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: 7797550
• 负责人: WANG MIN
• 金额: $ 41.38万
• 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 2012-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7797550
• 关键词: Amino Acids; Angiogenic Factor; Anti-Tumor Necrosis Factor Therapy; Apoptosis; Apoptotic; 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; Lower Extremity; Mediating; Membrane; Methods; Modeling; Molecular; Mus; Muscle; Myocardial Ischemia; Phenotype; Phosphotransferases; Play; Process; Proteins; Recovery; Recruitment Activity; Research Personnel; Rheumatoid Arthritis; Role; Secondary to; Series; Signal Pathway; Signal Transduction; Signaling Molecule; Site; Skeletal Muscle; Stem cells; TNF gene; TNFRSF1A gene; TNFRSF1B gene; TRAF2 gene; Testing; Tissues; Transactivation; Transgenic Mice; 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 therapeutic intervention; promoter; receptor; reconstitution; repaired; research study; response; skeletal

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）：有两个不同的TNF特异性质膜 - 定位受体，I型55 kDa TNFR（TNFR1）和II型75 kDa TNFR（TNFR2）。 TNFR1普遍表达，而TNFR2受到严格调节，主要在内皮细胞（EC）上发现。 TNF通过TNFR1和相关的衔接子分子引起了广泛的生物学作用，包括增殖，分化和凋亡。关于募集到TNFR2的蛋白质以及TNFR2在EC中的功能知之甚少。针对TNFR1和TNFR2的抗TNF疗法已成功治疗类风湿关节炎，但在治疗心血管疾病方面失败了。我们假设TNFR2信号传导在心血管系统中起有益的作用，例如缺血引起的动脉生成/血管生成和重塑。我们表明，TNFR2的遗传丧失，但没有TNFR1的遗传丧失会损害缺血引发的血液流量恢复，从而导致临界肢体缺血。这可能会通过动脉生成，血管生成或动员内皮祖细胞的动员而发生。我们已经建立了各种测定法，以便在TNFR2-KO小鼠中剖析这些缺陷。同时，我们已经努力定义TNFR2血管生成信号传导中的关键下游效应子。我们表明，Traf2是唯一已知的TNFR2相互作用蛋白，它调节了TNFR2的抗凋亡功能。我们已经确定了第一个TNFR2特异性激酶ETK，对于TNF诱导的EC迁移和管形成至关重要。因此，TNFR2的TNF激活导致在动脉生成/血管生成期间，EC存活，迁移和管形成的独特但合作的下游信号传导。 TNFR1，TNFR2，TRAF2和ETK的遗传缺陷小鼠的成功育种，从这些小鼠中分离小鼠肌肉微血管EC，并建立了体内血管生成/动脉生成测定法，使我们能够将信号解剖为TNFR2。我们提出以下特定目的：1）定义TNFR2使用TNFR2-KO小鼠介导血管生成/动脉生成的机制。 2）在EC中解剖TNFR2信号。 3）使用转基因小鼠模型来定义EC表达的TNFR2在炎症性血管生成中的作用。该提案应提供有关TNFR2及其下游效应子TRAF2和ETK在炎性血管生成/动脉生成中的作用的新信息，并促进了控制血管生成/动脉生成依赖性心血管疾病的新治疗方法的发展。血管的生长和成熟对于修复缺血性心脏，大脑和肢体至关重要。我们将研究膜受体TNFR2在此过程中的作用。我们的工作可能导致更好的缺血性疾病治疗。