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的基本原因有许多不同，其中大多数仍然未知。癫痫病基因的鉴定为疾病机制提供了宝贵的见解。然而，很少有癫痫基因在接近足以帮助指导有效疗法发展的分子理解的水平上被理解，而到目前为止，大多数成功仅限于通道蛋白。人类基因组测序的快速扩张已经确定了未知功能的新癫痫基因，需要新的方法来描述其疾病因果关系的机理。一个很好的例子是人类KCTD7基因，一种新指定的癫痫/神经退行性基因。 KCTD7的突变引起进行性肌阵挛性癫痫（EPM3），婴儿发作神经元粘膜脂肪促性脂肪促脂肪肌（CLN14）以及可能的其他疾病。但是，除了越来越多的报告确定患者KCTD7突变的报告外，基本上对KCTD7的分子功能一无所知（PubMed中的“ KCTD7”命中率为8个）。我们的目标是基于从我们的酵母研究中获得的新见解（酿酒酵母）获得KCTD7的潜在机制，并结合了神经元细胞死亡，线粒体功能和自噬的哺乳动物模型。我们实验室中的酵母遗传筛选发现了与氨基酸序列相似的酵母基因的新功能，与24成员的KCTD家族相似，该家族的人类蛋白质较差。 KCTD7专门在大脑的神经元中表达。我们在酵母中的研究表明，人类KCTD7在营养感应和自噬中的新功能。我们预测，所提出的项目的结果将对对KCTD7的基本分子机制的理解以及患者神经变性和癫痫构成的机制产生重大影响。在AIM 1中，我们将使用显微镜和生化方法来确定人类KCTD7在营养感应和自噬中在细胞系和原发性神经元中的作用。在AIM 2中，我们将描述KCTD7激活和功能的机制，在AIM 3中，我们将通过分析针对模仿EPM3/CLN14患者的新小鼠模型来测试这些分子机制的相关性。我们还期望为其他神经退行性过程提供宝贵的见解，并在癫痫研究中提高小鼠模型的效用。