Role of Integrin-Mediated Apoptosis during Angiogenesis

描述(由申请人提供)：这些研究的主要目标是阐明细胞经历受控细胞死亡或凋亡的机制，以响应特定类别的未连接整合素的表达。在缺乏合适的配体或存在整合素拮抗剂的情况下，这种整合素甚至可以介导细胞的凋亡，否则这些细胞仍然附着在周围的细胞外基质上。整合素拮抗剂诱导内皮细胞死亡的这种能力已被用于治疗几种血管生成依赖型疾病。然而，这些拮抗剂在体内诱导整合素介导的死亡(IMD)的机制仍然不清楚。因此，这项建议旨在对IMD进行表征，并确定这一过程对与血管生成相关的组织重塑的生理贡献。首先，将确定整合素和半胱氨酸天冬氨酸酶中影响IMD所需的最小结构域。这些信息将用于IMD诱导过程中形成的整合素/caspase复合体的生化表征。最后，将使用体内模型来评估IMD在血管生成的生理过程中的作用。这些研究将提高我们对未连接整合素诱导细胞凋亡的机制的理解，从而确定诱导IMD是否可以被开发为一种合理的抗血管生成治疗方法。

DESCRIPTION (provided by applicant): The primary goal of these studies is to elucidate the mechanisms by which cells undergo controlled cell death, or apoptosis, in response to the expression of specific classes of unligated integrins. In the absence of appropriate ligands or in the presence of integrin antagonists, such integrins can even mediate apoptosis in cells that otherwise remain adherent to their surrounding extracellular matrix. This ability of integrin antagonists to induce death among endothelial cells has been exploited in the treatment of several angiogenesis-dependent diseases. However, the mechanisms by which these antagonists elicit Integrin Mediated Death (IMD) in vivo have remained obscure. Therefore, this proposal is designed characterize IMD, and determine the physiological contributions of this process to tissue remodeling associated with angiogenesis. First, the minimal structural domains within integrins and caspases that are required to effect IMD will be determined. This information will be used in the biochemical characterization of integrin / caspase complexes that form during induction of IMD. Finally, in vivo models will be used to evaluate the role of IMD during the physiological process of angiogenesis. These investigations will improve our understanding of the mechanisms by which unligated integrins induce apoptosis, thus determining whether induction of IMD can be developed as a rational anti-angiogenic therapy.