Molecular mechanisms in Abdominal Aortic Aneuysm

腹主动脉瘤的分子机制

• 批准号: 8399030
• 负责人: Bo Liu
• 金额: $ 41.27万
• 依托单位: UNIVERSITY OF WISCONSIN-MADISON
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-12-15 至 2014-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8399030
• 关键词: Abdomen; Abdominal Aortic Aneurysm; Anabolism; Aneurysm; Angiotensin II; Animals; Aorta; Apoptosis; Apoptotic; Attenuated; Behavior; Biological; Cells; Cessation of life; Chronic; Complex; Data; Death Rate; Degenerative Disorder; Development; Disease; Elastases; Functional disorder; Future; Gene Expression; Genes; Growth; Hospitals; Human; In Vitro; Individual; Infiltration; Inflammation; Inflammatory; Investigation; Knockout Mice; Link; MEKs; Malignant neoplasm of prostate; Medial; Mediating; Mediator of activation protein; Mitogen-Activated Protein Kinases; Modeling; Molecular; Monocyte Chemoattractant Protein-1; Mus; Operative Surgical Procedures; Pathogenesis; Patients; Peptides; Perfusion; Phenotype; Phosphotransferases; Production; Proteins; Reagent; Regulation; Reporting; Resistance; Role; Rupture; Ruptured Aneurysm; Signal Transduction; Signaling Molecule; Smooth Muscle Myocytes; Stress; Testing; Therapeutic; Time; Tissues; United States; Up-Regulation; Vascular Diseases; age related; base; drug development; in vivo; inhibitor/antagonist; macrophage; malignant breast neoplasm; monocyte; mortality; mouse model; novel; novel therapeutics; prevent; programs; protein kinase C-delta; repaired; rho GTP-Binding Proteins; screening; tool; translational study; vascular inflammation

Abdominal aortic aneurysm is a common age related and potentially lethal disease that develops as the result of a complex interplay among chronic inflammation, extracelluar matrix (ECM) degradation, and impaired ECM biosynthesis associated with depletion of medial smooth muscle cells (SMCs). However, the precise role of medial SMCs in this intricate network has yet to be elucidated. Results from our preliminary studies suggest that the signaling molecule protein kinase C-delta (PKC¿) is upregulated in SMCs of human and animal aneurismal tissues. Using the CaCl2 model of aneurysm, we demonstrated that PKC¿ gene deficient mice are protected from the development of aneurysms. Preliminary histological analyses indicate that PKC¿ gene deficiency impairs infiltration of macrophages and prevents depletion of medial SMCs and degradation of ECM. These preliminary findings are novel and for the first time implicate PKC¿ in the pathogenesis of aneurysms. We speculate that PKC¿ might be an integral factor responsible for the apoptotic and pro-inflammatory behavior of SMCs associated with aneurysm. In this study, we propose three specific aims to test the hypothesis that PKC¿ is an important molecular factor contributing to medial SMC depletion and vascular inflammation. The pro-inflammatory function of PKCd is mediated through monocyte chemoattactant protein-1 (MCP-1). In Specific Aim I, we will confirm the aneurysm-resistant phenotype of PKC¿ knockout mice through the use of the CaCl2 model paired with a serial of histological analyses over the course of aneurysm development. In addition, we will test the role of PKC¿ using the elastase perfusion model that induces aneurysm through a different mechanism. In Specific Aim II, we will delineate mechanisms through which PKC¿ gene deficiency impairs aneurysm formation. First, we will test a new paradigm underlying MCP-1 gene expression involving Rho GTPase Cdc42 and MAP kinase ERK. Second, we will test whether restoring MCP-1 in the aortic wall rescues the impaired aneurysm in PKC¿ knockout mice. Third, we will assess the role of PKC¿ in macrophages and the potential contribution of inflammatory cells to the aneurysm resistant phenotype of PKC¿ null mice. In Specific Aim III, we will characterize two peptide inhibitors of PKC¿, one of which was developed during our preliminary studies, in order to develop a molecular reagent to antagonize PKC¿ in vivo. The potential efficacy of the selected inhibitor to attenuate aneurysm development will be determined using the CaCl2 model. We believe that arterial PKC¿ upregulation exemplifies an intracellular signaling network within SMCs that drives pro-inflammatory signaling and apoptosis. Through the proposed in vivo and in vitro studies, we will gain a better understanding of medial SMCs in the pathogenesis of abdominal aortic aneurysm, which will allow us to make contributions toward the development of novel therapies for this devastating vascular disease.

腹主动脉瘤是一种常见的年龄相关，可能是致命的疾病，其结果是 慢性炎症，外部核基质（ECM）降解和ECM受损的复杂相互作用 与培养基平滑肌细胞（SMC）耗竭相关的生物合成。但是，精确的角色 该复杂网络中的内侧SMC尚未阐明。我们初步研究的结果表明 信号分子蛋白激酶C-DELTA（PKC¿）在人类和动物的SMC中进行了更新 使用动脉瘤的CaCL2模型，我们证明了PKC€基因缺陷小鼠是 免受动脉瘤的发展。初步组织学分析表明PKC¿基因 缺乏会损害巨噬细胞的渗透，并防止培养基SMC的耗尽和ECM的降解。 这些初步发现是新颖的，是动脉瘤发病机理中首次隐含的pkc。 我们推测，PKC¿可能是负责凋亡和促炎的组成因素 与动脉瘤相关的SMC的行为。在这项研究中，我们提出了三个特定目标，以测试 假设PKCC是导致内侧SMC部署和的重要分子因素 血管炎症。 PKCD的促炎功能是通过单核细胞介导的 化学毒剂蛋白1（MCP-1）。在特定目的I中，我们将确认抗动脉瘤的表型 PKC¿通过使用CACL2模型与串行的组织学分析，敲除小鼠 动脉瘤开发过程。此外，我们将使用弹性酶灌注模型测试PKC¿的作用 这通过不同的机制影响动脉瘤。在特定的目标II中，我们将描述机制 PKC¿基因缺乏会损害动脉瘤的形成。首先，我们将测试一个新的范式 涉及Rho GTPase CDC42和MAP激酶ERK的基础MCP-1基因表达。第二，我们将测试 是否在主动脉墙中恢复MCP-1是否可以挽救PKC敲除小鼠中的动脉瘤。第三，我们 将评估PKC知识在巨噬细胞中的作用以及炎症细胞对 PKC¿NULL小鼠的抗动脉瘤表型。在特定的目标III中，我们将表征两个肽抑制剂 为了开发分子试剂，pkc。是在我们的初步研究中开发的 在体内对抗PKC？。所选抑制剂衰减动脉瘤的潜在有效性 将使用CACL2模型确定。我们认为动脉pkc¿上调一个 SMC中的细胞内信号传导网络驱动促炎的信号传导和凋亡。 通过拟议的体内和体外研究，我们将更好地了解媒体SMC 腹主动脉瘤的发病机理，这将使我们能够为发育做出贡献 这种毁灭性血管疾病的新疗法。