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

SMC TGF-β 信号传导在主动脉健康和动脉瘤形成中的作用

• 批准号: 8717714
• 负责人: David A Dichek
• 金额: $ 37.85万
• 依托单位: UNIVERSITY OF WASHINGTON
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-08-15 至 2017-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8717714
• 关键词: Abdominal Aortic Aneurysm; Adult; Alleles; Aneurysm; Angiotensin II; Animal Model; Aorta; Aortic Aneurysm; Aortic Diseases; Biological; Blood; Blood Vessels; Cardiac; Cell Differentiation process; Chronic; Clinical; Clinical Trials; Collagen; Complex; Complication; Consensus; Data; Descending aorta; Development; Diagnosis; Disease; Dissection; Elastin; Embryonic Development; Extracellular Matrix; FBN1; Foundations; Functional disorder; Gene Expression; Genetic; Germ Lines; Goals; Growth; Health; Homeostasis; Human; Immunosuppression; Incidence; Infusion procedures; Knowledge; Laboratories; LoxP-flanked allele; Maintenance; Marfan Syndrome; Measures; Medial; Medical; Modeling; Molecular; Morbidity - disease rate; Morphogenesis; Mus; Operative Surgical Procedures; Pathogenesis; Pathology; Pathway interactions; Physiological; Physiology; Play; Procedures; Property; Proteins; Research; Research Personnel; Role; Severities; Signal Pathway; Signal Transduction; Smooth Muscle Myocytes; Structure; Sudden Death; Tamoxifen; Testing; Therapeutic; Thick; Transforming Growth Factor beta; Trees; Uncertainty; Vascular Diseases; Vasomotor; Work; base; blood pressure regulation; cell injury; design; effective therapy; expectation; human morbidity; human mortality; mortality; mouse model; novel; postnatal; prevent; public health relevance; receptor; recombinase; research study; role model; therapy development

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.

描述（由申请人提供）：主动脉疾病，包括动脉瘤和夹层，是发病和死亡的常见原因。主动脉瘤和夹层很难诊断，通常采用昂贵且复杂的外科/介入手术进行治疗，所有这些手术都具有显著的并发症发生率。除了有效性有限的血压控制外，目前还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的发病机制了解有限。更具体地说，我们不了解保持主动脉健康的分子和细胞机制，也不了解这些机制为什么以及如何失败，导致动脉瘤，夹层，并经常导致猝死。该项目的广泛的长期目标是确定保护主动脉健康的机制，并操纵这些途径来预防主动脉疾病。有3个具体的目标，都在小鼠中进行。其目的是集中在定义由转化生长因子β（TGF-β）启动的细胞内信号在维持主动脉平滑肌细胞（SMC）健康中的作用，从而保护主动脉结构和功能。平滑肌细胞功能障碍和破坏是主动脉疾病的常见特征。因此，预防SMC功能障碍和破坏的策略可能会保护主动脉健康。这些目标利用了一种新的小鼠模型，其中SMC中一种关键TGF-β受体的遗传破坏消除了生理TGF-β信号传导。初步数据表明，TGF-β信号在主动脉SMC中具有有益作用，消除SMC中的TGF-β信号会损伤主动脉，并且保留SMC TGF-β信号将预防主动脉疾病。目标1将继续确定消除正常成年小鼠SMC TGF-β信号对主动脉健康的影响。目标2将测试在马凡氏综合征小鼠模型中SMC TGF-β信号的丢失是否会预防（如一个当前模型所预测的那样）或更可能加速他们的主动脉瘤疾病。目的3将检验以下假设：在获得性主动脉瘤形成（慢性血管紧张素II输注）的小鼠模型中，SMC TGF-β信号传导的丧失将加速SMC损伤和动脉瘤生长。所有目的的实验都旨在确定TGF-β发挥作用以维持SMC健康和保护主动脉结构和功能的途径。这3个目标的实现将阐明SMC中的生理性TGF-β信号传导是否对维持出生后主动脉稳态至关重要，并且还将揭示SMC中的TGF-β信号传导是否保护免于基于遗传和环境诱导的主动脉瘤的发展。应用这里获得的知识将阐明可用于开发保护主动脉健康并预防或稳定主动脉夹层和动脉瘤的新疗法的途径。