Optimization of a method to reduce expression of progerin, the cause of HGPS (Pro

减少早老蛋白表达的方法优化，早老蛋白是 HGPS 的病因（Pro

• 批准号: 7803810
• 负责人: LLOYD G MITCHELL
• 金额: $ 37.21万
• 依托单位: RETROTHERAPY, LLC
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-07-01 至 2012-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7803810
• 关键词: Age; Aging; Animal Model; Bulla; Cell Culture Techniques; Cells; Cellular Morphology; Cessation of life; Child; Chloride Ion Level; Code; Codon Nucleotides; Complementary DNA; Cystic Fibrosis; Cystic Fibrosis Transmembrane Conductance Regulator; Data; Development; Disease; Dominant-Negative Mutation; Epidermolysis Bullosa; Epithelial; Evaluation; Exons; Fluorescence-Activated Cell Sorting; Genes; Goals; Histology; Individual; Investigation; Lamin Type A; Lead; Libraries; Lung; Measures; Mediating; Messenger RNA; Methods; Muscular Dystrophies; Mutation; Myocardial Infarction; Normal Cell; Nuclear; Patients; Pattern; Phase; Physiological; Point Mutation; Premature aging syndrome; Process; Production; Progeria; Proteins; RNA Splicing; Reporting; Research; Site; Specificity; Spliceosomes; Staining method; Stains; Stroke; Structural Protein; Symptoms; Syndrome; Testing; Therapeutic; Time; Trans-Splicing; Transgenic Mice; Xenograft procedure; base; functional restoration; gain of function; gain of function mutation; mRNA Precursor; mutant; novel strategies; phase 1 study; plectin; pre-clinical; public health relevance; repaired; skin disorder

DESCRIPTION (provided by applicant): This proposal seeks to develop a specific and efficient means to reduce or eliminate the production of the progerin protein, the cause of the premature aging disease Hutchinson-Gilford Progeria Syndrome (HGPS). A de novo point mutation in codon 608 of the lamin A/C gene is present in nearly all cases of HGPS. This dominant gain-of-function mutation alters the processing of lamin A pre-mRNA and leads to the production of progerin. We have demonstrated the feasibility of this new approach that alters the processing of lamin A. The goal of this proposal is to produce and test a large library of candidate molecules for their ability to alter lamin A processing in the context of a marker gene. A small number of candidate molecules that most efficiently alter the production of the marker will be selected and tested individually in HGPS patient-derived cells. From these, a few lead candidate molecules that most specifically and efficiently reduce the production of progerin will be selected for further evaluation in Phase II if the results warrant continuation. PUBLIC HEALTH RELEVANCE: Children with Hutchinson-Gilford Progeria Syndrome suffer from many of the symptoms associated with normal physiologic aging. Death, usually from stroke or heart attack, occurs at a mean age of 13. At present, there is no treatment for this gain-of-function dominant mutation, although there are a number of approaches currently under investigation.

描述（由申请人提供）：该提案旨在开发一种特异性和有效的方法来减少或消除早老蛋白的产生，早老蛋白是导致过早衰老疾病哈钦森-吉尔福德早老综合征（HGPS）的原因。核纤层蛋白A/C基因608密码子的从头点突变存在于几乎所有的HGPS病例中。这种显性功能获得性突变改变了核纤层蛋白A前体mRNA的加工，并导致早老蛋白的产生。我们已经证明了这种改变核纤层蛋白A加工的新方法的可行性。该提案的目标是产生和测试候选分子的大型文库，以确定其在标记基因的背景下改变核纤层蛋白A加工的能力。将选择最有效地改变标记物的产生的少量候选分子，并在HGPS患者来源的细胞中单独测试。从这些中，如果结果保证继续，将选择最特异性和有效地减少早老蛋白产生的一些先导候选分子用于II期的进一步评价。 公共卫生相关性：患有Hutchinson-Gilford早衰综合征的儿童患有许多与正常生理衰老相关的症状。死亡，通常是中风或心脏病发作，发生在平均13岁。目前，没有治疗这种功能获得性显性突变的方法，尽管目前有许多方法正在研究中。