The Role of HDAC9/MITR in the Pathogenesis of Thoracic Aortic Aneurysm (TAA)

HDAC9/MITR 在胸主动脉瘤 (TAA) 发病机制中的作用

• 批准号: 9206191
• 负责人: MARK E LINDSAY
• 金额: $ 40.84万
• 依托单位: MASSACHUSETTS GENERAL HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-01-15 至 2020-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9206191
• 关键词: Ablation; Affect; Alleles; Anatomy; Aneurysm; Aorta; Aortic Aneurysm; Aortic Diseases; Automobile Driving; Binding; Blood Vessels; Catalytic Domain; Categories; Cell model; Cells; Cessation of life; Clinical; Clinical Research; Complex; Complication; Contractile Proteins; Coronary Arteriosclerosis; DNA; DNA-Binding Proteins; Data; Dependence; Developed Countries; Development; Disease; Dissection; EZH2 gene; Ectopic Expression; Epigenetic Process; Etiology; FBN1; Failure; Family; Functional disorder; Gene Expression Microarray Analysis; Gene Expression Profile; Gene Mutation; Genes; Genetic Predisposition to Disease; Genetic Transcription; HDAC9 gene; Hereditary Disease; Human; Hypertension; Impairment; In Vitro; Inheritance Patterns; Internal Ribosome Entry Site; Ischemic Stroke; Life; Link; Loeys-Dietz Syndrome; MADH3 gene; MYH11 gene; MYLK gene; Marfan Syndrome; Mediating; Mediator of activation protein; Mendelian disorder; Modeling; Modification; Molecular; Molecular Profiling; Mus; Muscle Cells; Muscle Contraction; Mutation; Names; Outcome; Pathogenesis; Pathogenicity; Pathologic; Pathway interactions; Patients; Pharmacology; Phenotype; Polycomb; Proteins; Risk; Risk Factors; Role; Signal Transduction; Small Interfering RNA; Smooth Muscle; Smooth Muscle Myocytes; Stroke; TGF Beta Signaling Pathway; TGFB2 gene; TGFBR1 gene; TGFBR2 gene; Techniques; Testing; Therapeutic; Thoracic Aortic Aneurysm; Thoracic aorta; Transcript; Transforming Growth Factor beta; Transforming Growth Factors; Transgenes; United States; Up-Regulation; Vascular Diseases; Vascular Smooth Muscle; Vinculin; abdominal aorta; base; calponin; cell motility; cell type; experimental study; gene discovery; gene function; gene repression; genome wide association study; high risk; human disease; hypercholesterolemia; in vivo; loss of function; male; member; mouse model; mutant; novel; overexpression; promoter; protein expression; public health relevance; response; restoration; sex; therapeutic target; transcription factor

 DESCRIPTION (provided by applicant): Aortic aneurysm is common, affecting up to 1% of people in the United States. Risk factors for aortic aneurysm include hypertension, hypercholesterolemia, and male sex. In contrast to aneurysm of the abdominal aorta, aneurysmal dilation of the ascending thoracic aorta (TAA) is heavily influenced by genetic predisposition, often associated with a Mendelian inheritance pattern. Considerable progress has been made in the elucidation of aneurysm pathogenesis through the clinical and experimental study of Mendelian disorders closely associated with TAA, such as Marfan syndrome (MFS) or Loeys-Dietz syndrome (LDS). Genes involved in TAA often encode members of the canonical transforming growth factor beta (TGF-β) signaling pathway, or alternatively encode positive effectors of smooth muscle contractile function. These human diseases have been termed transforming growth factor-β vasculopathies (TGFβVs) or smooth muscle contraction vasculopathies (SMCVs), respectively. Despite the aortic phenotypic similarities between TGFβVs and SMCVs, mechanistic links between the two forms of TAA remain obscure. To identify pathogenetic similarities between TGFβVs and SMCVs we created human vascular smooth muscle cellular models of genetically-triggered TAA and examined transcriptional signatures through microarray profiling. Transcripts were sought that showed similar dysregulation across these two groups. Interestingly, the epigenetic effector HDAC9 was found to be upregulated in TGFβVs and SMCVs. Interestingly, HDAC9 has recently been implicated in genome wide association screens (GWAS) involving patients with both large vessel stroke as well as coronary artery disease, although its mechanism of action in these human vascular diseases is poorly understood. In our experiments, cells expressing aneurysm transgenes mimicking human mutations TGFBR2G357W (TGFβV) and ACTA2R179H (SMCV) were found to have reduced migratory capacity, cytoskeletal abnormalities, and reduced expression of VSMC-specific transcripts for smoothelin, calponin, and vinculin. Importantly all of these phenotypes could be suppressed by siRNA mediated silencing of HDAC9. We went on to document increased expression of HDAC9 in aortas of Marfan (Fbn1C1039G/+) and Loeys-Dietz type 4 mice (Tgfb2-/+) that was accompanied by decreased VSMC specific protein expression, recapitulating in vitro observations. These preliminary data implicate HDAC9 as a critical mediator of vascular pathogenesis in TAA. In this application we will extensively investigate the mechanism of HDAC9 transcriptional induction (AIM1), the effect of increased HDAC9 on vascular smooth muscle cell phenotype (AIM2), and the feasibility of targeting HDAC9 activity for therapeutic benefit in experimental aortic aneurysm (AIM3).

 描述（由申请人提供）：主动脉瘤很常见，在美国影响高达1%的人。主动脉瘤的危险因素包括高血压、高胆固醇血症和男性。与腹主动脉瘤不同，胸升主动脉瘤样扩张（TAA）严重受遗传易感性的影响，通常与孟德尔遗传模式相关。通过对与TAA密切相关的Mendelian疾病（如Marfan综合征（MFS）或Loeys-Dietz综合征（LDS））的临床和实验研究，在阐明动脉瘤发病机制方面取得了相当大的进展。参与TAA的基因通常编码经典转化生长因子β（TGF-β）信号传导途径的成员，或者编码平滑肌收缩功能的正效应物。这些人类疾病分别被称为转化生长因子-β血管病（TGFβVs）或平滑肌收缩血管病（SMCV）。尽管TGFβ V和SMCV之间的主动脉表型相似，但两种形式的TAA之间的机制联系仍然不清楚。为了鉴定TGFβ V和SMCV之间的致病相似性，我们建立了遗传触发的TAA的人血管平滑肌细胞模型，并通过微阵列分析检查了转录特征。在这两组中寻找显示类似失调的转录本。有趣的是，发现表观遗传效应物HDAC 9在TGFβ V和SMCV中上调。有趣的是，HDAC 9最近被牵涉到涉及大血管中风以及冠状动脉疾病患者的全基因组关联筛选（GWAS）中，尽管其在这些人类血管疾病中的作用机制知之甚少。在我们的实验中，发现表达模拟人类突变TGFBR 2G 357 W（TGFβV）和ACTA 2 R179 H（SMCV）的动脉瘤转基因的细胞迁移能力降低，细胞骨架异常，平滑肌蛋白、钙调蛋白和黏着斑蛋白的VSMC特异性转录物表达降低。重要的是，所有这些表型都可以通过siRNA介导的HDAC 9沉默来抑制。我们继续记录了在Marfan（Fbn 1C 1039 G/+）和Loeys-Dietz 4型小鼠（Tgfb 2-/+）的腹主动脉中HDAC 9表达增加，伴随着VSMC特异性蛋白表达减少，概括了体外观察结果。这些初步数据表明HDAC 9是TAA血管发病机制的关键介质。在本申请中，我们将广泛研究HDAC 9转录诱导（AIM 1）的机制，增加HDAC 9对血管平滑肌细胞表型（AIM 2）的影响，以及靶向HDAC 9活性以获得实验性主动脉瘤（AIM 3）治疗益处的可行性。