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

基本信息

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
项目类别：
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

项目摘要

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定且有效的方法来减少或消除早衰蛋白的产生，早衰蛋白是早衰疾病哈钦森-吉尔福德早衰综合症（HGPS）的病因。几乎所有 HGPS 病例中都存在核纤层蛋白 A/C 基因密码子 608 的从头点突变。这种显性的功能获得性突变改变了核纤层蛋白 A 前 mRNA 的加工并导致早老素的产生。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。该提案的目标是生成并测试大型候选分子库，以确定它们在标记基因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产生的少量候选分子，并在 HGPS 患者来源的细胞中单独进行测试。从这些中，如果结果值得继续，将选择一些最具体、最有效地减少早老素产生的主要候选分子，用于第二阶段的进一步评估。公共卫生相关性：患有哈钦森-吉尔福德早衰综合症的儿童患有许多与正常生理衰老相关的症状。死亡通常死于中风或心脏病，平均年龄为 13 岁。目前，尽管有多种方法正在研究中，但尚无针对这种功能获得性显性突变的治疗方法。