE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-04-01 至 2011-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7390637
• 关键词: Amino Acids; Angiogenic Factor; Anti-Tumor Necrosis Factor Therapy; Apoptosis; Apoptotic; Appendix; Binding; Binding Sites; Biological; Biological Assay; Blood Vessels; Blood capillaries; Blood flow; Bone Marrow; Bone Marrow Cell Transplantation; Brain; Breeding; C-terminal; Cardiovascular Diseases; Cardiovascular system; Cell Survival; Cell membrane; Cells; Clinical; Complex; Congestive Heart Failure; Data; Defect; Development; Disease; Docking; Doctor of Philosophy; Endothelial Cells; Enhancers; Gene Expression; Genetic; Growth; Hematopoietic; Hindlimb; Image; Immune; Inflammation; Inflammatory; Inflammatory Infiltrate; Ischemia; Isolated limb perfusion; Lead; Ligands; Limb structure; Localized; Lower Extremity; Mediating; Membrane; Methods; Modeling; Molecular; Mus; Muscle; Myocardial Ischemia; Phenotype; Phosphotransferases; Play; Process; Proteins; Recovery; Recruitment Activity; Research Personnel; Rheumatoid Arthritis; Role; Score; Secondary to; Series; Signal Pathway; Signal Transduction; Signaling Molecule; Site; Skeletal Muscle; Skeletal system; Stem cells; TNF gene; TNF receptor-associated factor 2; TNFRSF1A gene; TNFRSF1B gene; TRAF2 gene; Testing; Tissues; Transactivation; Transgenic Mice; Transgenic Organisms; Tube; Tumor Necrosis Factor Receptor; Up-Regulation; Upper Extremity; Vascular Endothelial Cell; Vascular Endothelial Growth Factor Receptor-2; Work; angiogenesis; arteriole; base; capillary; cell motility; density; functional outcomes; in vivo; migration; mouse model; mutant; novel; novel therapeutics; promoter; receptor; reconstitution; repaired; research study; response

DESCRIPTION (provided by applicant): There are two distinct TNF-specific plasma membrane-localized receptors, type I 55 kDa TNFR (TNFR1) and type II 75 kDa TNFR (TNFR2). TNFR1 is expressed ubiquitously, whereas TNFR2 is tightly regulated and found predominantly on endothelial cells (EC). TNF via TNFR1 and associated adaptor molecules elicits a broad spectrum of biological effects including proliferation, differentiation and apoptosis. Little is known regarding the proteins recruited to TNFR2 and the function of TNFR2 in EC. Anti-TNF therapy targeting both TNFR1 and TNFR2 has been successful in treating rheumatoid arthritis but failed in the treatment of cardiovascular diseases. We hypothesize that TNFR2 signaling plays beneficial roles in the cardiovascular system such as ischemia-initiated arteriogenesis/angiogenesis and remodeling. We show that genetic loss of TNFR2, but not of TNFR1, impairs ischemia initiated blood flow recovery resulting in critical limb ischemia. This may occur via impaired arteriogenesis, angiogenesis or mobilization of endothelial progenitor cells. We have established various assays in order to dissect these defects in TNFR2-KO mice. Meanwhile, we have made efforts to define the critical downstream effectors in TNFR2 angiogenic signaling. We show that TRAF2, the only previously known TNFR2-interacting protein, regulates the anti-apoptotic function of TNFR2; we have identified the first TNFR2-specific kinase, Etk, critical for TNF-induced EC migration and tube formation. Thus TNF activation of TNFR2 leads to distinct but cooperative downstream signaling of EC survival, migration and tube formation during arteriogenesis/angiogenesis. The successful breeding of genetically-deficient mice for TNFR1, TNFR2, TRAF2 and Etk, isolation of mouse muscle microvessel EC from these mice and establishment of in vivo angiogenesis/arteriogenesis assays will allow us to dissect the signaling by TNFR2. We propose the following specific aims: 1) Define the mechanism by which TNFR2 mediates angiogenesis/arteriogenesis using TNFR2-KO mice. 2) Dissect TNFR2 signaling in EC. 3) Define the role of EC-expressed TNFR2 in inflammatory angiogenesis using transgenic mouse models. This proposal should provide novel information on the role of TNFR2 and its downstream effectors TRAF2 and Etk in inflammatory angiogenesis/arteriogenesis, and facilitate development of new therapeutic approaches to control angiogenesis/arteriogenesis-dependent cardiovascular diseases. Growth and maturation of blood vessels are critical for the repair of ischemic heart, brain and extremity. We will study the role of a membrane receptor TNFR2 in the process. Our work may lead to better treatments for ischemic diseases.

描述（由申请人提供）：有两种不同的TNF特异性质膜定位受体，I型55 kDa TNFR（TNFR 1）和II型75 kDa TNFR（TNFR 2）。TNFR 1广泛表达，而TNFR 2受到严格调控，主要存在于内皮细胞（EC）上。TNF通过TNFR 1和相关的衔接分子产生广泛的生物学效应，包括增殖、分化和凋亡。关于TNFR 2募集的蛋白质和TNFR 2在EC中的功能知之甚少。靶向TNFR 1和TNFR 2的抗TNF疗法已成功治疗类风湿性关节炎，但在治疗心血管疾病方面失败。我们假设TNFR 2信号在心血管系统中发挥有益作用，如缺血引发的动脉生成/血管生成和重塑。我们发现TNFR 2基因的缺失，而不是TNFR 1基因的缺失，会损害缺血引发的血流恢复，导致严重的肢体缺血。这可能通过受损的动脉生成、血管生成或内皮祖细胞的动员而发生。我们已经建立了各种测定法以剖析TNFR 2-KO小鼠中的这些缺陷。与此同时，我们已经努力确定TNFR 2血管生成信号的关键下游效应。我们发现，TRAF 2，以前唯一已知的TNFR 2相互作用的蛋白质，调节TNFR 2的抗凋亡功能，我们已经确定了第一个TNFR 2特异性激酶，Etk，TNF诱导的EC迁移和管形成的关键。因此，TNFR 2的TNF活化导致动脉生成/血管生成期间EC存活、迁移和管形成的独特但协同的下游信号传导。成功培育TNFR 1、TNFR 2、TRAF 2和Etk基因缺陷小鼠，从这些小鼠中分离小鼠肌肉微血管EC并建立体内血管生成/动脉生成测定将使我们能够剖析TNFR 2的信号传导。我们提出了以下具体目标：1）使用TNFR 2-KO小鼠定义TNFR 2介导血管生成/动脉生成的机制。2)剖析EC中的TNFR 2信号传导。3)使用转基因小鼠模型确定EC表达的TNFR 2在炎性血管生成中的作用。这一建议应提供新的信息TNFR 2及其下游效应TRAF 2和Etk在炎症性血管生成/动脉生成的作用，并促进新的治疗方法的发展，以控制血管生成/动脉生成依赖性心血管疾病。血管的生长和成熟对于缺血的心、脑和肢体的修复至关重要。我们将研究膜受体TNFR 2在这一过程中的作用。我们的工作可能会导致更好的治疗缺血性疾病。