Investigation of smooth muscle cell loss in progeria

早衰症平滑肌细胞损失的研究

• 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
• 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

 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（由适用提供）：Hutchinson-Gilford Forperia综合征（HGP）是一种毁灭性的早熟疾病。 HGP的儿童仅因心脏病发作或中风而死亡，平均年龄为13岁。大多数HGP病例是由层粘连蛋白A基因突变C1824T引起的。该突变激活一个加密剪接位点，并产生一个截短的层粘连蛋白突变体，名为Caryerin。尚不清楚促进蛋白如何导致HGPS患者威胁生命的心血管疾病。先前的研究表明，在人类患者和HGP小鼠模型中，大动脉中平滑肌细胞（SMC）的大规模丧失表型，强烈暗示这种表型与心血管故障和与HGP相关的死亡的联系。该提案的主要目标是阐明该表型背后的分子途径。基于我小组的最新研究（Zhang等，PNAS，2014年），我们假设一种机制，即孕激素的存在破坏了多个[ADP-核糖]聚合酶1（PARP1）蛋白质的稳定，并导致非基体终端连接（NHEJ）的激活（NHEJ）（NHEJ），误差DNA修复路径。因此，未修复的染色体在有丝分裂中遇到问题，从而导致HGPS SMC的有丝分裂灾难。在此提案中，我们建议通过（i）阐明孕激素如何导致PARP1下调，（ii）研究HGPS SMC中PARP1破坏的后果，以及（iii）确定NHEJ是否可以减轻HGPS中的SMC损失。我们将使用HGPS患者特异性诱导的多能干细胞（IPSC）在体外进行建模，并应用HGP的小鼠模型来测试我们在体内的假设。