Development Underpinnings of Acquired Aortic Aneurysm in Marfan Syndrome

描述(由申请人提供)：项目摘要对转化生长因子-2轴在人类血管疾病中的主要失调的认识彻底改变了对胸主动脉瘤(TAA)的病因学认识。对马凡综合征(MFS)的研究发现了对转化生长因子-2信号的初步认识。马凡综合征是一种常见的常染色体显性遗传病，由编码纤维蛋白-1(1)的基因突变引起。我们目前在MFS中的病理模型假设，纤维蛋白-1蛋白的表达减少导致转化生长因子-2的大潜伏复合体(LLC)的结合减少，从而提高了生物利用度。通过转化生长因子-2途径增加的信号会有害地影响细胞的性能和表型，从而导致心血管系统、主动脉瘤的发生。大多数观察到的这种综合征的临床表型，包括心血管表型，通常被认为是后天获得性的。然而，转化生长因子-2是一种在心血管系统中具有深远意义的发育细胞因子，该系统的扰动可能会预先干扰全身器官发生的多个方面。此外，纤维蛋白-1最近被证明与包括BMP和GDF在内的一系列转化生长因子-2家族成员结合，进一步扩大了纤维蛋白缺乏症的发育细胞因子失调的可能性(3)。将提供询问MFS小鼠模型的数据，这些模型显示心肌和动脉发育异常。我们认为心脏发育中的这些异常与第二心区(SHF)的致病增殖信号有关，SHF是最近发现的一个包括圆锥干和右室的发育区(4-6)。在这一应用中需要检验的主要假设是，由于缺乏纤维蛋白-1而导致的转化生长因子-2超家族成员信号的中断导致了发育中的SHF内的病理性增殖信号，从而促进了MFS的病理性心脏和近端主动脉的发育。这一假设将在三个具体目标上受到质疑。首先，将对重度MFS小鼠模型中SHF的异常发育进行完整的分析。在第二个目标中，将分离和鉴定来自纤维蛋白-1缺陷胚胎的SHF细胞，以识别驱动病理性细胞增殖的异常信号事件。在最终目标中，将探索操纵SHF异常扩张作为MFS的治疗策略，首先在SHF发育的小鼠胚胎干细胞(MESC)模型中进行实验，然后进行体内验证。重要的是，我们认为这种早期的SHF失调可能启动了MFS的致病顺序，并定义了MFS近端主动脉动脉瘤的解剖易感性。 公共卫生相关性：项目叙述(相关性)据估计，工业化国家高达1%的死亡是由主动脉瘤(增大)或夹层(撕裂)引起的并发症造成的。对主动脉瘤遗传原因的研究，如人类条件下的马凡综合征，已经发现了一些通路，如转化生长因子-2细胞因子通路，可以用普通药物来靶向。例如，降压药氯沙坦现在已经在治疗马凡综合征儿童的主动脉瘤方面显示出希望。这项研究提案扩展了这项有希望的工作，以调查主动脉发育过程中可能导致日后动脉衰竭的初始事件，并可能确定药物干预的新途径。

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. PUBLIC HEALTH RELEVANCE: Project Narrative (Relevance) It is estimated that up to 1% of death in industrialized countries is due to complications from aneurysm (enlargement) or dissection (tear) of the aorta. Investigation into inherited causes of aortic aneurysm such as the human condition Marfan syndrome have uncovered pathways, such as the transforming growth factor-2 cytokine pathway, that can be targeted with common medicines. For instance, the antihypertensive drug losartan, has now shown promise in treating aortic aneurysms in children with Marfan syndrome. This research proposal extends this promising work to investigate initial events during aortic development that may lead to arterial failure later in life and may identify novel pathways for pharmacologic intervention.