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: 8092214
• 负责人: MARK E LINDSAY
• 金额: $ 13.43万
• 依托单位: JOHNS HOPKINS UNIVERSITY
• 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/8092214
• 关键词: Accounting; Adolescent; Adult; Alleles; Anatomy; Aneurysm; Animals; Aorta; Aortic Aneurysm; Automobile Driving; Binding; Biological Assay; Biological Availability; Breeding; Cardiac; Cardiovascular system; Cell Differentiation process; Cell Lineage; Cell Proliferation; Cell model; Cells; Complex; Data; Development; Differentiation Antigens; Disease; DsRed; Embryo; Event; Extracellular Matrix; Extracellular Matrix Proteins; FBN1; Family member; Flow Cytometry; Follistatin; Gene Dosage; Genes; Heart; Human; In Vitro; Marfan Syndrome; Modeling; Mus; Mutation; Myocardial; Newborn Infant; Organogenesis; Pathologic; Pathology; Pathway interactions; Patients; Peptides; Performance; Phenotype; Predisposition; Pregnancy; Proteins; RNA; Reporter; Right ventricular structure; S Phase; Series; Signal Transduction; Smad Proteins; Smad protein; Smooth Muscle Myocytes; Specificity; Stem cells; Syndrome; System; Testing; Therapeutic; Thoracic Aortic Aneurysm; Transforming Growth Factor beta; Transgenic Organisms; Up-Regulation; Validation; Vascular Diseases; clinical phenotype; cytokine; embryonic stem cell; fibrillin; in vitro Model; in vivo; indexing; inhibitor/antagonist; insight; member; mouse model; mutant; prenatal; progenitor; receptor; response

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.

描述（由申请人提供）：项目摘要对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综合征 (MFS) 的研究发现的，马凡综合征 (MFS) 是一种常见的常染色体显性遗传疾病，由编码 fibrillin-1 的基因突变引起 (1)。我们目前的 MFS 病理学模型认为，fibrillin-1 蛋白表达减少会导致 TGF-2 大型潜在复合物 (LLC) 的结合减少，从而增加其生物利用度 (2)。通过 TGF-2 途径的信号传导增加会对细胞性能和表型产生有害影响，在心血管系统中会导致主动脉瘤。该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是一种已被充分描述的发育细胞因子，在心血管系统中具有极其重要的意义，并且先验地预计该系统的扰动会破坏全身器官发生的多个方面。此外，最近已证明 fibrillin-1 可以与 TGF-2 家族成员（包括 BMP 和 GDF）的扩展库结合，进一步扩大了 fibrillin 缺乏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区 (SHF) 中的致病性增殖信号有关，这是最近发现的一个包含圆锥干和右心室的发育区 (4-6)。本申请中要测试的主要假设是，由于 fibrillin-1 的缺失而导致 TGF-2 超家族成员信号传导的破坏，导致正在发育的 SHF 内发生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育。这一假设将在三个具体目标上受到质疑。首先，将在严重 MFS 的小鼠模型中对异常 SHF 的发展进行完整分析。第二个目标是从 fibrillin-1 缺陷胚胎中分离和表征 SHF 细胞，以识别驱动病理性细胞增殖的异常信号事件。最终目标是，通过在 SHF 发育的鼠胚胎干细胞 (mESC) 模型中进行初步实验以及随后的体内验证，将探索操纵异常 SHF 扩增作为 MFS 的治疗策略。重要的是，我们相信这种早期 SHF 失调可能引发致病序列，并确定 MFS 近端主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% 的死亡是由于主动脉瘤（扩大）或夹层（撕裂）引起的并发症。对主动脉瘤（例如人类马凡综合征）的遗传原因的调查发现了可以用普通药物靶向的途径，例如转化生长因子-2细胞因子途径。例如，抗高血压药物氯沙坦现已显示出治疗马凡综合征儿童主动脉瘤的前景。这项研究计划扩展了这项有前景的工作，以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。