Mints: Adaptor Proteins Coupling APP of Alzheimer's Disease to the Synapse

Mints：将阿尔茨海默病 APP 与突触偶联的接头蛋白

• 批准号: 7278165
• 负责人: ANGELA HO
• 金额: $ 1.22万
• 依托单位: UT SOUTHWESTERN MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-09-01 至 2007-10-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7278165
• 关键词: Adaptor Signaling Protein; Adult; Age; Alzheimer' s Disease; Amyloid Proteins; Amyloid beta-Protein; Amyloid beta-Protein Precursor; Award; Behavior; Binding; Biochemical; Biochemistry; Biology; Biotinylation; Brain; Brain region; Breathing; Cell membrane; Chromosome Pairing; Cognitive; Communication; Complex; Coupling; Culture Techniques; Deposition; Development; Disease; Dyes; Electron Microscopy; Electrophysiology (science); Elements; Embryonic Nervous System; Event; Exons; Family; Family member; Feeding behaviors; Fiber; Foundations; Genus Mentha; Goals; Hippocampus (Brain); Human; Individual; Kinetics; Knock-out; Knowledge; Laboratories; Learning; Maintenance; Membrane; Membrane Proteins; Memory; Molecular; Morphology; Mus; Mutant Strains Mice; Mutation; Names; Nerve; Neurodegenerative Disorders; Neurologic; Neuronal Plasticity; Neurons; Newborn Infant; Optics; PTB Domain; Parents; Pathogenesis; Pathologic Processes; Pathway interactions; Physiological; Physiology; Preparation; Principal Investigator; Production; Protein Isoforms; Proteins; Proteolysis; Pyramidal Cells; Regulation; Role; Slice; Staining method; Stains; Structure; Surface; Synapses; Synaptic Transmission; Synaptic Vesicles; Techniques; Time; Transgenes; Variant; age related; amyloid precursor protein processing; conditioned fear; density; in vivo; morris water maze; mutant; neurotransmission; post-doctoral training; postnatal; presenilin; presenilin-1; protein distribution; protein expression; synaptic function; tool

DESCRIPTION (provided by applicant): Brain function requires the proper networking and communication between neurons. Improper development and maintenance of neuronal function leads to neurological abnormalities. As such, mechanisms underlying physiological to pathological processes in the brain are not clear. Currently, the laboratory of Dr. Thomas C. S¿dhof has allowed me to expand my knowledge in basic events of synaptic transmission to clinically associated problems in Alzheimer's disease. We have identified an essential family of adaptor proteins named Mints that have been implicated in coupling synaptic functions such as targeting of proteins to nerve terminals, and neurotransmission, to the regulation of amyloid precursor protein (APP) processing relating to Alzheimer's disease. To ascertain Mints function directly, we have generated mice lacking individual Mint proteins (isoforms 1-3), or all possible combination of Mint family members. We can now directly study: (1) membrane protein targeting by surface biotinylation of cell membranes, and morphologically examine the expression and cellular distribution of proteins that Mints interact with; (2) functionally examine synaptic transmission by using hippocampal slice electrophysiological recordings, and optical recording techniques of cultured neurons to look at kinetics of synaptic vesicles. We will characterize the structural dynamic of synaptic junctions by electron microscopy, and E-PTA staining to quantify morphological parameter of synapses. To explore the significance of Mint and APP processing, we have generated mice deficient of Mints which carry a transgene that coexpresses mutant APP, and presenilin 1. We will study the pathogenic events leading to disease state by examining age-dependent APP proteolysis and amyloid beta deposition by combining morphological and biochemical techniques. These studies will not only clarify the function of Mints in targeting, and synaptic transmission, but will broaden our understanding in the biology of Mints and. APP in Alzheimer's disease. My long-term goal is to pursue my understanding of molecular mechanisms underlying neuronal plasticity, and neurodegenerative diseases integrating the tools and conceptual approaches that I have learned and gained over my past graduate and postdoctoral training. This award will allow me to have a transition period during which I can expand my knowledge and technical foundations to become an independent principal investigator.

描述（由申请人提供）： 大脑功能需要神经元之间的适当网络和通信。神经元功能发育和维持不当会导致神经系统异常。因此，大脑中生理到病理过程的潜在机制尚不清楚。目前，托马斯C. S dhof使我能够扩展我的知识，在突触传递的基本事件，以临床相关的问题，在阿尔茨海默氏症。我们已经确定了一个必要的家庭的衔接蛋白命名薄荷糖，已涉及耦合突触功能，如靶向蛋白质的神经末梢，神经传递，调节淀粉样前体蛋白（APP）的加工有关阿尔茨海默氏病。为了直接确定Mint的功能，我们已经产生了缺乏单个Mint蛋白（同种型1-3）或Mint家族成员的所有可能组合的小鼠。我们现在可以直接研究：（1）通过细胞膜的表面生物素化来靶向膜蛋白，并从形态学上检查Mint与之相互作用的蛋白质的表达和细胞分布;（2）通过使用海马切片电生理记录和培养神经元的光学记录技术来观察突触囊泡的动力学来功能性地检查突触传递。我们将通过电子显微镜和E-PTA染色来表征突触连接的结构动态，以量化突触的形态学参数。为了探索Mint和APP加工的意义，我们产生了Mint缺陷的小鼠，其携带共表达突变APP和早老素1的转基因。我们将结合形态学和生物化学技术，通过检查年龄依赖性APP蛋白水解和淀粉样β蛋白沉积来研究导致疾病状态的致病事件。这些研究不仅将阐明薄荷糖在靶向和突触传递中的功能，而且将拓宽我们对薄荷糖生物学的理解。APP在阿尔茨海默病中的作用我的长期目标是追求我对神经元可塑性和神经退行性疾病的分子机制的理解，整合我在过去的研究生和博士后培训中学到的工具和概念方法。这个奖项将使我有一个过渡期，在此期间，我可以扩大我的知识和技术基础，成为一个独立的首席研究员。