TRIPLET REPEAT DISEASE: REQUIREMENT FOR CASPASE CLEAVAGE

三联体重复疾病：CASPASE 裂解的要求

• 批准号: 6188773
• 负责人: Lisa M Ellerby
• 金额: $ 32.29万
• 依托单位: BUCK INSTITUTE FOR RESEARCH ON AGING
• 依托单位国家: 美国
• 财政年份: 1999
• 资助国家: 美国
• 起止时间: 1999-09-28 至 2002-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6188773
• 关键词: Huntington's disease; apoptosis; ataxia; atrophy; clinical research; cysteine endopeptidases; genetic disorder; glutamine; human tissue; laboratory mouse; laboratory rat; molecular pathology; nerve /myelin protein; neural degeneration; protein sequence; proteolysis; site directed mutagenesis; tissue /cell culture; transfection

The long-term objective of these studies is to develop an effective therapy for dominantly inherited, late onset, neurodegenerative diseases caused by expansions in CAG repeats. The CAG/polyglutamine expansion has been found to form the molecular basis for at least seven neurodegenerative diseases. These include Huntington's disease (HD), spinal and bulbar muscular atrophy (SBMA, Kennedy's disease), Machado-Joseph disease (MJD or SCA-3), dentatorubropallidoluysian atrophy (DRPLA), and spinocerebellar ataxias types 1, 2, and 6 (SCA-1, SCA-2, and SCA-6). In all cases, there is selective death of neurons in different brain regions and the clinical symptoms correlate with the affected regions. The function of most of these disease causing proteins is unknown and the proteins appear to be functionally unrelated except for the polyglutamine tract. Expansion of the glutamine repeat in all these proteins appears to confer upon the disease protein a toxic gain-of-function that is selectively deleterious to neurons. The goal of the proposed research is to define a common relationship between these seven disease-associated gene products. We will test our hypothesis that the seven polyglutamine containing proteins are pro-apoptotic, and that the pro-apoptotic phenotype is dependent upon cleavage of these proteins by cell death executioners, the caspases.

这些研究的长期目标是开发一种有效的治疗由CAG重复扩增引起的显性遗传性、晚发性神经退行性疾病的方法。CAG/聚谷氨酰胺扩增已被发现形成至少七种神经退行性疾病的分子基础。这些疾病包括亨廷顿氏病（HD）、脊髓和球性肌萎缩症（SBMA，肯尼迪病）、Machado-Joseph病（MJD或SCA-3）、齿状体白球性萎缩症（DRPLA）和脊髓小脑共济失调1、2和6型（SCA-1、SCA-2和SCA-6）。在所有病例中，不同脑区的神经元都有选择性死亡，临床症状与受影响的脑区有关。大多数这些致病蛋白的功能是未知的，除了聚谷氨酰胺束外，这些蛋白似乎在功能上无关。所有这些蛋白中谷氨酰胺重复序列的扩增似乎赋予了疾病蛋白一种毒性的功能获得，这种功能获得对神经元有选择性地有害。拟议研究的目标是确定这七种疾病相关基因产物之间的共同关系。我们将验证我们的假设，即7种含聚谷氨酰胺的蛋白质是促凋亡的，而促凋亡的表型依赖于细胞死亡刽子手半胱天冬酶对这些蛋白质的切割。