Protection from Atherosclerosis by c-Met Agonist

c-Met 激动剂预防动脉粥样硬化

• 批准号: 6691247
• 负责人: LATHA PAKA
• 金额: $ 19.78万
• 依托单位: ANGION BIOMEDICA CORPORATION
• 依托单位国家: 美国
• 财政年份: 2003
• 资助国家: 美国
• 起止时间: 2003-09-22 至 2004-09-21
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6691247
• 关键词: apoptosis; atherosclerosis; biological signal transduction; biomimetics; cardiovascular disorder chemotherapy; cell proliferation; cytoprotection; disease /disorder model; disease /disorder prevention /control; drug design /synthesis /production; drug screening /evaluation; fibrosis; genetically modified animals; hepatocyte growth factor; histology; isozymes; laboratory mouse; low density lipoprotein; molecular size; nitric oxide; nitric oxide synthase; oxidized lipid; vascular endothelium

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.

描述（由申请人提供）：导致内皮细胞凋亡和新内膜血管平滑肌细胞增生的细胞死亡途径的激活是动脉粥样硬化病变进展的初始触发因素。由于细胞凋亡是高度调控的细胞过程并介导动脉粥样硬化斑块的发展，因此靶向抑制内皮细胞凋亡是治疗动脉粥样硬化的有效方法。分散因子（SF）也称为肝细胞生长因子（HGF）已被确定为一种强大的内皮特异性抗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意义，因为SF/HGF仅刺激内皮细胞生长，而不复制血管平滑肌细胞，并且基于SF/HGF的疗法可有效治疗动脉粥样硬化。我们开发了一种SF/HGF活性的小分子模拟物（c-met激动剂），它是通过噬菌体展示和分子建模技术的新颖组合合理设计的。初步研究表明，这种被命名为 C6 的小分子化合物具有有效的 SF/HGF 样活性。在体外，C6 激活 SF/HGF 受体 c-met 介导 SF/HGF 的生物学功能，例如肾细胞分散、内皮细胞增殖和细胞凋亡保护。在拟议的研究中，我们将评估 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C6诱导内皮增殖的生化和信号转导途径以及抗凋亡作用。我们研究的目标是开发一种新的治疗策略来改变内皮细胞的存活并逆转动脉粥样硬化斑块的进展，其特征是进行性内皮细胞凋亡和组织纤维化。这些研究有望提供有关 C6 作为动脉粥样硬化性血管疾病新治疗方法的可行性和功效的基础临床前信息。如果成功，生成的数据对于 C6 或其他针对内皮细胞凋亡和再生的结构相关化合物的未来临床开发和优化至关重要。