Unexpected Roles for the alpha2beta1 Integrin

α2β1 整合素的意想不到的作用

• 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
• 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
• 来源: https://reporter.nih.gov/project-details/7389503
• 关键词: Biochemical; Blood Vessels; Cells; Collagen Receptors; Coupled; Data; Development; Drug Delivery Systems; ECM receptor; Endothelial Cells; Equilibrium; Exhibits; Extracellular Matrix; Family; In Vitro; Integrin alpha2beta1; Integrins; Knockout Mice; Maintenance; Molecular; Morphogenesis; Mus; Phenotype; Play; Regulation; Role; Shapes; Signal Transduction; Stimulus; Techniques; Testing; Tube; Tumor Angiogenesis; Wild Type Mouse; angiogenesis; base; defined contribution; in vivo; mast cell; mouse model; mutant; novel therapeutics; receptor; size; tumor; tumor growth

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起重要作用。整联蛋白很容易作为药物靶标，可以为新颖的治疗方法提供途径。还在体外和体内评估了A1B1和A2B1整合素，两种主要内皮细胞胶原受体在血管生成中的作用。 Senger及其同事认为，胶原蛋白受体是肿瘤微环境内主要细胞外基质分子的受体，对于新容器的发展至关重要。但是，我们最近在A2B1整联蛋白缺乏小鼠中的发现表明，A2B1整联蛋白提供了抗血管生成，而不是促血管生成刺激。我们在初步数据中表明，与它们的野生型同窝对照相比，A2-NULL小鼠表现出更快的肿瘤生长和血管生成。我们此外表明，形成的肿瘤血管的大小和形状异常，表明整联蛋白虽然不是血管生成本身所必需的，但对于正常的血管形态发生和成熟是必需的。基于此令人兴奋的初步数据，我们假设A2B1整合素是维护和控制血管静止设定点或开关所必需的。该假设的Fuirthermore表明，A2B1整合素表达通过反对来自A1B1整联蛋白的促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个特定目的：特定目的＃1：定义A2B1整合素在维持血管生成设定值平衡或使用体外生化和细胞生物学技术的组合与Vivo小鼠模型相结合的贡献。作为此目标的一部分，我们将比较野生型小鼠中肿瘤血管生成的分子调节，缺乏A2B1整合素表达的小鼠以及表达突变体A2整合素亚基的小鼠表现出“活化表型”。具体目的＃2：定义A2B1整联蛋白在体内血管成熟中的作用，以及整联蛋白在体外内皮细胞形态发生和管形成中的作用。特定目的＃3：定义A2B1整联蛋白和A1P1整合素对肿瘤血管生成的贡献之间急剧差异的机制。特定目的＃4：定义肥大细胞在调节肿瘤生长和刺激肿瘤血管生成中表达A2B1整合素的作用。