Marfan Aortic Embryologic Origin Influences miR-29b Regulators and Targets

马凡主动脉胚胎起源影响 miR-29b 调节因子和靶点

• 批准号: 9105863
• 负责人: Michael Peter Fischbein
• 金额: $ 30.37万
• 依托单位: STANFORD UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-04-01 至 2021-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9105863
• 关键词: Abdomen; Affect; Age; Anatomy; Aneurysm; Animal Model; Antisense Oligonucleotides; Aorta; Aortic Aneurysm; Aortic Segment; Apolipoprotein E; Apoptosis; Atherosclerosis; Biological Models; Blood Vessels; Cause of Death; Clinical; Connective Tissue Diseases; County; Data; Deposition; Development; Disease; Dissection; Elastin; Embryo; Extracellular Matrix; FBN1; Frequencies; Functional disorder; Gene Mutation; Gene Targeting; Genes; Growth and Development function; Health; Heart; Human; Individual; Laboratories; Lead; Life; Link; Location; Marfan Syndrome; Mediating; Mesoderm; MicroRNAs; Molecular; Neural Crest; Neural Crest Cell; Paraxial Mesoderm; Pathway interactions; Patients; Plant Roots; Play; Prevention strategy; Reporting; Role; Rupture; Signal Transduction; Site; Smooth Muscle Myocytes; Structure; Testing; Therapeutic; Thoracic Aortic Aneurysm; Transforming Growth Factor beta; Transforming Growth Factors; Translating; Tunica Adventitia; Untranslated RNA; Vascular Diseases; Vascular Smooth Muscle; Work; abdominal aorta; aortic arch; ascending aorta; base; clinical practice; cytokine; human disease; in vitro Model; in vivo; induced pluripotent stem cell; innovation; intima media; mouse model; new therapeutic target; novel; postnatal; public health relevance; regional difference; research study; targeted treatment; transcription factor

 DESCRIPTION (provided by applicant): Marfan syndrome (MFS) is an autosomal-dominant systemic connective tissue disorder that affects 1 in 5000 individuals. Patients with MFS typically develop aortic root aneurysms with ensuing aortic dissection or rupture remaining the leading cause of death. Previous studies have demonstrated that the underlying fibrillin-1 gene mutation in MFS increases the activity of transforming growth factor-β (TGF-β). Although TGF-β blockade inhibits aortic root aneurysm development in murine models of MFS, the molecular mechanism by which TGF- β signaling leads to aneurysm development remains unknown. MicroRNAs (miRNAs) are short non-coding single-stranded RNAs that function to regulate hundreds of genes. Our laboratory has reported that miR-29b plays a key pathogenic role in early aneurysm development in a Marfan mouse model (Fbn1C1039G/+). miR-29b is known to regulate genes involved in apoptosis and ECM deposition/remodeling. Importantly, how TGF-β increases miR-29b expression in a manner that is temporally and spatially restricted to the aortic root during early postnatal life, is not clear. The aorta is a heterogeneous structure composed of three layers, the intima, media and adventitia. Lineage studies have shown that vascular smooth muscle cells (SMC) in the different anatomic segments of the aorta have distinct embryological origins. Recent studies have suggested that the diversity of SMC origin may explain site specific location of aneurysm development. Our laboratory has developed induced-pluripotent stem (iPS) cells from human MFS patients and have successfully differentiated them into SMC from different embryologic origins (second heart field, neural crest cells and paraxial mesoderm). This in vitro model system will allow us to study how SMC origin influences regional differences in aneurysm formation. Complementary experiments will be performed using an in vivo Marfan animal model, thus increasing the translational potential of these studies. The overall working hypothesis that differences in the embryonic origin of smooth muscle cells lead to distinct miR-29b-mediated extracellular matrix remodeling and contributes to aortic root aneurysm formation in Marfan syndrome will be tested by the following two specific aims: AIM 1: Determine if the miR-29b upstream regulators and downstream targets are different in Marfan human induced pluripotent stem cell (iPSC)-derived vascular SMCs from different embryologic origins. AIM 2: Contrast the role of miR-29b in the development of aneurysms within aortic segments originating from distinct embryonic origins utilizing the Fbn1C1039G/+ (aortic root; second heart field) and Ang II ApoE (abdominal; mesoderm) mouse models. This proposal will provide a mechanistic framework explaining aneurysm development in MFS. Investigating the pathways that participate in extracellular matrix (ECM) degeneration in the aortic root specifically might translate into more anatomically directed therapeutics.

 描述（由申请人提供）：马凡氏综合征（MFS）是一种常染色体显性全身性结缔组织疾病，每5000例患者中有1例受累。MFS患者通常会发生主动脉根部动脉瘤，随后发生主动脉夹层或破裂，这仍然是死亡的主要原因。先前的研究表明MFS中潜在的β-淀粉样蛋白-1基因突变增加了转化生长因子-β（TGF-β）的活性。尽管TGF-β阻断剂可抑制MFS小鼠模型中主动脉根部动脉瘤的发展，但TGF- β信号传导导致动脉瘤发展的分子机制仍不清楚。 MicroRNA（miRNAs）是一类短的非编码单链RNA，其功能是调控数百个基因。我们的实验室已经报道了miR-29 b在Marfan小鼠模型（Fbn 1C 1039 G/+）的早期动脉瘤发展中起关键的致病作用。已知miR-29 b调节参与细胞凋亡和ECM沉积/重塑的基因。重要的是，TGF-β如何在出生后早期以时间和空间限制于主动脉根部的方式增加miR-29 b表达尚不清楚。 主动脉是由三层组成的异质结构，即内膜、中膜和外膜。谱系研究表明，血管平滑肌细胞（SMC）在不同的解剖段的主动脉有不同的胚胎起源。最近的研究表明，SMC起源的多样性可以解释动脉瘤发生的部位特异性。我们的实验室已经开发了诱导多能干细胞（iPS）从人类MFS患者，并已成功地分化成SMC从不同的胚胎起源（第二心脏领域，神经嵴细胞和近轴中胚层）。这种体外模型系统将使我们能够研究SMC起源如何影响动脉瘤形成的区域差异。将使用体内马凡氏动物模型进行补充实验，从而增加这些研究的转化潜力。将通过以下两个具体目标来检验总体工作假设，即平滑肌细胞胚胎起源的差异导致不同的miR-29 b介导的细胞外基质重塑，并有助于马凡氏综合征中主动脉根动脉瘤的形成：AIM 1：确定miR-29 b上游调控因子和下游靶点在Marfan人诱导多能干细胞（iPSC）中是否不同-来源于不同胚胎来源的血管平滑肌细胞。 目标2：使用Fbn 1C 1039 G/+（主动脉根;第二心脏区域）和Ang II ApoE（腹部;中胚层）小鼠模型，对比miR-29 b在源自不同胚胎来源的主动脉段内动脉瘤发生中的作用。 该提案将提供一个机制框架，解释MFS中动脉瘤的发展。研究参与主动脉根部细胞外基质（ECM）变性的途径可能会转化为更具解剖学指导的治疗方法。