Role of DYRK1A/MNB in Synaptic growth and function

DYRK1A/MNB 在突触生长和功能中的作用

基本信息

批准号：
8876829
负责人：
KAREN T CHANG
金额：
$ 36.09万
依托单位：
UNIVERSITY OF SOUTHERN CALIFORNIA
依托单位国家：
美国
项目类别：
财政年份：
2013
资助国家：
美国
起止时间：
2013-07-16 至 2016-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8876829
关键词：
Actins Address Affect Alzheimer&apos s Disease Biochemical Biological Biological Models Brain Candidate Disease Gene Cells Chromosomes, Human, Pair 21 Communication Cytoskeleton Development Disease Down Syndrome Drosophila genus Drosophila melanogaster Dynamin Electrophysiology (science)Endocytosis Event Foundations Functional disorder Future Genetic Goals Growth Health Homeostasis Human Genome Image Imaging Techniques In Vitro Intervention Knowledge Light Mediating Mental Retardation Microtubules Molecular Morphology Mutation National Institute of Neurological Disorders and Stroke Nervous system structure Neuromuscular Junction Neurons Parkinson Disease Phosphatidylinositols Phosphoric Monoester Hydrolases Phosphorylation Phosphorylation Site Phosphotransferases Physiological Physiology Play Protein Isoforms Protein Kinase Proteins Recycling Regulation Research Role Signal Transduction Specificity Structure Synapses Synaptic Transmission Synaptic Vesicles Techniques Testing Therapeutic Tyrosine base dosage genetic analysis in vivo insight locomotor deficit microtubule-associated protein 1B nervous system disorder neurotransmission new therapeutic target polymerization research study small hairpin RNA spatiotemporal synaptic function synaptojanin therapeutic development transmission process

项目摘要

DESCRIPTION (provided by applicant): Regulation of synaptic protein phosphorylation by kinases plays a critical role in synaptic development and synaptic transmission. Yet, despite the identification of over 500 protein kinases in the human genome, our current knowledge of the kinases located in the synapse and mechanisms underlying their regulation of synaptic structure and neurotransmission in vivo are quite limited. The goal of this project is to elucidate the role f the evolutionarily conserved DYRK1A/MNB kinase in regulating synaptic structure and function, using Drosophila as a model system. DYRK1A/MNB is located in the Down syndrome critical region on chromosome 21, upregulated in Down syndrome, and a strong candidate gene for mental retardation and locomotor deficits in Down syndrome. Understanding DYRK1A/MNB function will thus shed light on fundamental mechanisms underlying neuronal function in health and disease. Our preliminary results show that DYRK1A/MNB is enriched in the neuromuscular junction, and DYRK1A/MNB hypomorphic mutations have profound effects on synaptic morphology and endocytosis. We found that DYRK1A/MNB phosphorylates and affects the activity of synaptojanin, a phosphoinositol phosphatase important for endocytosis. This has led to our central hypothesis that DYRK1A/MNB plays a critical role in regulating synaptic structure and synaptic vesicle recycling. In this proposal, we will take an integrated approach combining genetics, biochemical, and cell biological and electrophysiological analyses to address the following questions: 1) what are the effects of DYRK1A/MNB dosage imbalance on synaptic morphology and function? 2) What is the spatiotemporal requirement of DYRK1A/MNB in regulating synaptic morphology and function? 3) Does DYRK1A/mnb regulate synaptic transmission through phosphorylation of synaptojanin? 4) What are mechanisms underlying DYRK1A/MNB induced changes in synaptic growth? Accomplishing these goals will lay an important foundation for future studies identifying new protein targets and signaling mechanisms that affect synaptic function. As defective synaptic transmission is associated with a number of neurological disorders and DYRK1A is implicated in Down syndrome, information obtained from this study will help to understand the molecular basis of synaptic dysfunction in these diseases and help to contribute to therapeutic development in the future.

描述（由申请人提供）：激酶对突触蛋白磷酸化的调节在突触发育和突触传递中起着关键作用。然而，尽管在人类基因组中鉴定了超过 500 种蛋白激酶，但我们目前对位于突触中的激酶及其调节体内突触结构和神经传递的机制的了解相当有限。该项目的目标是使用果蝇作为模型系统，阐明进化上保守的 DYRK1A/MNB 激酶在调节突触结构和功能中的作用。 DYRK1A/MNB位于21号染色体上的唐氏综合症关键区域，在唐氏综合症中表达上调，是唐氏综合症智力低下和运动缺陷的强候选基因。因此，了解 DYRK1A/MNB 功能将有助于揭示健康和疾病中神经元功能的基本机制。我们的初步结果表明，DYRK1A/MNB 在神经肌肉接头中富集，DYRK1A/MNB 亚形突变对突触形态和内吞作用具有深远影响。我们发现 DYRK1A/MNB 磷酸化并影响突触蛋白（一种对内吞作用重要的磷酸肌醇磷酸酶）的活性。这导致了我们的中心假设：DYRK1A/MNB 在调节突触结构和突触小泡回收中发挥着关键作用。在本提案中，我们将采取结合遗传学、生化、细胞生物学和电生理学分析的综合方法来解决以下问题：1）DYRK1A/MNB剂量不平衡对突触形态和功能有何影响？ 2）DYRK1A/MNB调节突触形态和功能的时空要求是什么？ 3) DYRK1A/mnb 是否通过 synaptojanin 磷酸化来调节突触传递？ 4) DYRK1A/MNB 诱导突触生长变化的机制是什么？实现这些目标将为未来研究确定影响突触功能的新蛋白质靶点和信号机制奠定重要基础。由于突触传递缺陷与许多神经系统疾病有关，而 DYRK1A 与唐氏综合症有关，因此从这项研究中获得的信息将有助于了解这些疾病中突触功能障碍的分子基础，并有助于为未来的治疗开发做出贡献。