Investigation of smooth muscle cell loss in progeria

早衰症平滑肌细胞损失的研究

基本信息

批准号：
9486185
负责人：
KAN CAO
金额：
$ 2.08万
依托单位：
UNIV OF MARYLAND, COLLEGE PARK
依托单位国家：
美国
项目类别：
财政年份：
2015
资助国家：
美国
起止时间：
2015-12-15 至 2020-11-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9486185
关键词：
13 year old Adult Age Aging Animal Model Aorta Arteries Atherosclerosis Binding Proteins Blood Vessels Cardiovascular Diseases Cardiovascular system Cell Death Cell Differentiation process Cell Maintenance Cell model Cells Cessation of life Child Chromosome abnormality Chromosomes Clinical DNA DNA Repair DNA Repair Pathway Disease Down-Regulation Environment Genes Goals Human In Vitro Investigation Lamin Type A Lead Life Maintenance Mediating Mitosis Mitotic Modeling Molecular Mus Muscle Cells Mutation Myocardial Infarction Names Nonhomologous DNA End Joining Pathway interactions Patients Phenotype Play Poly Adenosine Diphosphate Ribose Poly(ADP-ribose) Polymerases Polymerase Premature aging syndrome Progeria Proteins RNA Splicing Rare Diseases Reporting Research Role Single Strand Break Repair Site Smooth Muscle Myocytes Stroke Syndrome System Testing Tissue Engineering Tissues Transgenic Mice Vascular Smooth Muscle aged attenuation base homologous recombination in vivo in vivo Model induced pluripotent stem cell insight mouse model mutant p53-binding protein 1 prevent public health relevance repaired response senescence

项目摘要

DESCRIPTION (provided by applicant): Hutchinson-Gilford progeria syndrome (HGPS) is a devastating premature aging disease. Children with HGPS exclusively die of heart attacks or strokes at an average age of 13 years. The majority of HGPS cases are caused by a mutation C1824T in the lamin A gene. This mutation activates a cryptic splicing site and produces a truncated lamin A mutant named progerin. It is unknown how progerin causes the life-threatening cardiovascular diseases in HGPS patients. Previous research revealed a profound phenotype of massive loss of smooth muscle cells (SMCs) in large arteries in both human patients and HGPS mouse models, strongly suggesting a connection of this phenotype with the cardiovascular malfunction and death associated with HGPS. The primary goal of this proposal is to elucidate the molecular pathway behind this phenotype. Based on a recent study from my group (Zhang et al., PNAS 2014), we hypothesize a mechanism that the presence of progerin destabilizes Poly [ADP-ribose] polymerase 1 (PARP1) protein and leads to the activation of non-homologous end joining (NHEJ), the error-prone DNA repair pathway. Consequently, the mis-repaired chromosomes encounter problems in mitosis, which results in mitotic catastrophe of HGPS SMCs. In this proposal, we propose to test this idea by (i) elucidating how progerin lead to PARP1 down- regulation, (ii) studying the consequence of PARP1 disruption in HGPS SMCs, and (iiI) determining whether attenuation of NHEJ can alleviate SMC loss in HGPS. We will use HGPS patient specific induced pluripotent stem cells (iPSCs) to model SMC loss in vitro as well as apply mouse models of HGPS to test our hypothesis in vivo.

描述（由申请人提供）：哈钦森-吉尔福德早衰综合症 (HGPS) 是一种毁灭性的过早衰老疾病，患有 HGPS 的儿童平均在 13 岁时就会死于心脏病或中风。大多数 HGPS 病例是由突变引起的。核纤层蛋白 A 基因中的 C1824T 突变激活了一个隐秘的剪接位点，并产生了名为 progerin 的截短核纤层蛋白 A 突变体。先前的研究揭示了人类患者和 HGPS 小鼠模型中大动脉中平滑肌细胞 (SMC) 大量损失的强烈表型，表明这种表型与心血管疾病有关。该提案的主要目标是阐明这种表型背后的分子途径（Zhang 等人，PNAS 2014）。早老蛋白的存在会破坏多聚[ADP-核糖]聚合酶1 (PARP1) 蛋白的稳定性，并导致非同源末端连接 (NHEJ) 的激活，这是一种容易出错的 DNA 修复途径，错误修复的染色体在有丝分裂中会遇到问题。，这会导致 HGPS SMC 的有丝分裂灾难。在本提案中，我们建议通过 (i) 阐明早衰蛋白如何导致有丝分裂灾难。 PARP1 下调，(ii) 研究 HGPS SMC 中 PARP1 破坏的后果，以及 (iii) 确定 NHEJ 的减弱是否可以减轻 HGPS 中 SMC 的损失。我们将使用 HGPS 患者特异性诱导多能干细胞 (iPSC) 来模拟 SMC。体外损失以及应用 HGPS 小鼠模型来测试我们的体内假设。