Roles of SMC TGF-beta Signaling in Aortic Health and Aneurysm Formation

描述（由申请人提供）：主动脉疾病，包括动脉瘤和夹层，是发病率和死亡率的常见原因。主动脉瘤和夹层很难诊断，通常需要昂贵和复杂的手术/介入治疗，所有这些都有显著的并发症发生率。除了控制血压，这是有限的效果，目前没有有效的药物治疗主动脉瘤和夹层。缺乏有效的治疗方法是由于我们对主动脉疾病发病机制的了解有限。更具体地说，我们既不了解维持主动脉健康的分子和细胞机制，也不了解这些机制失效的原因和方式，从而导致动脉瘤、解剖，并经常导致猝死。该项目的长期目标是确定维持主动脉健康的机制，并操纵这些途径来预防主动脉疾病。有三个特定的目标，都是在老鼠身上进行的。目的是确定转化生长因子β （TGF-¿）引发的细胞内信号在维持主动脉平滑肌细胞（SMC）健康，从而保持主动脉结构和功能中的作用。SMC功能障碍和破坏是主动脉疾病的共同特征。因此，预防SMC功能障碍和破坏的策略可能会保持主动脉健康。目的是利用一种新的小鼠模型，其中SMC中关键TGF-¿受体的遗传破坏消除了生理TGF-¿信号。初步数据表明，TGF-¿信号对主动脉SMC有益，消除SMC中的TGF-¿信号会损害主动脉，保留SMC中的TGF-¿信号可预防主动脉疾病。目的1将继续确定消除正常成年小鼠SMC TGF-¿信号对主动脉健康的影响。目的2将测试马凡氏综合征小鼠模型中SMC TGF-¿信号的缺失是否会预防（如目前一个模型所预测的）或更有可能加速其主动脉瘤疾病。目的3将验证在小鼠获得性主动脉瘤形成模型（慢性血管紧张素II输注）中SMC TGF-¿信号的丧失会加速SMC损伤和动脉瘤生长的假设。所有目的的实验都旨在确定TGF-¿维持SMC健康和维持主动脉结构和功能的途径。完成这三个目标将阐明SMC中的生理性TGF-¿信号是否对维持出生后主动脉稳态至关重要，并将揭示SMC中的TGF-¿信号是否可以防止遗传和环境诱导的主动脉瘤的发展。在这里获得的知识的应用将阐明可以开发新的治疗方法的途径，以保持主动脉健康，防止或稳定主动脉夹层和动脉瘤。

DESCRIPTION (provided by applicant): Diseases of the aorta, including aneurysms and dissections, are common causes of morbidity and mortality. Aortic aneurysms and dissections are difficult to diagnose and are typically treated with expensive and complex surgical/interventional procedures, all of which have significant complication rates. Other than blood pressure control, which is of limited efficacy, there are currently no effective medical therapies for aortic aneurysms and dissections. The absence of effective therapies is due to our limited understanding of the pathogenesis of aortic disease. More specifically, we do not understand the molecular and cellular mechanisms that preserve aortic health nor do we understand why and how these mechanisms fail, resulting in aneurysms, dissections, and often in sudden death. The broad, long-term objective of this project is to define the mechanisms that preserve aortic health and to manipulate these pathways to prevent aortic disease. There are 3 specific aims, all carried out in mice. The aims are focused on defining the role of intracellular signals initiated by transforming growth factor beta (TGF-¿) in maintaining the health of smooth muscle cells (SMC) in the aorta, thereby preserving aortic structure and function. Dysfunction and destruction of SMC are common features of aortic diseases. Accordingly, strategies that prevent SMC dysfunction and destruction will likely preserve aortic health. The aims make use of a novel mouse model, in which genetic disruption of a critical TGF-¿ receptor specifically in SMC eliminates physiological TGF-¿ signaling. Preliminary data suggest that TGF-¿ signaling has beneficial effects in aortic SMC, that eliminating TGF-¿ signaling in SMC damages the aorta, and that preserving SMC TGF-¿ signaling will prevent aortic disease. Aim 1 will continue to define the consequences on aortic health of eliminating SMC TGF-¿ signaling in normal adult mice. Aim 2 will test whether loss of SMC TGF-¿ signaling in a mouse model of Marfan syndrome will prevent (as predicted by one current model) or-more likely-accelerate their aortic aneurysmal disease. Aim 3 will test the hypothesis that loss of SMC TGF-¿ signaling in a mouse model of acquired aortic aneurysm formation (chronic angiotensin II infusion) will accelerate SMC damage and aneurysm growth. Experiments in all aims are designed to identify pathways through which TGF-¿ acts to maintain SMC health and preserve aortic structure and function. Accomplishment of these 3 aims will clarify whether physiologic TGF-¿ signaling in SMC is critical for maintaining postnatal aortic homeostasis and will also reveal whether TGF-¿ signaling in SMC protects against the development of both genetically based and environmentally induced aortic aneurysms. Application of the knowledge acquired here will illuminate pathways that could be exploited to develop novel therapies that preserve aortic health and prevent or stabilize aortic dissections and aneurysms.