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

基本信息

批准号：
9912106
负责人：
Michael Peter Fischbein
金额：
$ 28.76万
依托单位：
STANFORD UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2016
资助国家：
美国
起止时间：
2016-04-01 至 2022-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9912106
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 Pathogenicity Pathologic Pathway interactions Patients Plant Roots Play Prevention strategy RNA Reporting Role Rupture Signal Transduction Site Smooth Muscle Myocytes Structure Testing Therapeutic Thoracic Aortic Aneurysm Transforming Growth Factors Translating Tunica Adventitia Untranslated RNA Vascular Diseases Vascular Smooth Muscle abdominal aorta aortic arch ascending aorta base clinical practice cytokine experimental study human disease human pluripotent stem cell in vitro Model in vivo induced pluripotent stem cell innovation intima media mouse model new therapeutic target novel postnatal postnatal development public health relevance regional difference targeted treatment transcription factor

项目摘要

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（由适用提供）：Marfan综合征（MFS）是一种常染色体统治的系统性连接的组织疾病，影响5000个个体中的1个。 MFS患者通常会出现主动脉根动脉瘤，以确保主动脉夹层或破裂是死亡的主要原因。先前的研究表明，MFS中的基本原蛋白-1基因突变会增加转化生长因子-β（TGF-β）的活性。尽管TGF-β阻断抑制了MFS鼠模型中主动脉根动脉瘤的发育，但TGF-β信号传导导致动脉瘤发育的分子机制仍未知。 microRNA（miRNA）是短的非编码单链RNA，可调节数百个基因。我们的实验室报告说，在Marfan小鼠模型（FBN1C1039G/+）中，miR-29b在早期动脉瘤发育中起关键的致病作用。已知miR-29b调节涉及细胞凋亡和ECM沉积/重塑的基因。重要的是，TGF-β如何以在产后早期暂时和空间上限制为主动脉根的方式增加miR-29b的表达，这尚不清楚。主动脉是一个由三层，媒体和外膜组成的异质结构。谱系研究表明，主动脉不同解剖段中的血管平滑肌细胞（SMC）具有独特的胚胎性起源。最近的研究表明，SMC起源的多样性可以解释站点开发的特定位置。我们的实验室已经开发了来自人类MFS患者的诱导性茎（IPS）细胞，并成功地将它们从不同的胚胎学起源（第二心脏田，神经Crest细胞和近期中胚层）区分为SMC。这种体外模型系统将使我们能够研究SMC来源如何影响动脉瘤形成的区域差异。互补实验将使用体内Marfan动物模型进行，从而增加这些研究的翻译潜力。 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）衍生的来自不同胚胎的血管SMC。目标2：对比miR-29b在主动脉片段中使用FBN1C1039G/+（主动脉）根的不同胚胎起源的主动脉段中动脉瘤的作用；第二心脏场）和ANG II APOE（腹部；中胚层）小鼠模型。该提案将提供一个机械框架，以解释MFS中的动脉瘤开发。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解剖学的疗法。