Hutchinson Gilford Progeria Syndrome and Atherosclerosis

哈钦森吉尔福德早衰综合症和动脉粥样硬化

• 批准号: 7664507
• 负责人: Stephen G. Young
• 金额: $ 36.62万
• 依托单位: UNIVERSITY OF CALIFORNIA LOS ANGELES
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-09-01 至 2011-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7664507
• 关键词: Acids; Affect; Age; Aging; Alleles; Alopecia; Alternative Splicing; Amino Acids; Animal Model; Animals; Appearance; Applications Grants; Atherosclerosis; Bacterial Artificial Chromosomes; Biogenesis; Birth; Boxing; C-terminal; Carbon; Cardiomyopathies; Cardiovascular system; Cause of Death; Cell Death; Cell Line; Cell Nucleus; Cell Survival; Cells; Cessation of life; Charcot-Marie-Tooth Disease; Child; Cholesterol; Clip; Coronary; Coronary heart disease; Cysteine; Defect; Dental; Development; Diet; Disease; Dysplasia; Educational workshop; Electroporation; Employee Strikes; Endothelial Cells; Enzymes; Exhibits; Exons; Failure to Thrive; Familial partial lipodystrophy; Fibroblasts; Figs - dietary; Fracture; Functional disorder; Future; Gene Expression; Gene Targeting; Genes; Genetic; Genomics; Hand; Hereditary Disease; Heterozygote; Human; Inflammatory; Inherited; Injury; Joints; Knockout Mice; Laboratories; Lamin Type A; Lamins; Left; Mechanics; Medicine; Messenger RNA; Micrognathism; Missense Mutation; Modeling; Molecular Profiling; Mus; Muscle Weakness; Muscular Dystrophies; Mutation; Normal Cell; Nuclear; Nuclear Lamina; Nucleotides; Online Mendelian Inheritance In Man; Osteolysis; Osteoporosis; Participant; Patients; Phenotype; Physiological; Positioning Attribute; Post-Translational Protein Processing; Predisposition; Principal Investigator; Process; Production; Progeria; Property; Proteins; RNA Splicing; Relative (related person); Reporting; Research; Research Personnel; Research Priority; Role; S-farnesylcysteine alpha-carboxyl methyl ester; Series; Shapes; Site; Skin; Spliced Genes; Structural Protein; Syndrome; System; Time; Transcript; Transgenic Mice; Transgenic Organisms; United States National Institutes of Health; Vascular Diseases; Work; age related; arterial lesion; atherogenesis; bone; cell type; cerebral artery; clavicle; experience; farnesylation; human disease; in vivo; insight; interest; isoprenylation; lamin C; mouse model; mutant; prelamin A; premature; premature atherosclerosis; prevent; programs; protein farnesyltransferase; protein-S-isoprenylcysteine O-methyltransferase; skeletal abnormality

DESCRIPTION (provided by applicant): Mutations in LMNA, the gene for lamin A/C, have been shown to cause several forms of muscular dystrophy, a cardiomyopathy, familial partial lipodystrophy, one form of Charcot Marie Tooth neuropathy, mandibuloacral dysplasia, and Hutchinson Gilford progeria syndrome (HGPS). HGPS patients have many aging-like phenotypes, including a wizened appearance, alopecia, osteoporosis, and coronary heart disease. HGPS is a merciless disease; death occurs on average at age 13, nearly always from atherosclerosis in the coronary and cerebral arteries. A recent NIH workshop on HGPS concluded that a thorough understanding of vascular disease in HGPS syndrome represents a key research priority. In most cases, HGPS is caused by a de novo single nucleotide substitution in exon 11. This mutation generates a cryptic splice site, resulting in an in-frame deletion of 50 amino acids near the carboxyl terminus of the lamin A. Interestingly, the deletion prevents the endoproteolytic processing of prelamin A. The objective of this grant application is to create mouse models of HGPS for the purpose of exploring mechanisms underlying the strikingly increased susceptibility to atherosclerosis in HGPS. The Principal Investigator (PI), Dr. Stephen G. Young, is well-positioned to pursue this objective. For the past 10 years, the PI has worked both on the posttranslational processing enzymes required for the biogenesis of lamin A and on the genetic underpinnings of atherosclerosis. For both projects, the PI has relied heavily on studies with gene targeted mice. Recently, the PI showed that the targeted inactivation of Zmpste24 prevents the proper endoproteolytic processing of lamin A, leading to the accumulation of prelamin A. Of note, Zmpste24-/- mice have a host of phenotypes similar to those in HGPS. The PI has also created mice lacking other enzymes involved in the posttranslational processing of the lamins (protein farnesyltransferase, Rcel, and Icmt). The first aim of this application is to create, with gene-targeting approaches, authentic mouse models of HGPS. The second specific aim is to compare, at both cellular and whole-animal levels, phenotypes in HGPS mouse models and the Zmpste24-deficient mice. The third specific aim is to understand mechanisms underlying the strikingly high susceptibility to atherosclerosis in HGPS. The PI's laboratory has extensive experience in analyzing atherogenesis in mice and is thrilled with the prospect of exploring mechanisms of atherosclerosis in HGPS.

描述（由申请人提供）： LMNA中的突变是层粘连蛋白A/C的基因，已被证明会引起几种形式的肌肉性营养不良，一种心肌病，一种家族性的部分脂肪营养不良，一种形式的Charcot Marie牙齿神经病，Mandibuloactary，Mandibuloacroacral Donsplasia，以及Hutchinson Gilford Progeria Progeria Cyndrome（Hutchinson Gilford Progeria cyndrome（Hgilford progeria consyndrome））。 HGPS患者有许多类似衰老的表型，包括纤维外观，脱发，骨质疏松症和冠状动脉疾病。 HGP是一种无情的疾病。死亡平均在13岁时发生，几乎总是来自冠状动脉和脑动脉的动脉粥样硬化。 HGP最近的NIH研讨会得出的结论是，对HGPS综合征血管疾病的透彻理解是关键的研究优先事项。 在大多数情况下，HGP是由外显子11中的单个单核苷酸取代引起的。该突变会产生一个隐秘的剪接位点，从而导致固定膜的50个氨基酸的框架缺失。 该赠款应用的目的是创建HGP的小鼠模型，目的是探讨HGPS中对动脉粥样硬化的敏感性显着提高的机制。首席研究员（PI）Stephen G. Young博士良好地追求这一目标。在过去的10年中，PI既有层粘连蛋白A的生物发生所需的翻译后加工酶，也是动脉粥样硬化的遗传基础所需的。对于这两个项目，PI都在很大程度上依赖于基因靶向小鼠的研究。最近，PI表明ZMPSTE24的靶向失活阻止了层粘连蛋白A的适当内蛋白溶解加工，从而导致预胺A的积累。 PI还创建了缺乏其他酶的小鼠，参与层粘连蛋白的翻译后加工（蛋白质Farneyltransferase，rcel和iCMT）。 该应用程序的第一个目的是通过基因靶向方法创建HGP的真实鼠标模型。第二个具体目的是在HGP小鼠模型和ZMPSTE24缺陷小鼠中比较细胞和全动物水平的表型。第三个具体目的是了解HGP中对动脉粥样硬化的极高敏感性的基础机制。 PI的实验室在分析小鼠的动脉粥样硬化方面具有丰富的经验，并且对探索HGPS动脉粥样硬化机制的前景感到兴奋。