TRANSCRIPTIONAL RESPONSES TO MITOCHONDRIAL DYSFUNCTION

对线粒体功能障碍的转录反应

• 批准号: 7807914
• 负责人: Rajiv R Ratan
• 金额: $ 139.94万
• 依托单位: WINIFRED MASTERSON BURKE MED RES INST
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/7807914
• 关键词: Age; Aging; Alzheimer' s Disease; Amyloid; Antioxidants; Attention; Autopsy; Be++ element; Beryllium; Binding Sites; Biochemical Genetics; Biogenesis; CCL4 gene; Cells; Cessation of life; Citric Acid Cycle; Code; Collaborations; Complex; Cyclic AMP Response Element; Cyclic AMP-Responsive DNA-Binding Protein; Cystamine; DNA Damage; Data; Defect; Disease; Disease Progression; EMSA; Elements; Enzymes; Failure; Free Radicals; Functional disorder; GTP Binding; Gene Expression; Generations; Genes; Genetic Transcription; Glutamine; Huntington Disease; Lead; Maintenance; Manganese; Manganese Superoxide Dismutase; Maps; Mediating; Metabolic stress; Mitochondria; Modeling; Modification; Molecular; Mus; Nerve Degeneration; Neurodegenerative Disorders; Neurons; Nuclear; Open Reading Frames; Oxidative Stress; Pathogenesis; Patients; Protein Binding; Proteins; Regulation; Respiratory Chain; Response Elements; Rodent Model; Role; Sampling; Senile Plaques; Serum; Site; Specificity; Synapses; TAF4 gene; Testing; Toxic effect; Transcription Coactivator; Transcriptional Activation; Transglutaminases; Tricarboxylic Acids; Up-Regulation; amyloid peptide; benzotriazole; chromatin immunoprecipitation; cis acting element; crosslink; cytochrome c; gene repression; human Huntingtin protein; human SOD2 protein; in vitro Model; inhibitor/antagonist; ketoglutarate dehydrogenase; mitochondrial dysfunction; mitochondrial genome; monomer; multicatalytic endopeptidase complex; mutant; neuron loss; novel; nuclear respiratory factor; peptide A; polyglutamine; prevent; programs; protein aggregate; protein protein interaction; research study; response; transcription factor

Several converging lines of inquiry suggest a central role for mitochondria! dysfunction in diseases of aging such as Alzheimer's disease (AD). Dysfunctional mitochondria perturb cellular activities in numerous ways including energy depletion, free radical generation and release of pro-death proteins. Thus, it is not surprising that increased attention has recently turned to the transcriptional mechanisms by which cells compensate for perturbations in mitochondrial functions. Genes involved in this adaptation include those involved in the tricarboxylic acid (TCA) cycle, the respiratory chain (e.g., cytochrome c), and mitochondrial antioxidant capacity (e.g., manganese containing mitochondrial superoxide dismutase (MnSOD). Accordingly our global hypothesis is that AD and HD result, in part, from the failure of compensatory, transcriptional mechanisms involved in adaptation to mitochondrial dysfunction. We believe this failure results from transcriptional dysregulation induced by toxic proteins (i.e., p-amyloid, mutant huntingtin) acting alone or in conjunction with the crosslinking enzyme, transglutaminase (TGase). In preliminary studies, we have shown that pharmacological suppression of TGase augments expression of a nuclear gene for a mitochondrial component, cytochrome c. In three specific aims, we will examine whether TGase can modulate the transcription of cytochrome c and MnSOD in primary cortical neurons and whether the negative modulation of these and other "adaptive" responses by Tgase contributes to mitochondrial dysfunction observed in in vitro models of AD and HD. Together the studies may provide a unifying model for transcriptional dysregulation and mitochondrial dysfunction in age- associated neurodegeneration.

多项研究线索表明线粒体发挥着核心作用！疾病中的功能障碍 衰老，例如阿尔茨海默病（AD）。功能失调的线粒体会干扰细胞活动 多种方式，包括能量消耗、自由基产生和促死亡物质的释放 蛋白质。因此，最近越来越多的注意力转向转录也就不足为奇了。 细胞补偿线粒体功能扰动的机制。基因 参与这种适应的包括那些参与三羧酸（TCA）循环、 呼吸链（例如细胞色素 c）和线粒体抗氧化能力（例如锰） 含有线粒体超氧化物歧化酶（MnSOD）。因此，我们的全球假设是 AD 和 HD 部分是由于参与的补偿性转录机制失败造成的。 适应线粒体功能障碍。我们相信这种失败是由转录造成的 由有毒蛋白质（即 p-淀粉样蛋白、突变型亨廷顿蛋白）单独或联合作用引起的失调 与交联酶、转谷氨酰胺酶 (TGase) 结合。在初步研究中，我们 已经表明，药物抑制 TGase 会增强核基因的表达 线粒体成分，细胞色素 c.在三个具体目标中，我们将研究 TGase 是否 可以调节初级皮质神经元中细胞色素 c 和 MnSOD 的转录 Tgase 对这些和其他“适应性”反应的负调节是否有助于 AD 和 HD 体外模型中观察到线粒体功能障碍。这些研究一起可能 为年龄相关的转录失调和线粒体功能障碍提供了一个统一的模型 相关的神经变性。