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: 8576915
• 负责人: David A Dichek
• 金额: $ 36.77万
• 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/8576915
• 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; 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; Transforming Growth Factor beta Receptors; 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。主动脉瘤和夹层难以诊断，并且通常采用昂贵且复杂的外科/介入手术进行治疗，所有这些都具有复杂性。除了血压控制效果有限外，目前还没有针对主动脉瘤和夹层的有效药物治疗。有效治疗方法的不足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、夹层和动脉瘤。该项目的广泛、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，所有这些目标都集中在小鼠身上。关于定义转化生长因子β（TGF-¿）引发的细胞内信号的作用) 维持主动脉平滑肌细胞 (SMC) 的健康，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，其中关键的 TGF-¿ SMC 中特异的受体消除了生理性 TGF-¿初步数据表明 TGF-¿信号传导对主动脉 SMC 具有有益作用，可消除 TGF-¿ SMC 中的信号传导会损害主动脉，而保护 SMC TGF-¿目标 1 将继续确定消除 SMC TGF-¿ 对主动脉健康的影响。目标 2 将测试 SMC TGF-¿ 是否丢失。马凡综合征小鼠模型中的信号传导将预防（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 SMC TGF-¿ 缺失的假设。获得性主动脉瘤形成的小鼠模型（慢性血管紧张素 II 输注）中的信号传导将加速 SMC 损伤和动脉瘤生长。所有目的的实验旨在确定 TGF-¿维持 SMC 健康并保护主动脉结构和功能的作用将澄清这 3 个目标是否具有生理性 TGF-¿ SMC 中的信号传导对于维持产后主动脉稳态至关重要，并且还将揭示 TGF-¿ SMC 中的信号传导可防止基于遗传和环境引起的主动脉瘤的发展，此处获得的知识的应用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。