Unexpected Roles for the alpha2beta1 Integrin

描述（申请人提供）：细胞外基质受体整合素家族在血管生成中起重要作用。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。两种主要的内皮细胞胶原受体a1B1和a2B1整合素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，胶原受体，肿瘤微环境中主要的细胞外基质分子的受体，对新血管的形成至关重要。然而，我们最近在a2B1整合素缺乏的小鼠中发现，a2B1整合素提供了一种抗血管生成而不是促血管生成的刺激。我们在初步数据中表明，与野生型对照相比，a2缺失小鼠表现出更快的肿瘤生长和更多的血管生成。我们进一步表明，形成的肿瘤血管的大小和形状异常，这表明整合素虽然不是血管生成本身所必需的，但却是正常血管形态发生和成熟所必需的。基于这些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静压设定值或开关所必需的。这一假设进一步表明，a2B1整合素表达通过反对来自a1B1整合素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。为了验证这一假设，我们提出了以下4个具体目标：具体目标#1：利用体外生化和细胞生物学技术结合体内小鼠模型，确定a2B1整合素在维持血管生成设定值或开关平衡中的作用。作为本研究的一部分，我们将比较野生型小鼠、缺乏a2B1整合素表达的小鼠和表达具有“活化表型”的突变型a2整合素亚基的小鼠肿瘤血管生成的分子调控。特定目标#2：确定a2B1整合素在体内血管成熟中的作用，以及整合素在体外内皮细胞形态发生和管形成中的作用。特定目标#3：定义a2B1整合素和a1p1整合素对肿瘤血管生成的巨大差异的潜在机制。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.