Molecular mechanisms in Abdominal Aortic Aneuysm

腹主动脉瘤是一种常见的与年龄相关的潜在致命性疾病，其结果是 慢性炎症、细胞外基质(ECM)降解和ECM受损之间的复杂相互作用 与中膜平滑肌细胞(SMCs)耗竭相关的生物合成。然而，它的确切作用是 这个错综复杂的网络中的中间SMC还没有被阐明。我们的初步研究结果表明 信号分子蛋白激酶C-增量(PKC？)在人和动物的SMC中表达上调 动脉瘤组织。利用CaCl2动脉瘤模型，我们证明了PKC基因缺陷的小鼠是 防止动脉瘤的发展。初步的组织学分析表明，PKC基因 缺乏会损害巨噬细胞的渗透，并阻止中层SMC的耗竭和ECM的降解。 这些初步发现是新的，并首次将PKC与动脉瘤的发病机制联系在一起。 我们推测PKC可能是导致细胞凋亡和促炎的一个不可或缺的因素。 与动脉瘤相关的SMC的行为。在这项研究中，我们提出了三个具体目标来测试 假设PKC？是导致中层SMC耗竭的重要分子因素 血管发炎。PKCd的促炎作用是通过单核细胞介导的 趋化蛋白-1(MCP-1)。在特定的目标一，我们将确认的动脉瘤抵抗表型 通过使用CaCl2模型结合一系列组织学分析，对PKC基因敲除小鼠 动脉瘤的发展过程。此外，我们将使用弹性酶灌流模型来测试PKC的作用 这会通过不同的机制导致动脉瘤。在具体目标二中，我们将描述机制。 PKC基因缺失可通过此机制损害动脉瘤的形成。首先，我们将测试一种新的范式 潜在的MCP-1基因表达涉及Rho GTP酶CDC42和MAP激酶ERK。第二，我们将测试 主动脉壁恢复MCP-1能否挽救PKC基因敲除小鼠受损的动脉瘤。第三，我们 将评估PKC在巨噬细胞中的作用以及炎症细胞在 PKC基因缺失小鼠的抗动脉瘤表型。在特定目标III中，我们将表征两种多肽抑制剂 其中一种是在我们的初步研究中开发的，目的是开发一种分子试剂 在体内拮抗PKC。所选抑制剂延缓动脉瘤发展的潜在疗效 将使用CaCl2模型来确定。我们认为，动脉PKC的上调是一种 SMC内的细胞内信号网络，驱动促炎信号和细胞凋亡。 通过建议的体内和体外研究，我们将更好地了解 腹主动脉瘤的发病机制，这将使我们能够为发展做出贡献 治疗这种毁灭性血管疾病的新疗法。

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.