Role of Integrin-Mediated Apoptosis during Angiogenesis

描述（由申请人提供）：这些研究的主要目的是阐明细胞响应特定类别的未连接整合素表达而发生受控细胞死亡或凋亡的机制。在不存在合适的配体或存在整联蛋白拮抗剂的情况下，这样的整联蛋白甚至可以介导细胞凋亡，否则这些细胞保持粘附于其周围的细胞外基质。整联蛋白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性疾病。然而，这些拮抗剂在体内引起整联蛋白介导的死亡（IMD）的机制仍然不清楚。因此，本提案旨在表征IMD，并确定该过程对与血管生成相关的组织重塑的生理贡献。首先，将确定影响IMD所需的整合素和半胱天冬酶内的最小结构域。该信息将用于IMD诱导过程中形成的整合素/半胱天冬酶复合物的生物化学表征。最后，在体内模型将被用来评估IMD在血管生成的生理过程中的作用。这些调查将提高我们的理解的机制，其中未连接的整合素诱导细胞凋亡，从而确定是否诱导IMD可以开发为一个合理的抗血管生成治疗。

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.