The Role of SM22 in the Pathogenesis of Aortic Aneurysms

描述（由申请人提供）：在工业化国家，主动脉瘤占所有死亡人数的1-2%。马凡氏综合征（Marfan syndrome， MSF）是一种常见的遗传性疾病，在了解主动脉瘤发病机制方面研究得最多。目前，还没有被证实的药物可以预防动脉瘤的发展、分离和破裂。因此，迫切需要开发有效的治疗方法。更好地了解动脉瘤的发病机制将为动脉瘤的治疗提供新的靶点。马凡氏综合征是由FBN1蛋白突变引起的，该突变激活TGF -信号以驱动动脉瘤形成。使用马凡氏小鼠模型，在马凡氏患者中发现FBN1C1039G突变，氯沙坦被发现可以预防动脉瘤的形成。与已建立的TGF -信号传导模式不同，最近在胸主动脉瘤和夹层患者中发现的平滑肌细胞（SMC）肌动蛋白（ACTA2）和肌球蛋白（MYH11）等细胞骨架蛋白突变，突出了肌动蛋白细胞骨架收缩功能障碍在动脉瘤发病中的新机制。SM22是一种肌动蛋白结合蛋白，已知在马凡氏动脉瘤患者中显著下调。我们发表的研究表明，SM22缺乏破坏肌动蛋白细胞骨架，促进血管损伤后的氧化应激和血管炎症。最近，一系列研究表明，SM22是一种多功能蛋白，通过激活Erk1/2和氧化应激介导的NF-kB途径调节VSMC表型调节。在此，我们拟探讨SM22在动脉瘤发病机制中的作用。我们的初步结果表明，Fbn1C1039G/+马凡小鼠背景中Sm22的缺失加剧了动脉瘤的形成和破裂。本研究的目的是在一种新的马凡小鼠模型中确定SM22在动脉瘤形成发病机制中的分子机制。我们假设SM22缺陷伴FBN1缺陷通过刺激已建立的TGF - Erk1/2信号通路和肌动蛋白细胞骨架收缩功能障碍诱导的氧化应激和炎症信号通路的串扰而加重动脉瘤形成和破裂。目的1：我们将系统地描述Sm22-/- fbn1c1039g /+小鼠体内动脉瘤形成和破裂的发病机制；目的2：我们将利用成熟的分子、细胞和生物信息学方法，确定SM22缺乏对FBN1缺陷VSMCs中TGF - Erk1/2、氧化应激和NF-kB通路激活的分子机制。这项研究的成功完成将有助于揭示动脉瘤形成和破裂的发病机制。SM22可能是主动脉瘤新疗法的靶点。重要的是，这项研究将为一种新的模拟人类动脉瘤形成和破裂的小鼠动脉瘤模型提供验证。

DESCRIPTION (provided by applicant): Aortic aneurysms account for 1-2% of all deaths in industrialized countries. Marfan syndrome (MSF) is a common genetic disease that represents the most well studied situation for understanding the pathogenesis of aortic aneurysms. Currently, there are no proven drugs preventing aneurysm progression, dissection and rupture. Therefore, there is a pressing need to develop effective therapies. A better understanding of the pathogenesis of aortic aneurysms should provide new targets for developing treatments to aneurysms. Marfan syndrome is caused by FBN1 protein mutations that activate TGF� signaling to drive aneurysm formation. Using a Marfan mouse model that harbors the FBN1C1039G mutation found in Marfan patients, losartan was discovered to prevent aneurysm formation. Distinct from the well-established TGF� signaling paradigm, recent discoveries of mutations in smooth muscle cell (SMC) actin cytoskeleton proteins such as SM �actin (ACTA2) and �-myosin (MYH11) in patients with thoracic aortic aneurysm and dissection highlight a new mechanism of actin cytoskeleton contractile dysfunction in the pathogenesis of aneurysms. SM22, an actin binding protein, is known to significantly downregulated in the aneurysms of Marfan patients. Our published studies demonstrate that SM22 deficiency disrupts actin cytoskeleton and promotes oxidative stress and vascular inflammation upon vascular injury. Recently, a series of studies show that SM22 is a multifunctional protein that regulates VSMC phenotypic modulation via activating Erk1/2, and Oxidative stress-mediated NF-kB pathways. Here we propose to explore the role of SM22 in the pathogenesis of aneurysms. Our preliminary results show that deletion of Sm22 in the Fbn1C1039G/+ Marfan mouse background exacerbates aneurysm formation and rupture. The goal of this proposal is to determine the molecular mechanisms of SM22 in the pathogenesis of aneurysm formation in a new Marfan mouse model. We hypothesize that SM22 deficiency with defective FBN1 aggravates aneurysm formation and rupture by stimulating the crosstalk of both the established TGF�Erk1/2 signaling pathways and the actin cytoskeleton contractile dysfunction-induced oxidative stress and inflammation signaling pathways. Aim 1: we will systematically characterize the pathogenesis of aneurysm formation and rupture in our Sm22-/-Fbn1C1039G/+ mice in vivo; Aim 2: we will determine the molecular mechanisms of SM22 deficiency on TGF�Erk1/2, oxidative stress and NF-kB pathway activation in FBN1 defective VSMCs using well established molecular, cellular and bioinformatics approaches. Successful completion of this research will shed light on the pathogenesis of aneurysm formation and rupture. SM22 may represent a target for new therapies for aortic aneurysms. Importantly, this study will provide validation for a new mouse aneurysm model that mimics closely human aneurysm formation and rupture.