A Pharmacological Strategy for Ataxia Telangiectasia

共济失调毛细血管扩张症的药理学策略

• 批准号: 6650755
• 负责人: DAVID S. LAWRENCE
• 金额: $ 19.83万
• 依托单位: ALBERT EINSTEIN COLLEGE OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2002
• 资助国家: 美国
• 起止时间: 2002-09-01 至 2005-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6650755
• 关键词: DNA damage; SDS polyacrylamide gel electrophoresis; aminoglycoside antibiotics; ataxia telangiectasia; biological signal transduction; combination chemotherapy; drug screening /evaluation; gene expression; gene mutation; genetic promoter element; neocarzinostatin; nervous system disorder chemotherapy; neuropharmacology; pharmacokinetics; tissue /cell culture; transfection /expression vector; western blottings

DESCRIPTION (provided by applicant): Ataxia telangiectasia (A-T) is a rare childhood disorder characterized by the eventual loss of motor control, moderate to severe immunodeficiency, premature aging, and a pronounced predisposition to cancer. The gene defective in A-T has recently been identified (atm). The vast majority of mutations that produce the AT phenotype generate ATM protein truncations. A number of studies have recently shown that the aminoglycoside family of antibiotics mediate suppression of termination codons, albeit in a context-dependent fashion that can be exceedingly modest. We have examined global gene expression differences between human A-T and wild type cell lines. An unexpected outcome of these studies is the observation that ATM expression can be pharmacologically up-regulated. Consequently, it may be possible to induce ATM activity in an A-T genetic background by using drugs that suppress nonsense mutations in combination with agents that activate the atm promoter. The proposed research program seeks to (1) identify the global biochemical signals that activate the atm promoter, (2) assess the mechanism of action of atm promoter activating drugs, (3) evaluate a library of FDA-approved drugs for their ability to suppress nonsense mutations and serve as adjuvants for the aminoglycoside antibiotic family, (4) assess the combinatorial action of drugs that suppress nonsense mutations and activator atm promoter function, and (5) examine the effect of these agents on ATM induction and activation in A-T cell lines.

描述（由申请人提供）：共济失调性毛细血管扩张症（A-T）是一种罕见的儿童疾病，其特征为最终失去运动控制、中度至重度免疫缺陷、过早衰老和明显的癌症易感性。A-T缺陷基因最近已被鉴定（atm）。产生AT表型的绝大多数突变产生ATM蛋白截短。最近的一些研究表明，抗生素的氨基糖苷类家族介导终止密码子的抑制，尽管以上下文依赖的方式，可能是非常温和的。我们检查了人类A-T和野生型细胞系之间的整体基因表达差异。这些研究的一个意想不到的结果是观察到ATM表达可以被上调。因此，通过使用抑制无义突变的药物与激活atm启动子的药物组合，有可能在A-T遗传背景中诱导ATM活性。拟议的研究计划旨在（1）确定激活atm启动子的全球生化信号，（2）评估atm启动子激活药物的作用机制，（3）评估FDA批准的药物库抑制无义突变的能力，并作为氨基糖苷类抗生素家族的佐剂，（4）评估抑制无义突变和激活剂atm启动子功能的药物的组合作用，和（5）检查这些药剂对A-T细胞系中ATM诱导和激活的作用。