Role of Integrin-Mediated Apoptosis during Angiogenesis

整合素介导的细胞凋亡在血管生成过程中的作用

• 批准号: 6616114
• 负责人: MATTHEW D POTTER
• 金额: $ 4.16万
• 依托单位: SCRIPPS RESEARCH INSTITUTE, THE
• 依托单位国家: 美国
• 财政年份: 2002
• 资助国家: 美国
• 起止时间: 2002-08-01 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/6616114
• 关键词: angiogenesis; apoptosis; biological signal transduction; cell adhesion; cell proliferation; cysteine endopeptidases; flow cytometry; immunoprecipitation; integrins; laboratory mouse; laboratory rabbit; protein binding; protein structure function; receptor expression; transfection; western blottings

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.

描述（由申请人提供）：这些研究的主要目标是阐明细胞响应特定类别的未连接整合素的表达而经历受控细胞死亡或凋亡的机制。在缺乏适当配体或存在整联蛋白拮抗剂的情况下，此类整联蛋白甚至可以介导细胞凋亡，否则细胞仍粘附于周围的细胞外基质。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多种血管生成依赖性疾病。然而，这些拮抗剂在体内引发整合素介导的死亡（IMD）的机制仍不清楚。因此，该提案旨在表征 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化表征。最后，体内模型将用于评估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的整合素诱导细胞凋亡的机制的理解，从而确定 IMD 的诱导是否可以开发为合理的抗血管生成疗法。