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

基本信息

批准号：
7267576
负责人：
WANG MIN
金额：
$ 41.25万
依托单位：
YALE UNIVERSITY
依托单位国家：
美国
项目类别：
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/7267576
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

项目摘要

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 (TNFR1) 和 II 型 75 kDa TNFR (TNFR2)。 TNFR1 广泛表达，而 TNFR2 受到严格调控，主要在内皮细胞 (EC) 上表达。 TNF 通过 TNFR1 和相关衔接分子引发广泛的生物效应，包括增殖、分化和凋亡。关于 TNFR2 募集的蛋白质以及 TNFR2 在 EC 中的功能知之甚少。同时针对TNFR1和TNFR2的抗TNF疗法在治疗类风湿性关节炎方面取得了成功，但在治疗心血管疾病方面却失败了。我们假设 TNFR2 信号传导在心血管系统中发挥有益作用，例如缺血引发的动脉生成/血管生成和重塑。我们发现，TNFR2 的遗传缺失（而非 TNFR1）会损害缺血引发的血流恢复，从而导致严重的肢体缺血。这可能是由于动脉生成、血管生成或内皮祖细胞动员受损而发生。我们建立了各种测定法来剖析 TNFR2-KO 小鼠中的这些缺陷。同时，我们努力定义 TNFR2 血管生成信号传导中的关键下游效应器。我们发现 TRAF2 是唯一已知的 TNFR2 相互作用蛋白，可调节 TNFR2 的抗凋亡功能；我们已经鉴定出第一个 TNFR2 特异性激酶 Etk，它对于 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。成功培育出 TNFR1、TNFR2、TRAF2 和 Etk 基因缺陷小鼠，从这些小鼠中分离出小鼠肌肉微血管 EC，并建立体内血管生成/动脉生成测定，将使我们能够剖析 TNFR2 的信号传导。我们提出以下具体目标：1) 使用 TNFR2-KO 小鼠定义 TNFR2 介导血管生成/动脉生成的机制。 2) 剖析 EC 中的 TNFR2 信号传导。 3) 使用转基因小鼠模型定义 EC 表达的 TNFR2 在炎症血管生成中的作用。该提案应提供关于 TNFR2 及其下游效应子 TRAF2 和 Etk 在炎症血管生成/动脉生成中的作用的新信息，并促进开发新的治疗方法来控制血管生成/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脏、大脑和四肢的修复至关重要。我们将研究膜受体 TNFR2 在此过程中的作用。我们的工作可能会带来更好的缺血性疾病治疗方法。