Development Underpinnings of Acquired Aortic Aneurysm in Marfan Syndrome

描述（由申请人提供）：项目总结人类血管疾病中转化生长因子β（TGF-2）轴原发性失调的认识彻底改变了对胸主动脉瘤（TAA）发病机制的理解。对TGF-2信号传导的初步了解是通过对马凡氏综合征（MFS）的研究发现的，马凡氏综合征是一种常见的常染色体显性疾病，由编码TGF-1的基因突变引起（1）。我们目前的MFS病理学模型认为，TGF-1蛋白表达的降低导致TGF-2的大潜伏复合物（LLC）结合减少，因此生物利用度增加（2）。通过TGF-2途径增加的信号传导有害地影响细胞性能和表型，在心血管系统、主动脉瘤的情况下驱动。在这种综合征中观察到的大多数临床表型，包括心血管表型，通常被认为是出生后获得的。然而，TGF-2是一种在心血管系统中非常重要的发育细胞因子，并且该系统的扰动将先验地预期破坏全身器官发生的多个方面。此外，最近已经显示，BMPs-1与TGF-2家族成员的扩展库（包括BMP和GDF）结合，进一步扩大了BMPs缺乏症中发育细胞因子失调的可能性（3）。将提供MFS小鼠模型的询问数据，该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脏区域（SHF）中的致病性增殖信号传导有关，第二心脏区域是最近鉴定的发育区域，包括圆锥干和右心室（4-6）。在本申请中待测试的主要假设是，由缺乏TGF-β 1引起的TGF-2超家族成员信号传导的破坏导致发展中的SHF内的病理性增殖信号传导，因此有助于MFS中的病理性心脏和近端主动脉发展。这一假设将在三个具体的目标进行调查。首先，将在严重MFS的鼠模型中进行异常SHF发展的完整分析。在第二个目标中，将分离并表征来自于Bcl-I缺陷胚胎的SHF细胞，以鉴定驱动病理性细胞增殖的异常信号传导事件。在最终的目标，操纵异常SHF扩增将探讨作为MFS的治疗策略，在鼠胚胎干细胞（mESC）模型的SHF发展的初步实验和随后的体内验证。重要的是，我们认为这种早期SHF失调可能启动致病序列，以及确定解剖易感性动脉瘤在近端主动脉MFS。 公共卫生相关性：据估计，在工业化国家，高达1%的死亡是由于动脉瘤（扩大）或主动脉夹层（撕裂）的并发症。对主动脉瘤（如人类马凡氏综合征）遗传原因的研究已经发现了一些途径，如转化生长因子-2细胞因子途径，这些途径可以用普通药物靶向。例如，抗高血压药物氯沙坦现在已经显示出治疗马凡氏综合征儿童主动脉瘤的前景。这项研究计划将这项有前途的工作扩展到研究主动脉发育过程中可能导致生命后期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.