Development Underpinnings of Acquired Aortic Aneurysm in Marfan Syndrome

马凡综合征获得性主动脉瘤的发展基础

• 批准号: 8582647
• 负责人: MARK E LINDSAY
• 金额: $ 12.85万
• 依托单位: MASSACHUSETTS GENERAL HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-05-16 至 2014-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8582647
• 关键词: Development; Underpinnings; Acquired; Aortic; Aneurysm

DESCRIPTION (provided by applicant): Project Summary The recognition of primary dysregulation of the transforming growth factor beta (TGF-2) axis in human vascular disease has revolutionized the pathogenetic understanding of thoracic aortic aneurysm (TAA). Initial insight into TGF-2 signaling was discovered by the study of the Marfan syndrome (MFS), a common, autosomal dominant condition caused by mutations in the gene encoding fibrillin-1 (1). Our current model of pathology in MFS posits that decreased expression of the fibrillin-1 protein leads to decreased binding of and therefore increased bioavailability of the large latent complex (LLC) of TGF-2 (2). Increased signaling through the TGF-2 pathway deleteriously influences cellular performance and phenotype, driving in the case of the cardiovascular system, aortic aneurysm. The majority of observed clinical phenotypes in this syndrome, including cardiovascular phenotypes, have commonly been considered as postnatally acquired. However, TGF-2 is a well-described developmental cytokine of profound importance in the cardiovascular system and perturbation of this system would a priori be expected to disrupt multiple aspects of systemic organogenesis. Additionally, fibrillin-1 has recently been shown to bind to an extended repertoire of TGF-2 family members including BMPs and GDFs, further expanding the possibilities for developmental cytokine dysregulation in fibrillin deficiency (3). Data will be presented of interrogation of mouse models of MFS, which demonstrate abnormalities of myocardial and arterial development. We believe these abnormalities in cardiac development are related to pathogenic proliferative signaling in the second heart field (SHF), a recently identified developmental field encompassing the conotruncus and right ventricle (4-6). The major hypothesis to be tested in this application is that disruption of TGF-2 superfamily member signaling caused by an absence of fibrillin-1 leads to pathologic proliferative signaling within the developing SHF and therefore contributes to pathologic cardiac and proximal aortic development in MFS. This hypothesis will be interrogated in three specific aims. In the first, a complete analysis of aberrant SHF development wil be undertaken in murine models of severe MFS. In the second aim, SHF cells from fibrillin-1 deficient embryos will be isolated and characterized, to identity aberrant signaling events driving pathologic cellular proliferation. In the final aim, manipulation of aberrant SHF expansion will be explored as a therapeutic strategy in MFS, with initial experimentation in a murine embryonic stem cell (mESC) model of SHF development and with subsequent in vivo validation. Importantly, we believe this early SHF dysregulation may initiate the pathogenic sequence as well as define the anatomic susceptibility to aneurysm in the proximal aorta in MFS.

描述（由申请人提供）：项目摘要识别人血管疾病中转化生长因子β（TGF-2）轴的原发性失调已彻底改变了对胸部主动脉瘤（TAA）的致病理解。通过研究Marfan综合征（MFS）的研究发现了对TGF-2信号传导的最初见解，这是一种由编码Fibrillin-1的突变引起的常见，常染色体显性疾病（1）。我们当前在MFS中的病理模型认为，降低原纤维蛋白-1蛋白的表达会导致结合减少，因此提高了TGF-2的大型潜伏复合物（LLC）的生物利用度（2）。通过TGF-2途径增加信号传导有害地影响了细胞性能和表型，在心血管系统（主动脉动脉瘤）的情况下驱动。该综合征中大多数观察到的临床表型，包括心血管表型，通常被认为是产后获得的。然而，TGF-2是一种描述良好的发育细胞因子，在心血管系统中非常重要，并且该系统的扰动将有望破坏系统性器官发生的多个方面。此外，最近已经显示，纤维素-1与包括BMP和GDF在内的TGF-2家族成员的扩展曲目结合，进一步扩大了纤维蛋白缺乏症中发育性细胞因子失调的可能性（3）。数据将介绍MFS小鼠模型的询问，该模型证明了心肌和动脉发育的异常。我们认为，心脏发育中的这些异常与第二个心脏场（SHF）中的致病性增殖信号传导有关，这是一个最近确定的涵盖Conotruncus和右心室的发育场（4-6）。在此应用中要检验的主要假设是，由于缺乏纤维蛋白-1的缺乏，TGF-2超家族构件信号的破坏会导致发育中的SHF内的病理增殖信号传导，因此有助于病理心脏和近端主动脉发育。该假设将在三个特定目标中审问。首先，将在严重MF的鼠模型中对异常SHF开发进行完整的分析。在第二个目标中，将分离并表征来自原纤维蛋白1缺陷胚胎的SHF细胞，以驱动病理细胞增殖的身份异常的信号传导事件。在最终目标中，将在MFS中探索对异常SHF扩展的操纵，并在SHF开发的鼠胚胎干细胞（MESC）模型中进行初步实验，并随后进行体内验证。重要的是，我们认为这种早期的SHF失调可能启动致病序列，并定义MFS近端主动脉中动脉瘤的解剖敏感性。