Lamin A Mutation and Hutchinson-Gilford Progeria

核纤层蛋白 A 突变和 Hutchinson-Gilford 早衰症

• 批准号: 7104070
• 负责人: Howard J Worman
• 金额: $ 26.4万
• 依托单位: COLUMBIA UNIVERSITY HEALTH SCIENCES
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-05-01 至 2009-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7104070
• 关键词: alkyltransferase; cell line; cytotoxicity; enzyme inhibitors; gene mutation; genetically modified animals; human genetic material tag; laboratory mouse; lamins; nuclear membrane; premature aging; prenylation; protein structure function

DESCRIPTION (provided by applicant): Hutchinson-Gilford progeria syndrome (HGPS), a condition with features of premature aging, is caused by a dominant de novo mutation in LMNA, the gene that encodes lamins A and C, intermediate filament proteins associated with the nuclear envelope. The mutation in HGPS introduces an abnormal splice site that leads the expression of a lamin A mutant with 50 amino acids deleted near its carboxyl-terminal end. The mutant lamin A has been called progerin. Different mutations in lamins A and C cause cardiomyopathy and muscular dystrophy, partial lipodystrophy syndromes, a peripheral neuropathy and atypical Werner syndrome. Some of these disorders share clinical features with HGPS while others are quite different. It is not known how mutations in lamins A and C cause HGPS or other diseases. We hypothesize that different mutations in these proteins cause alterations in nuclear structure and chromatin organization that lead to abnormalities in gene expression. In HGPS, progerin expression, possibly in combination with decreased expression of normal lamins A and C, is responsible for this chain of events. Our goal is to test this hypothesis. In Aim 1, we will study the biochemistry of progerin and its effects on the cell nucleus. We will determine if progerin, like normal prelamin A, is farnesylated and processed by endoproteolysis. We will investigate the effects of progerin on nuclear and chromatin structure and on the dynamics of other nuclear envelope proteins using fluorescent photobleaching methods. In Aim 2, we will generate transgenic mice expressing progerin in epidermis and determine if they develop pathological and functional abnormalities similar to those in skin of human subjects HGPS and normal aging skin. We will also cross progerin transgenic mice to heterozygous Lmna "knockout" mice to determine if reduced wild type protein levels have additional effects. In Aim 3, we will determine if a farnesyltransferase inhibitor blocks prenylation of progerin and determine if blocking progerin prenylation reverses cellular alterations and tissue abnormalities in progerin-expressing transgenic mice, hence connecting the experimental work in Aims 1 and 2. This project will establish how mutations in nuclear lamins A and C cause HGPS, and if inhibition of protein farnesylation is a potential therapeutic intervention.

描述（由申请人提供）：Hutchinson-Gilford Forperia综合征（HGP）是一种具有过早衰老特征的疾病，是由LMNA中的主要DE突变引起的，该基因编码了层粘连蛋白A和C核信封。 HGP中的突变引入了一个异常的剪接位点，该剪接位点导致层粘连蛋白A突变体的表达，其在其羧基末端附近删除了50个氨基酸。突变层粘连蛋白A被称为孕激素。 lamins A和C的不同突变引起心肌病和肌肉营养不良，部分脂肪营养不良综合征，外周神经病和非典型Werner综合征。这些疾病中的一些与HGP共享临床特征，而另一些则截然不同。尚不知道lamins A和C中的突变如何引起HGP或其他疾病。我们假设这些蛋白质中的不同突变会导致核结构和染色质组织的改变，从而导致基因表达异常。在HGP中，可能与正常层粘连蛋白A和C的表达降低结合的过程表达是该事件链的原因。我们的目标是检验这一假设。在AIM 1中，我们将研究孕激素的生物化学及其对细胞核的影响。我们将确定像正常前预后A一样，过程是否是通过内蛋白水解处理的。我们将使用荧光光漂白方法研究过程对过程对核和染色质结构以及其他核包膜蛋白的动力学的影响。在AIM 2中，我们将产生表达表皮中孕激素的转基因小鼠，并确定它们是否形成了与人类受试者皮肤HGPS和正常衰老皮肤相似的病理和功能异常。我们还将跨越后代蛋白转基因小鼠到杂合LMNA“基因敲除”小鼠，以确定降低的野生型蛋白水平是否具有额外作用。在AIM 3中，我们将确定雌激素的Farnesylansylansfrass抑制剂抑制剂是否促进了孕激素的原始化，并确定封闭后代蛋白的序列化是否会逆转到表达转基因小鼠的细胞改变和组织异常，从而在目标1和2中连接实验性工作。核层粘连蛋白A和C的突变会引起HGP，如果抑制蛋白质法尼化是一种潜在的治疗干预措施。