Role of nebula/DSCR1 in mitochondria

nebul/DSCR1 在线粒体中的作用

• 批准号: 7128459
• 负责人: KAREN T CHANG
• 金额: $ 9万
• 依托单位: TRUSTEES OF INDIANA UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-09-19 至 2009-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7128459
• 关键词: A, Calcineurin; Address; Adenine Nucleotides; Adverse effects; Affect; Aging; Alzheimer' s Disease; Aneuploidy; Apoptosis; Behavioral Assay; Biochemical Genetics; Biological Models; Brain; Calcineurin inhibitor; Cell Survival; Cell physiology; Chromosomes, Human, Pair 21; Clinical; Congenital Heart Defects; Cultured Cells; Cyclic AMP-Dependent Protein Kinases; DSCR1 protein; Development; Down Syndrome; Drosophila genus; Ethnic group; Etiology; Genes; Genetic; Goals; Homologous Gene; Human; Lead; Learning; Live Birth; Longevity; Maintenance; Mechanical Stress; Mediating; Memory; Mental Retardation; Mitochondria; Mitochondrial Proteins; Modeling; Molecular; Muscle hypotonia; Mutation; Neurofibrillary Tangles; Neurons; Normal Cell; Numbers; Patients; Phenotype; Physiological; Physiology; Ploidies; Predisposition; Presenile Alzheimer Dementia; Protein Overexpression; Reporting; Research; Role; Senile Plaques; Signal Pathway; Testing; Trisomy; Whole Organism; base; enzyme activity; fetal; loss of function; mitochondrial dysfunction; mitochondrial permeability transition pore; nervous system disorder; novel; size; tau-1

DESCRIPTION (provided by applicant): The long-term goal of this research is to understand the molecular mechanisms underlying the phenotypes seen in Down syndrome (DS). DS, due to partial or full trisomy of chromosome 21, is the most common aneuploidy and affects approximately 1 in 700 live births in all ethnic groups. DS patients have numerous clinical problems including mental retardation, congenital heart defects, hypotonia and early onset Alzheimer's disease (AD), but the causes of these phenotypic features are not clearly understood. The Down syndrome critical region 1 (DSCR1) gene, located on chromosome 21, is up-regulated in fetal DS brain and encodes an inhibitor of calcineurin. Using Drosophila as a model system, we have previously shown that the Drosophila homolog of human DSCR1, nebula, is crucial for learning and memory. Recently we discovered that nebula also interacts with a mitochondrial protein, the adenine nucleotide translocator (ANT), and influences its activity. Furthermore, we found that nebula is required for normal mitochondrial function and maintenance of mitochondrial integrity. These results, together with reports showing mitochondrial dysfunction in DS and AD, lead us to hypothesize that abnormal expression of nebula/DSCR1 in DS causes mitochondrial dysfunction and subsequent adverse effects on normal cell function, leading to increased susceptibility to AD. To address these hypotheses, we propose the following Specific Aims: 1) To determine the physiological consequences of abnormal mitochondrial function due to nebula mutations. 2) To identify genes regulating nebula localization and function in mitochondria. 3) To investigate whether nebula/DSCR1 over-expression increases susceptibility to developing pathological features of AD.

描述（由申请人提供）：这项研究的长期目标是了解唐氏综合症（DS）中表现型的分子机制。 DS是由于染色体的部分或全部三体性，是最常见的非整倍性，在所有族裔中，大约有700个活生生中的大约1个。 DS患者存在许多临床问题，包括智力低下，先天性心脏缺陷，低调和早期的阿尔茨海默氏病（AD），但这些表型特征的原因尚不清楚。位于21染色体上的唐氏综合征临界区域1（DSCR1）基因在胎儿DS脑中被上调，并编码钙调神经素的抑制剂。我们以前使用果蝇作为模型系统，以前已经表明，人类DSCR1的果蝇同源物对于学习和记忆至关重要。最近，我们发现星云还与线粒体蛋白，腺嘌呤核苷酸易位剂（ANT）相互作用，并影响其活性。此外，我们发现星云是正常的线粒体功能和线粒体完整性维持所必需的。这些结果以及显示DS和AD中线粒体功能障碍的报道，使我们假设DS中星云/DSCR1的异常表达会导致线粒体功能障碍，并随后对正常细胞功能产生不利影响，从而导致AD的易感性增加。为了解决这些假设，我们提出以下具体目的：1）确定由于星云突变引起的线粒体功能异常的生理后果。 2）鉴定调节线粒体中的星云定位和功能的基因。 3）研究星云/DSCR1是否过表达是否会增加对发展AD病理特征的敏感性。