Unexpected Roles for the alpha2beta1 Integrin

α2β1 整合素的意想不到的作用

基本信息

批准号：
7389503
负责人：
MARY M. ZUTTER
金额：
$ 28.75万
依托单位：
VANDERBILT UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2005
资助国家：
美国
起止时间：
2005-07-01 至 2010-04-30
项目状态：
已结题

项目摘要

DESCRIPTION (provided by applicant): The integrin family of extracellular matrix receptors plays an important role in angiogenesis. Integrins are readily accessible as drug targets and may provide an avenue to novel therapeutic approaches. The role of the a1B1 and a2B1 integrins, the 2 major endothelial cell collagen receptors, in angiogenesis also has been evaluated in vitro and in vivo. Senger and colleagues argued that collagen receptors, receptors for the predominant extracellular matrix molecules within the microenvironment of tumors, are critical for the development of new vessels. However, our recent findings in a2B1 integrin-deficierit mice suggest that the a2B1 integrin provides an anti-angiogenic rather than a pro-angiogenic stimulus. We show in Preliminary Data that a2-null mice exhibit more rapid tumor growth and increased angiogenesis when compared to their wildtype littermate controls. We furthermore show that the tumor vessels formed were of abnormal size and shape, suggesting that the integrin, although not required for angiogenesis per se, is required for normal vascular morphogenesis and maturation. Based on this exciting preliminary data, we hypothesize that the a2B1 integrin is required for maintainance and control of the angiostatic setpoint or switch. This hypothesis fuirthermore suggests that a2B1 integrin expression favors an anti-angiogenic phenotype by opposing pro-angiogenic signals from the a1B1 integrin to modulate and control tumor angiogenesis. To test this hypothesis we propose the following 4 Specific Aims: SPECIFIC AIM #1: To define the contributions of the a2B1 integrin in maintaining balance of the angiogenic setpoint or switch using a combination of in vitro biochemical, and cell biologic techniques coupled with in vivo mouse models. As part of this Aim, we will compare the molecular regulation of tumor angiogenesis in wild-type mice, mice lacking expression of the a2B1 integrin, and mice expressing a mutant a2 integrin subunit that exhibits "the activated phenotype." SPECIFIC AIM #2: To define the role of the a2B1 integrin in vessel maturation in vivo and the role of the integrin in endothelial cell morphogenesis and tube formation in vitro. SPECIFIC AIM #3: To define the mechanisms underlying the dramatic differences between the contributions of the a2B1 integrin and the a1p1 integrin to tumor angiogenesis. SPECIFIC AIM #4: To define the role of a2B1 integrin expression by mast cells in regulating tumor growth and stimulating tumor angiogenesis.

描述（由申请人提供）：细胞外基质受体的整合素家族在血管生成中发挥重要作用。整合素很容易作为药物靶点，并可能为新的治疗方法提供途径。 a1B1 和 a2B1 整合素（两种主要的内皮细胞胶原蛋白受体）在血管生成中的作用也已在体外和体内进行了评估。 Senger 及其同事认为，胶原蛋白受体（肿瘤微环境中主要细胞外基质分子的受体）对于新血管的发育至关重要。然而，我们最近在 a2B1 整合素缺陷小鼠中的发现表明，a2B1 整合素提供抗血管生成而不是促血管生成刺激。我们在初步数据中表明，与野生型同窝对照小鼠相比，a2 缺失小鼠表现出更快的肿瘤生长和更多的血管生成。我们还表明，形成的肿瘤血管具有异常的大小和形状，这表明整联蛋白虽然本身不是血管生成所必需的，但却是正常血管形态发生和成熟所必需的。基于这一令人兴奋的初步数据，我们假设 a2B1 整合素是维持和控制血管抑制设定点或开关所必需的。该假设还表明，a2B1 整联蛋白表达通过对抗来自 a1B1 整联蛋白的促血管生成信号来调节和控制肿瘤血管生成，从而有利于抗血管生成表型。为了检验这一假设，我们提出以下 4 个具体目标：具体目标 #1：结合体外生化和细胞生物学技术与体内结合，确定 a2B1 整合素在维持血管生成设定点或开关平衡方面的贡献鼠标模型。作为该目标的一部分，我们将比较野生型小鼠、缺乏 a2B1 整联蛋白表达的小鼠和表达表现出“激活表型”的突变 a2 整联蛋白亚基的小鼠对肿瘤血管生成的分子调节。具体目标#2：确定 a2B1 整合素在体内血管成熟中的作用以及整合素在内皮细胞形态发生和体外管形成中的作用。具体目标#3：明确 a2B1 整合素和 a1p1 整合素对肿瘤血管生成的贡献之间的巨大差异的机制。具体目标#4：确定肥大细胞表达的 a2B1 整合素在调节肿瘤生长和刺激肿瘤血管生成中的作用。