Regulation of Integrins in Neovasculature Development

血管生成过程在许多疾病的发病机制中起着关键作用，包括但不是 仅限于肿瘤生长/转移、糖尿病视网膜病变和损伤后的组织重塑。血管生成是 在血管内皮细胞生长因子和细胞黏附受体的驱动下，内皮细胞和 血细胞。我们已经证明，血管生成中的关键调控事件之一是 血管内皮生长因子受体2和V 3整合素。然而，病理后果和结构要求 这种串扰还有待确定。我们已经证明了许多整合素依赖的函数是 受Akt途径控制。然而，由于下游靶点的复杂性，Akt的确切作用 异构体在调节不同的血管生成细胞事件中的作用仍然知之甚少。作为我们的特定 假设，我们认为VEGFR2/V3复合体在整合素依赖的调控中起关键作用 功能和整体血管生成反应；Akt激酶通路在调节中起中心作用 病理性血管生成过程中整合素活性和细胞外基质组成的变化。以下是 提出了检验这些假设的具体目标：目标1.确定结构要求和 3整合素与血管内皮细胞生长因子2的复合体内外生物学作用为了证明 复合体的关键调节作用，我们将使用最近生成和表征的 化合物。？3/VEGFR2复合体的作用将在体外血管生成相关检测中进行评估。这个 该复合体在体内植入性肿瘤、伤口和缺血组织中的作用将得到阐明。特价 将考虑整合素和3/VEGFR2复合体在骨调节中的作用 骨髓来源的细胞向新生血管募集。这些研究不仅将确定基本的机制 在血管生成方面，它们将导致一种新的抗血管生成策略的产生。目标2.进一步澄清 Akt途径对整合素和细胞外基质的调节机制。A)使用Akt-1和Akt-2为空 我们将进一步阐明Akt信号在细胞周期调控中的作用。 整合素活性。Akt1/2信号在整合素依赖的细胞外基质调节中的作用 表达和组装将被确定。由于Akt1影响了所涉及的多种细胞类型的功能 在血管生成方面，我们将确定内皮Akt1在血管生成中的作用。详细了解如何 成功的合作发生在血管生成的发起者，血管内皮生长因子，效应系统，整合素， 将为心脏病学、血管医学和医学领域新治疗策略的开发奠定基础 癌症治疗。

The process of angiogenesis plays a crucial role in the pathogenesis of numerous diseases, including but not limited to tumor growth/metastasis, diabetic retinopathy, and in tissue remodeling upon injury. Angiogenesis is driven by Vascular Endothelial Growth Factor (VEGF) and cell adhesion receptors, integrins on endothelial and blood cells. We have shown that one of the crucial regulatory events in angiogenesis is the cross-talk between VEGF receptor 2 and ¿V¿3 integrin. However, the pathological consequences and structural requirements for this crosstalk have yet to be determined. We have shown that a number of integrin-dependent functions are controlled by Akt pathway. However, due to the complexity of downstream targets, the exact role of Akt isoforms in the regulation of distinct cellular events of angiogenesis remains poorly understood. As our specific hypotheses, we propose that VEGFR2/¿V¿3 complex is crucial for the regulation of integrin-dependent functions and for the overall angiogenic response; and that Akt kinase pathway plays a central role in regulation of integrin activity and extracellular matrix composition during pathological angiogenesis. The following Specific Aims are proposed to test these hypotheses: Aim 1. To determine the structural requirements and the biological role of the complex between ¿3 integrin and VEGFR2 in vitro and in vivo. In order to demonstrate the key regulatory role of the complex, we will disrupt it using recently generated and characterized compounds. The role of the ¿3/VEGFR2 complex will be assessed in angiogenesis-related assays in vitro. The role of the complex will be elucidated in vivo in implanted tumors, wounds and ischemic tissues. Special consideration will be given to the role of ¿3 integrin and ¿3/VEGFR2 complex in the regulation of bone marrow-derived cell recruitment to neovasculature. These studies will not only determine the basic mechanisms of angiogenesis, they will lead to the generation of a new anti-angiogenic strategy. Aim 2. To further elucidate the mechanisms of integrin and extracellular matrix regulation by Akt pathway. A) Using Akt-1 and Akt-2 null mice recently characterized by our lab, we will further elucidate the role of Akt signaling in the regulation of integrin activity. The role of Akt1/2 signaling in the regulation of integrin-dependent extracellular matrix expression and assembly will be determined. Since Akt1 influenced functions of numerous cell types involved in angiogenesis, we will define the role of endothelial Akt1 in angiogenesis. A detailed understanding of how successful collaboration occurs between an initiator of angiogenesis, VEGF, an effector system, the integrins, will create the basis for the development of novel therapeutic strategies in cardiology, vascular medicine and cancer treatment.