Synapse-to-nucleus signaling components in PSDs

PSD 中的突触到细胞核信号传导组件

• 批准号: 7057256
• 负责人: BRYEN A JORDAN
• 金额: $ 12.89万
• 依托单位: NEW YORK UNIVERSITY SCHOOL OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-04-25 至 2008-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7057256
• 关键词: biological signal transduction; cell cell interaction; cell nucleus; cerebellum; electrostimulus; gene mutation; hippocampus; immunocytochemistry; intracellular transport; laboratory rat; liquid chromatography mass spectrometry; nerve /myelin protein; neuron component; nuclear proteins; occipital lobe /cortex; protein localization; protein protein interaction; protein structure function; protein transport; proteomics; synapses; synaptogenesis; tissue /cell culture

The candidate, Dr. Bryen A. Jordan holds a Ph.D. degree from the Dept of Pharmacology at the NYU School of medicine. He is currently a research assistant professor at the Dept of Biochemistry at NYU School of Medicine. The career goals of the candidate are to obtain sufficient skills and knowledge during the award period to become an independent researcher at a medical or academic institution. The scientific goal of the proposal is to better understand the role of the postsynaptic density (PSD) in synaptic function. The proposed aims of the K01 will allow the candidate to master skills in mass spectrometry/proteomics, imaging analysis and electrophysiology which will greatly enhance the ability of the candidate to do independent research. The candidate will also gain important experimental and theoretical knowledge in the fundamentals of neurobiology to pursue a career in neuroscience. Dr. Edward Ziff will advise and guide the candidate to become an independent scientist. Dr. Ziff has previously trained a number of highly successful researchers including Dr. Michael Greenberg and Dr. Thomas Kouzarides. Additionally, Dr. Moses Chao, Dr. Bernardo Rudy and Dr. Thomas Neubert wilf serve as co-mentors and provide general and specific guidance throughout the term of the proposal. NYU Medical Center and Dr. Edward Ziff provide a exemplary environment to conduct research for the candidate to obtain further training. A specialized cellular structure known as the PSD lies in direct apposition to active zones in most excitatory synapses. Assembled at the PSD are proteins that mediate and transmit presynaptic input, such as ionotropic glutamate receptors, scaffolding proteins and kinases and phosphatases. However recent proteomic studies demonstrate that the PSD is far more complex than previously thought. The long-term objective of this grant is to explore the molecular composition of PSDs and identify novel components that regulate synaptic function. Preliminary work has identified 452 proteins from PSDs purified from whole brains. This work has uncovered a novel set of proteins with nuclear localization signals that are highly enriched in PSDs. One of these can shuttle rapidly into the nucleus in response to NMDA receptor stimulation. Specific aims are to 1)- Identify region-specific differences in PSD composition by liquid chromatography and mass spectrometry of purified PSDs from hippocampus, striatum and cerebellum. 2)- To characterize the nuclear translocation of our identified targets in dissociated neurons and in slice cultures by chemical and electrical stimulation 3)- to explore the mechanisms and components of nuclear translocation in response to synaptic stimulation and to assess the function of these proteins in the nucleus. This project will provide an in-depth look at the complexity of the PSD and identify region specific factors. Furthermore, this project will analyze novel proteins that can shuttle to the nucleus in response to synaptic stimulation. This work will increase our understanding of synaptic function which is critical in learning and memory.

候选人布赖恩·A·乔丹博士拥有纽约大学医学院药理学系的博士学位。他目前是纽约大学医学院生物化学系的研究助理教授。候选人的职业目标是在获奖期间获得足够的技能和知识，成为一名医学或学术机构的独立研究员。该提案的科学目标是更好地理解 突触后密度(PSD)在突触功能中的作用K01的拟议目标将使候选人掌握质谱学/蛋白质组学、成像分析和电生理学方面的技能，这将极大地提高候选人进行独立研究的能力。应聘者还将获得神经生物学基础方面的重要实验和理论知识，以在神经科学领域发展。爱德华·齐夫博士将建议和指导候选人成为一名独立科学家。齐夫博士之前培养过许多非常成功的研究人员，包括迈克尔·格林伯格博士和托马斯·库扎里德斯博士。此外，摩西·赵博士、贝尔纳多·鲁迪博士和托马斯·纽伯特·威尔夫博士担任共同导师，在整个提案期间提供一般和具体的指导。纽约大学医学中心和Edward Ziff博士为候选人提供了一个进行研究以获得进一步培训的模范环境。 在大多数兴奋性突触中，一种被称为PSD的特殊细胞结构直接与活动区相对应。在PSD处组装的是介导和传递突触前输入的蛋白质，如离子型谷氨酸受体、支架蛋白、激酶和磷酸酶。然而，最近的蛋白质组学研究表明，PSD比之前认为的要复杂得多。这项拨款的长期目标是探索PSD的分子组成，并识别调节突触功能的新成分。初步工作已经从从整个大脑中提纯的PSD中鉴定出452种蛋白质。这项工作发现了一组新的具有核定位信号的蛋白质，这些蛋白质在PSD中高度浓缩。其中一种可以在NMDA受体刺激下迅速穿梭到核内。具体目的是：1)--用高效液相色谱和质谱仪鉴定纯化后的海马区、纹状体和小脑中PSD组成的区域差异。2)-在化学和电刺激下在分离的神经元和切片培养中表征我们识别的靶点的核移位3)-探索响应突触刺激的核移位的机制和成分，并评估这些蛋白质在核中的功能。该项目将深入研究私营部门司的复杂性，并确定区域具体因素。此外，该项目将分析能够穿梭到细胞核以响应突触刺激的新蛋白质。这项工作将增加我们对突触功能的理解，突触功能在学习和记忆中至关重要。