Unexpected Roles for the alpha2beta1 Integrin

描述(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。整合素作为药物靶点很容易获得，并可能为新的治疗方法提供一条途径。两种主要的内皮细胞胶原受体a1b1和a2b1整合素在体外和体内血管生成中的作用也得到了评估。森格和他的同事认为，胶原蛋白受体是肿瘤微环境中主要细胞外基质分子的受体，对新血管的发展至关重要。然而，我们最近在a2b1整合素缺陷小鼠中的发现表明，a2b1整合素提供了一种抗血管生成的刺激，而不是促进血管生成的刺激。我们在初步数据中显示，与野生型小鼠对照相比，a2基因缺失的小鼠肿瘤生长更快，血管生成增加。我们进一步表明，肿瘤血管的大小和形状都不正常，这表明整合素虽然本身不是血管生成所必需的，但对于正常的血管形态形成和成熟是必需的。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止血设定点或开关所必需的。这一假说进一步表明，a2b1整合素的表达通过与a1b1整合素的促血管生成信号相反来调节和控制肿瘤血管生成，从而有利于抗血管生成表型。为了验证这一假设，我们提出了以下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以及体内小鼠模型，确定a2b1整合素在维持血管生成设定点或开关的平衡中的作用。作为这一目标的一部分，我们将比较野生型小鼠、缺乏a2b1整合素表达的小鼠以及表达突变的a2整合素亚单位的小鼠的肿瘤血管生成的分子调控。特异性目的2：明确a2b1整合素在体内血管成熟中的作用，以及整合素在体外内皮细胞形态发生和管状形成中的作用。具体目的#3：确定a2b1整合素和a1p1整合素在肿瘤血管生成中的显著差异的机制。特异性目的#4：明确肥大细胞表达a2b1整合素在调节肿瘤生长和刺激肿瘤血管生成中的作用。

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.