Molecular Genetics of Vascular Disease

血管疾病的分子遗传学

• 批准号: 7734902
• 负责人: Elizabeth G Nabel
• 金额: $ 311.68万
• 依托单位: NATIONAL HUMAN GENOME RESEARCH INSTITUTE
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/7734902
• 关键词: Age; Arteries; Blood Vessels; Cardiovascular Diseases; Cardiovascular system; Cell Cycle Progression; Cell Cycle Proteins; Cell Proliferation; Cessation of life; Clinical; Clinical Trials; Complex; Coronary; Cyclin-Dependent Kinase Inhibitor; Cyclin-Dependent Kinases; Data; Diagnosis; Disease; Dominant-Negative Mutation; Dose; Down-Regulation; Farnesyl Transferase Inhibitor; Fibroblasts; Functional disorder; Genes; Genetic; Genomics; Genotype; Goals; Human; Injury; Investigation; Laboratories; Lamin Type A; Lipids; Mediating; Microtubules; Molecular Genetics; Molecular and Cellular Biology; Mus; Myocardial Infarction; Nuclear; Nuclear Export; Nuclear Structure; Patients; Pattern; Phenotype; Phosphorylation; Phosphotransferases; Physiological; Point Mutation; Premature aging syndrome; Procedures; Production; Progeria; Proteins; Serine; Signal Pathway; Site; Smooth Muscle Myocytes; Stents; Stroke; Syndrome; Therapeutic; Therapeutic Intervention; Tipifarnib; Triage; Tubulin; Vascular Diseases; Vascular remodeling; Work; Wound Healing; arterial remodeling; case control; cell growth; genome wide association study; interest; migration; mouse model; mutant; neointima formation; p27 Cell Cycle Protein; p27 Enzyme Inhibitor; prevent; protein degradation; repaired; response; restenosis; stathmin

Our laboratory is interested in the molecular genetics of vascular diseases. We utilize several approaches, including molecular and cellular biology studies, genetic studies in mice, and clinical investigations in patients with vascular diseases. Our focus is on the genetics and genomics of vascular remodeling during common, complex cardiovascular diseases and during premature aging syndromes. Vascular proliferative diseases are characterized by smooth muscle cell (VSMC) proliferation and migration. KIS (kinase interacting with stathmin) targets two key regulators of cell proliferation and migration, the cyclin-dependent kinase inhibitor p27Kip1 and the microtubule destabilizing protein stathmin. Phosphorylation of p27Kip1 by KIS leads to cell-cycle progression, whereas the target sequence and the physiological relevance of stathmin phosphorylation by KIS in VSMCs are unknown. Vascular wound repair in KIS-/- mice results in accelerated neointima formation, which is composed predominantly of VSMCs. Deletion of KIS led to increased migratory activity of VSMCs accompanied by increased cytoplasmic tubulin destabilizing activity, whereas proliferation of VSMCs was abolished due to delayed nuclear export and degradation of p27Kip1. This pro-migratory phenotype was the result of increased stathmin protein levels due to a lack of stathmin phosphorylation by KIS at serine 38 and diminished stathmin protein degradation. Down-regulation of stathmin in KIS-/- VSMCs fully restored the phenotype, and stathmin-/- mice demonstrated normal responses to vascular injury. These data suggest that KIS protects against excessive neointima formation by stathmin-mediated inhibition of VSMC migration and that VSMC migration represents a major mechanism of vascular wound repair, constituting a relevant target and mechanism for therapeutic interventions. We are continuing a genome-wide association study of a vascular disease, termed in-stent restenosis (ISR), in order to understand the potential genetic contribution. ISR is an example of a human cardiovascular disease characterized by abnormal vascular remodeling. We are using a case-control approach to analyze genotypes collected from multiple clinical US sites. Our goal is to identify genomic profiles of patients with ISR in order to better diagnose and triage patients undergoing these procedures and to potentially refine therapeutics. Finally, we have collaborated with the Francis Collins lab on investigations of the premature aging syndrome, Hutchinson-Gilford Progeria Syndrome. HGPS is a dramatic form of human premature aging in which death occurs at a mean age of 13, usually from heart attack or stroke. Almost all cases of HGPS are caused by a de novo point mutation in the lamin A gene that results in production of a mutant lamin A protein, termed progerin which in turn is permanently modified by a lipid farnesyl group, and acts as a dominant negative, disrupting nuclear structure. Previous work has shown that treatment with farnesyltransferase inhibitors (FTIs) can prevent and even reverse this nuclear abnormality in cultured HGPS fibroblasts. In addition, we have previously created a mouse model of HGPS that shows progressive loss of vascular smooth muscle cells in the media of the large arteries, in a pattern that is strikingly similar to the cardiovascular disease seen in patients with HGPS. New work now demonstrates that the dose-dependent administration of the FTI tipifarnib to this HGPS mouse model can significantly prevent both the onset of the cardiovascular phenotype as well as the late progression of already existing cardiovascular disease. In summary, our studies of the molecular genetics of vascular remodeling have explored p27-KIS signaling pathways, the genomics of ISR, and pathological arterial remodeling in HGPS.

我们的实验室对血管疾病的分子遗传学感兴趣。我们使用了几种方法，包括分子和细胞生物学研究，小鼠的遗传研究以及血管疾病患者的临床研究。我们的重点是常见，复杂的心血管疾病和过早衰老综合症期间血管重塑的遗传学和基因组学。 血管增殖性疾病的特征是平滑肌细胞（VSMC）增殖和迁移。 KIS（激酶与Stathmin相互作用）靶向细胞增殖和迁移的两个关键调节剂，依赖细胞周期蛋白依赖性激酶抑制剂P27KIP1和微管破坏稳定的蛋白质蛋白质。 KIS对P27KIP1的磷酸化导致细胞周期进展，而KIS在VSMC中，靶序序和性磷酸化的生理相关性尚不清楚。 KIS - / - 小鼠的血管伤口修复会导致加速的新内膜形成，主要由VSMC组成。 KIS的缺失导致VSMC的迁移活性增加，并伴随着细胞质小管蛋白不稳定活性，而VSMC的增殖由于延迟的核出口和P27KIP1的降解而废除了VSMC的增殖。这种迁移的表型是由于KIS在丝氨酸38处缺乏磷酸化磷酸化而导致的蛋白质水平升高的结果，并减少了Stathmin蛋白降解。 KIS - / - VSMC中的Stathmin的下调完全恢复了表型，而Stathmin - / - 小鼠表现出对血管损伤的正常反应。这些数据表明，KIS通过Stathmin介导的对VSMC迁移的抑制来防止过度的新内膜形成，并且VSMC迁移代表了血管伤口修复的主要机制，构成了治疗干预措施的相关目标和机制。 为了了解潜在的遗传贡献，我们正在继续对一种被称为内部再狭窄（ISR）的血管疾病（ISR）的血管疾病的研究。 ISR是人类心血管疾病的一个例子，其特征是异常血管重塑。我们正在使用一种病例对照方法来分析从多个临床场所收集的基因型。我们的目标是确定ISR患者的基因组谱，以便更好地诊断和分类患者接受这些手术，并潜在地改进治疗疗法。 最后，我们与弗朗西斯·柯林斯（Francis Collins）实验室合作，研究了早熟综合征哈钦森 - 吉尔福德·富丽综合症（Hutchinson-Gilford Progeria综合症）。 HGP是人类早熟的一种戏剧性形式，死亡的平均年龄通常为13岁，通常是由于心脏病发作或中风。几乎所有的HGP病例都是由层蛋白A基因中的从头突变引起的，该基因产生了突变层粘连蛋白A蛋白的产生，称为肌蛋白，这又被脂质Farnesyl基团永久修饰，并充当主导的阴性阴性，破坏了核结构。先前的工作表明，Farneylsylansferse酶抑制剂（FTI）的治疗可以预防甚至逆转培养的HGP成纤维细胞中这种核异常。此外，我们以前已经创建了HGP的小鼠模型，该模型显示了大动脉介质中血管平滑肌细胞的逐渐丧失，这种模式与HGPS患者中的心血管疾病非常相似。现在的新工作表明，FTI tipifarnib剂量依赖于该HGPS小鼠模型可以显着防止心血管表型的发作以及已经存在的心血管疾病的晚期进展。 总而言之，我们对血管重塑的分子遗传学的研究探索了P27-KIS信号通路，ISR的基因组学以及HGP中的病理动脉重塑。

项目成果

Data and safety monitoring of rosiglitazone trials.

罗格列酮试验的数据和安全性监测。

• DOI: 10.1016/s0140-6736(07)60975-1
• 发表时间: 2007
• 期刊: Lancet (London, England)
• 作者: Nabel,ElizabethG;Shurin,SusanB;Simons-Morton,DeniseG;Gordon,David
• 通讯作者: Gordon,David

Genomics of in-stent restenosis: early insights into a complex disease.

支架内再狭窄的基因组学：对复杂疾病的早期见解。

• DOI: 10.1161/circulationaha.105.574780
• 发表时间: 2005
• 期刊: Circulation
• 影响因子: 37.8
• 作者: Ganesh,SanthiK;Nabel,ElizabethG
• 通讯作者: Nabel,ElizabethG

Treating COPD.

治疗慢性阻塞性肺病。

• DOI: 10.1056/nejmc076025
• 发表时间: 2007
• 期刊: The New England journal of medicine
• 作者: Kiley,JamesP;Nabel,ElizabethG
• 通讯作者: Nabel,ElizabethG

Conflict of interest--or conflict of priorities?

利益冲突——还是优先事项冲突？

• DOI: 10.1056/nejme068238
• 发表时间: 2006
• 期刊: The New England journal of medicine
• 作者: Nabel,ElizabethG

Fostering the independence of new investigators.

培养新调查人员的独立性。

• DOI: 10.1093/sleep/28.10.1221
• 发表时间: 2005
• 期刊: Sleep
• 影响因子: 5.6
• 作者: Nabel,ElizabethG