Tension-induced SGK-1 Signaling in AAA

高血压(HTN)是心血管死亡的主要危险因素，超过30%的美国人 目前都受到了影响。血压升高对主动脉壁重构的影响非常显著。 对一般血管疾病的影响，特别是动脉瘤的形成。血管紧张素II(AngII)是一种有效的 血管活性多肽，通过刺激白介素6(IL-6)和 单核细胞趋化蛋白-1(MCP-1)，以增加主动脉壁内巨噬细胞的数量。 有趣的是，腹主动脉瘤(Aaa)的患者也一直表现出升高。 血浆和主动脉组织中IL-6水平升高，并伴有致密的巨噬细胞浸润。定义由张力引起的 激酶驱动细胞因子的产生对于确定AAA药物治疗的潜在靶点至关重要。近期 有证据表明血清和糖皮质激素诱导的激酶-1(SGK-1)是一种机械敏感的激酶 这会导致内膜增生、动脉粥样硬化和肺动脉高压及其下游 几种转录因子的调节可以调节IL-6和MCP-1的产生。因此，它是 假设HTN促进SGK-1的VSMC激活以产生促炎细胞因子 聚集巨噬细胞以促进AAA的生长。第一个具体目标是分析张力诱导的SGK-1 C57BL/6野生型和SGK-1基因敲除大鼠主动脉VSMCs的活化及细胞因子的表达 (SGK-1KO)小鼠。这种条件培养液刺激单核/巨噬细胞迁移的能力 还将对渗透膜进行评估。在第二个目标中，C57BL/6和SGK-1KO小鼠诱导HTN (通过血管紧张素转换酶输注)将评估SGK-1的激活情况，以及促炎细胞因子IL-6的产生 和MCP-1，巨噬细胞聚集。这种炎症反应对SGK-1活性的依赖性 将通过使用选择性SGK-1抑制剂治疗诱发HTN的野生型小鼠来进一步探索 EMD638683。第三个具体目标将集中在SGK-1在启动和促进AAA形成中的作用 通过应用CaCl2诱导AAA的有效模型，并用EMD638683治疗小鼠。这个 末端程序将评估AAA的直径和目标细胞因子和蛋白水解酶的产生。机遇 对于升高的张力，将通过在两者中诱导HTN和并发AAA来探讨这一效应 小鼠品系并进行平行生化分析。通过在HTN之间建立该链路， 炎症和通过SGK-1活性启动降解性血管重塑，未来研究 可以利用靶向抑制疗法来减轻腹主动脉的动脉瘤样变性。此外， 这个项目中概述的实验将为Ruddy博士提供一个机会，让他利用 MUSC和心血管研究实验室扩展她的研究方法，发展导师关系 素质，增强她的批判性思维能力，并增强她的风度，推动她走向 一名独立研究人员。

Hypertension (HTN) is a major risk factor for cardiovascular mortality and greater than 30% of Americans are currently affected. The impact of elevated blood pressure on aortic wall remodeling has significant implications for vascular disease in general, and aneurysm formation specifically. AngiotensinII (AngII) is a potent vasoactive peptide and contributes to vascular inflammation by stimulating production of interleukin-6 (IL-6) and monocyte chemoattractant protein-1 (MCP-1) to augment the population of macrophages within the aortic wall. Interestingly, patients with abdominal aortic aneurysms (AAA) have also consistently demonstrated elevated plasma and aortic tissue levels of IL-6, along with dense macrophage infiltration. Defining the tension-induced kinase driving cytokine production is vital to identifying a potential target for pharmacotherapy of AAA. Recent evidence has identified serum and glucocorticoid inducible kinase-1 (SGK-1) as a mechanically sensitive kinase that contributes to intimal hyperplasia, atherosclerosis, and pulmonary hypertension, and its downstream regulation of several transcription factors can modulate the production of IL-6 and MCP-1. Therefore, it is hypothesized that HTN promotes VSMC activation of SGK-1 to produce pro-inflammatory cytokines that accumulate macrophages to propagate AAA growth. The first specific aim will analyze tension-induced SGK-1 activation and cytokine expression from aortic VSMCs harvested from C57Bl/6 wild-type and SGK-1 knockout (SGK-1KO) mice. The ability of this conditioned media to stimulate monocyte/macrophage migration through a permeable membrane will also be assessed. In the second aim, C57Bl/6 and SGK-1KO mice with induced HTN (via AngII infusion) will be evaluated for the activation of SGK-1, production of pro-inflammatory cytokines IL-6 and MCP-1, and accumulation of macrophages. Dependence of this inflammatory response on SGK-1 activity will be further explored by treating wild-type mice subjected to induced HTN with the selective SGK-1 inhibitor EMD638683. The third specific aim will focus on the role of SGK-1 in initiating and propagating AAA formation by employing a validated model of AAA induction with CaCl2 application and treating mice with EMD638683. The terminal procedure will evaluate AAA diameter and production of target cytokines and proteases. The opportunity for elevated tension to augment this effect will be explored by inducing HTN and concurrent AAA in the two mouse strains and conducting parallel biochemical analysis. By establishing this link between HTN, inflammation, and the initiation of degradative vascular remodeling through the activity of SGK-1, future studies may utilize targeted inhibitor therapies to attenuate aneurysmal degeneration in the abdominal aorta. Moreover, the experimentation outlined in this project will provide an opportunity for Dr. Ruddy to engage the resources of MUSC and the Cardiovascular Research Laboratory to expand her research methodology, develop mentorship qualities, enhance her critical-thinking skills, and augment her grantsmanship to propel her toward a career as an independent researcher.