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: 8851668
• 负责人: David A Dichek
• 金额: $ 38.05万
• 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 2016-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8851668
• 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; genetic approach; human morbidity; human mortality; mortality; mouse model; novel; postnatal; prevent; 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，所有这些都具有显着的并发症发生率。除了效果有限的血压控制外，目前还没有针对主动脉瘤和夹层的有效药物疗法。由于我们对主动脉疾病发病机制的了解有限，因此缺乏有效的治疗方法。更具体地说，我们不了解维持主动脉健康的分子和细胞机制，也不了解这些机制为何以及如何失效，从而导致动脉瘤、夹层，并常常导致猝死。该项目的广泛、长期目标是确定维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 个具体目标，全部在小鼠身上进行。目标集中于确定转化生长因子β (TGF-¿) 引发的细胞内信号在维持主动脉平滑肌细胞 (SMC) 健康中的作用，从而保护主动脉结构和功能。 SMC 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持主动脉健康。目的是利用一种新型小鼠模型，其中对 SMC 中的关键 TGF-β 受体进行基因破坏，消除了生理性 TGF-β 信号传导。初步数据表明，TGF-¿ 信号传导对主动脉 SMC 具有有益作用，消除 SMC 中的 TGF-¿ 信号传导会损害主动脉，而保留 SMC TGF-¿ 信号传导将预防主动脉疾病。目标 1 将继续确定消除正常成年小鼠 SMC TGF-¿ 信号传导对主动脉健康的影响。目标 2 将测试马凡综合征小鼠模型中 SMC TGF-¿ 信号的丧失是否会预防（如当前模型所预测的）或更可能加速其主动脉瘤疾病。目标 3 将检验以下假设：获得性主动脉瘤形成小鼠模型（慢性血管紧张素 II 输注）中 SMC TGF-¿ 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-¿ 维持 SMC 健康和保护主动脉结构和功能的途径。这三个目标的实现将阐明 SMC 中的生理性 TGF-¿ 信号传导对于维持产后主动脉稳态是否至关重要，还将揭示 SMC 中的 TGF-¿ 信号传导是否可以防止遗传和环境诱发的主动脉瘤的发展。应用此处获得的知识将阐明可用于开发保持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。