Mechanisms of Neurodegeneration

神经退行性变的机制

• 批准号: 8841838
• 负责人: J. Marie Hardwick
• 金额: $ 35.44万
• 依托单位: JOHNS HOPKINS UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-09-01 至 2016-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8841838
• 关键词: Adolescence; Aging; Amino Acid Sequence; Amino Acids; Attention; Autophagocytosis; Autophagosome; BTB/POZ Domain; Biochemical; Brain; Cell Death; Cell Line; Cessation of life; Child; Clinical; Collection; Complex; Cytoplasmic Tail; Defect; Development; Disease; Employee Strikes; Epilepsy; Etiology; Family; Family member; Feedback; GABA-B Receptor; Genes; Genetic Engineering; Genetic Screening; Genetic study; Glean; Goals; Health; Homologous Gene; Human; Individual; Informatics; Knock-out; Knockout Mice; Link; Magnetic Resonance Imaging; Mammalian Cell; Mammals; Membrane; Microscopy; Mitochondria; Modeling; Molecular; Mutation; Myoclonus; N-terminal; Nerve Degeneration; Nervous system structure; Neuronal Ceroid-Lipofuscinosis; Neurons; Neurotransmitters; Nutrient; Organelles; Pathogenesis; Pathway interactions; Patients; Phosphotransferases; Population; Positioning Attribute; Process; Progressive Myoclonic Epilepsies; Protein Family; Proteins; PubMed; Recycling; Reporting; Research; Role; Saccharomyces cerevisiae; Seizures; Signal Transduction; Sirolimus; Stress; Syndrome; Testing; Therapeutic; Translating; Yeasts; base; detection of nutrient; economic impact; fungus; gamma-Aminobutyric Acid; genome-wide; human disease; human genome sequencing; infancy; insight; member; mouse model; mutant; nervous system disorder; neuron loss; novel; novel strategies; protein aggregate; response; success; tumorigenesis; yeast genetics

DESCRIPTION (provided by applicant): There are many different underlying causes of epilepsy and associated neurodegeneration, most of which are still unknown. Identification of epilepsy disease genes has provided valuable insight into disease mechanisms. However, few epilepsy genes are understood at a level that approaches a molecular understanding sufficient to help guide development of effective therapeutics, and thus far most successes are limited to channel proteins. Rapid expansion of human genome sequencing has identified new epilepsy genes of unknown function, and new approaches are needed to delineate their mechanisms of disease causality. A case in point is the human KCTD7 gene, a newly designated epilepsy/neurodegeneration gene. Mutations in KCTD7 cause progressive myoclonic epilepsy (EPM3), infantile onset neuronal ceroid lipofuscinosis (CLN14), and possibly other disorders. However, except for a growing number of reports identifying KCTD7 mutations in patients, essentially nothing is known about the molecular functions of KCTD7 (8 hits for "KCTD7" in PubMed). Our goal is to uncover the underlying mechanisms of KCTD7 based on novel insights gained from our studies in yeast (Saccharomyces cerevisiae), combined with mammalian models of neuronal cell death, mitochondrial function and autophagy. A yeast genetic screen in our lab uncovered new functions for a yeast gene that has significant amino acid sequence similarity to the 24-member KCTD family of poorly characterized human proteins. KCTD7 is expressed specifically in neurons of the brain. Our studies in yeast suggest new unexpected functions for human KCTD7 in nutrient sensing and autophagy. We predict that the results of the proposed project will have a significant impact on the understanding of basic molecular mechanisms of KCTD7 as well as the mechanisms that underlie neurodegeneration and epilepsy in patients. In Aim 1, we will use microscopy and biochemical approaches to establish the role of human KCTD7 in nutrient sensing and autophagy in cell lines and primary neurons. In Aim 2, we will delineate mechanisms of KCTD7 activation and function, and in Aim 3 we will test the relevance of these molecular mechanisms by analyzing a new mouse model genetically engineered to mimic EPM3/CLN14 patients. We also expect to provide valuable insight into other neurodegenerative processes, and to advance the utility of mouse models in epilepsy research.

描述（由申请人提供）：癫痫和相关神经变性有许多不同的潜在原因，其中大部分仍然未知。癫痫疾病基因的鉴定为疾病机制提供了有价值的见解。然而，很少有癫痫基因被理解到接近足以帮助指导有效治疗方法开发的分子理解水平，并且迄今为止大多数成功仅限于通道蛋白。人类基因组测序的快速扩展已经确定了功能未知的新癫痫基因，需要新的方法来描述其疾病因果关系的机制。一个恰当的例子是人类KCTD 7基因，一个新命名的癫痫/神经变性基因。KCTD 7的突变导致进行性肌阵挛性癫痫（EPM 3）、婴儿型神经元蜡样质脂褐质沉积症（CLN 14）和可能的其他疾病。然而，除了越来越多的报告确定患者中的KCTD 7突变，基本上对KCTD 7的分子功能一无所知（PubMed中“KCTD 7”有8个命中）。我们的目标是基于我们在酵母（酿酒酵母）中的研究中获得的新见解，结合神经元细胞死亡，线粒体功能和自噬的哺乳动物模型，揭示KCTD 7的潜在机制。我们实验室的酵母遗传筛选发现了一个酵母基因的新功能，该基因与24个成员的KCTD家族的特征不明显的人类蛋白质具有显着的氨基酸序列相似性。KCTD 7在脑神经元中特异性表达。我们在酵母中的研究表明，人KCTD 7在营养传感和自噬中具有新的意想不到的功能。我们预测，拟议项目的结果将对理解KCTD 7的基本分子机制以及患者神经变性和癫痫的基础机制产生重大影响。在目标1中，我们将使用显微镜和生物化学方法来确定人KCTD 7在细胞系和原代神经元中的营养感测和自噬中的作用。在目标2中，我们将描述KCTD 7激活和功能的机制，在目标3中，我们将通过分析经基因工程改造以模拟EPM 3/CLN 14患者的新小鼠模型来测试这些分子机制的相关性。我们还希望为其他神经退行性过程提供有价值的见解，并推动小鼠模型在癫痫研究中的应用。