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与年龄相关且可能致命的疾病。 慢性炎症、细胞外基质 (ECM) 降解和 ECM 受损之间复杂的相互作用 然而，生物合成与内侧平滑肌细胞（SMC）的消耗有关。 我们的初步研究结果表明，这个复杂网络中的内侧 SMC 尚未阐明。 信号分子蛋白激酶 C-delta (PKC¿) 在人和动物的 SMC 中上调 使用动脉瘤的 CaCl2 模型，我们证明了 PKC¿基因缺陷小鼠是 初步组织学分析表明 PKC¿基因 缺乏会损害巨噬细胞的浸润并防止内侧 SMC 的消耗和 ECM 的降解。 这些初步发现是新颖的，并且首次涉及 PKC¿在动脉瘤的发病机制中。 我们推测 PKC¿可能是导致细胞凋亡和促炎的一个重要因素 在这项研究中，我们提出了三个具体目标来测试与动脉瘤相关的 SMC 行为。 假设 PKC¿是导致内侧 SMC 耗竭的重要分子因素 PKCd 的促炎功能是通过单核细胞介导的。 在特定目标 I 中，我们将确认 chemoattactant Protein-1 (MCP-1) 的动脉瘤抵抗表型。 PKC??通过使用 CaCl2 模型并结合一系列组织学分析来敲除小鼠 此外，我们将测试 PKC 的作用。使用弹性蛋白酶灌注模型 通过不同的机制诱发动脉瘤。在特定目标 II 中，我们将描述机制。 通过 PKC¿首先，我们将测试一个新的范例。 涉及 Rho GTPase Cdc42 和 MAP 激酶 ERK 的潜在 MCP-1 基因表达 其次，我们将测试。 恢复主动脉壁中的 MCP-1 是否可以挽救 PKC 中受损的动脉瘤？第三，我们淘汰小鼠。 将评估 PKC 的作用??在巨噬细胞中以及炎症细胞对 PKC 的动脉瘤抵抗表型¿在特定目标 III 中，我们将表征两种肽抑制剂。 PKC?? ，其中一个是我们在初步研究期间开发的，目的是开发一种分子试剂 对抗 PKC¿所选抑制剂减轻动脉瘤发展的潜在功效。 将使用 CaCl2 模型来确定我们认为动脉 PKC¿上调例证了 SMC 内驱动促炎信号传导和细胞凋亡的细胞内信号网络。 通过所提出的体内和体外研究，我们将更好地了解内侧 SMC 腹主动脉瘤的发病机制，让我们为腹主动脉瘤的发展做出贡献 针对这种破坏性血管疾病的新疗法。