PRECLINICAL STUDIES OF ATAXIA-TELANGIECTASIA

共济失调-毛细血管扩张症的临床前研究

• 批准号: 2471887
• 负责人: RICHARD A GATTI
• 金额: $ 28.02万
• 依托单位: UNIVERSITY OF CALIFORNIA LOS ANGELES
• 依托单位国家: 美国
• 财政年份: 1998
• 资助国家: 美国
• 起止时间: 1998-01-01 至 2001-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/2471887
• 关键词: ataxia telangiectasia; clinical research; complementary DNA; ethnic group; gene mutation; human genetic material tag; human subject; neurogenetics; nucleic acid sequence

A well established and senior investigator in the field of AT has proposed this work to improve the diagnosis and treatment of AT. The proposal aims to understand the relationship between specific mutations and clinical symptoms. Because as many as 1% of the general population may carry a defective ATM (A-T mutated) gene, and these individuals may compromise perhaps 5% of all cancer patients, it is hoped that these studies will also offer better diagnosis for AT-carriers. The ATM gene is large, with 66 small exons, thereby presenting a challenging technical problem for mutation screening. At UCLA, Dr. Gatti has a unique repository of cells, mRNAs, and DNAs from greater than 200 A-T patients and their families. This resource allowed him to play a major role in the positional cloning that led to the isolation of the ATM gene in 1995. Since then greater than 200 mutations have been defined; more than half of these have come from his laboratory. Almost all of these mutations have been detected by screening mRNA/cDNA, using a protein truncation test and conformation sensitive gel electrophoresis (CSGE). Dr. Gatti will complete the task of defining cDNA defects and their corresponding genomic (gDNA) mutations on the remaining cDNAs and their screen DNA on 100 additional patients from whom cDNA is not available. Dr. Gatti will use restriction endonuclease finger printing, chemical cleavage, and semi-automated single strand conformational polymorphism screening methods. He will also participate in testing the efficiency of "smart chips" and other newly-introduced screening techniques in order to minimize the amount of actual sequencing necessary to define each mutation. Since most patients are compound heterozygotes, his resources should allow the characterization of 400 mutations. Dr. Gatti will also determine the affected haplotypes for each patient and, whenever possible, within each family. He will then compare the type and site of each mutation with the clinical symptoms of patients from multiple-affected families and ethnic groups with founder effect mutations. Families with variant phenotypes will be studied. Dr. Gatti anticipates that his research project will ultimately help to define the single common biological mechanism that underlies this complex syndrome. Based on this understanding, he then hopes to design a rational approach to an effective therapy of the affected children.

一位在 AT 领域颇有建树的高级研究员提出了 这项工作旨在改善 AT 的诊断和治疗。该提案的目的 了解特定突变与临床之间的关系 症状。因为多达 1% 的总人口可能携带 ATM（A-T 突变）基因有缺陷，这些人可能会妥协 也许占所有癌症患者的 5%，希望这些研究能够 还为 AT 携带者提供更好的诊断。 ATM基因很大， 66 个小外显子，从而提出了具有挑战性的技术问题 突变筛查。在加州大学洛杉矶分校，加蒂博士拥有一个独特的细胞库， 来自超过 200 名 A-T 患者及其家人的 mRNA 和 DNA。 这一资源使他在定位克隆中发挥了重要作用 这导致了 1995 年 ATM 基因的分离。从那时起，超过 已定义 200 个突变；其中一半以上来自 他的实验室。几乎所有这些突变都已被检测到 使用蛋白质截断测试和构象筛选 mRNA/cDNA 敏感凝胶电泳（CSGE）。加蒂博士将完成的任务 定义 cDNA 缺陷及其相应的基因组 (gDNA) 突变 剩余的 cDNA 及其筛选 DNA 来自另外 100 名患者 没有 cDNA 的人。 Gatti 博士将使用限制性核酸内切酶 指纹识别、化学切割和半自动单链 构象多态性筛选方法。他还将参加 测试“智能芯片”和其他新推出的产品的效率 筛选技术，以尽量减少实际测序量 需要定义每个突变。由于大多数患者都是复合型 杂合子，他的资源应该允许表征 400 突变。加蒂博士还将确定每个受影响的单倍型 耐心并尽可能在每个家庭中进行。然后他会比较 每个突变的类型和位点与患者的临床症状 来自具有创始人效应的多重影响家庭和种族群体 突变。将研究具有变异表型的家族。加蒂博士 预计他的研究项目最终将有助于定义 这种复杂综合征背后的单一常见生物学机制。 基于这样的认识，他接下来希望能够设计出一种理性的方法 以便对受影响的儿童进行有效的治疗。