Protection from Atherosclerosis by c-Met Agonist

描述(由申请人提供)：细胞死亡通路的激活导致内皮细胞凋亡和新生血管平滑肌细胞增生是动脉粥样硬化病变进展的初始触发因素。由于细胞凋亡是一个高度调控的细胞过程，并介导动脉粥样硬化斑块的发展，靶向抑制内皮细胞凋亡是治疗动脉粥样硬化的有效途径。散射因子(SF)又称肝细胞生长因子(HGF)，是一种强大的内皮特异性抗细胞凋亡和促有丝分裂因子。这些发现在心血管疾病领域具有重要的意义，因为SF/HGF只刺激血管内皮细胞的生长，而不复制血管平滑肌细胞，基于SF/HGF的治疗可能在治疗动脉粥样硬化方面有效。我们开发了一种模拟SF/HGF活性的小分子(c-met激动剂)，它是通过噬菌体展示和分子建模技术的新组合进行合理设计的。初步研究表明，这种命名为C6的小分子化合物具有很强的SF/HGF样活性。在体外，C6通过激活SF/HGF受体c-met来介导SF/HGF的生物学功能，如肾细胞分散、内皮细胞增殖和细胞保护等。在拟议的研究中，我们将评估我们的c-Met激动剂C6在动脉粥样硬化小鼠模型中的保护作用。我们将进一步评估参与诱导内皮细胞增殖的生化和信号转导途径以及C6的抗凋亡作用。我们的研究目标是开发一种新的治疗策略来改善内皮细胞的存活，并逆转以内皮细胞凋亡和组织纤维化为特征的动脉粥样硬化斑块的进展。这些研究承诺为C6作为动脉粥样硬化性血管疾病的一种新的治疗方法的可行性和有效性提供基础的临床前信息。如果成功，产生的数据将对C6或其他以内皮细胞凋亡和再生为目标的结构相关化合物的未来临床开发和优化至关重要。

DESCRIPTION (provided by applicant): Activation of cell death pathways leading to endothelial cell apoptosis and neointimal vascular smooth muscle cell hyperplasia is an initial trigger of the progression of atherosclerotic lesions. Because apoptosis is a highly regulated cellular process and mediates the development of atherosclerotic plaques, targeted inhibition of endothelial cell apoptosis is an effective approach to the treatment of atherosclerosis. Scatter factor (SF) also known as hepatocyte growth factor (HGF) has been identified as a powerful endothelial specific anti apoptotic and mitogenic factors. These findings have important implications in the field of cardiovascular disease since SF/HGF stimulates growth of endothelial cells exclusively without replication of vascular smooth muscle cells and SF/HGF based therapies could be effective in the treatment of atherosclerosis. We have developed a small molecule mimetic of SF/HGF activity (c-met agonist) that was rationally designed through a novel combination of phage display and molecular modeling technology. Preliminary studies have revealed that this small molecule compound, designated as C6 has potent SF/HGF like activity. In vitro, C6 activates SF/HGF receptor, c-met to mediate biological functions of SF/HGF, such as renal cell scatter, endothelial cell proliferation, and cellular protection against apoptosis. In the proposed studies, we will evaluate the protective effects of our c-met agonist, C6 in atherosclerotic mouse models. We will further evaluate the biochemical and signal transduction pathways involved in inducing endothelial proliferation and the anti apoptotic effects of C6. The goal of our research is to develop a novel therapeutic strategy to modify endothelial cell survival and to reverse the progression of atherosclerotic plaque, which is characterized, by a progressive endothelial cell apoptosis and tissue fibrosis. These studies promise to provide fundamental, preclinical information about the feasibility and efficacy of C6 as a new therapeutic approach for atherosclerotic vascular disease. If successful, the data generated will be critical for future clinical development and optimization of C6 or other structurally related compounds that target endothelial apoptosis and regeneration.