Synapse-to-nucleus signaling components in PSDs

候选人布莱恩·A博士乔丹拥有博士学位。纽约大学医学院药理学系学位。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，成为医疗或学术机构的独立研究人员。该提案的科学目标是更好地了解 突触后致密物（PSD）在突触功能中的作用。K 01的拟议目标将使候选人掌握质谱/蛋白质组学，成像分析和电生理学方面的技能，这将大大提高候选人进行独立研究的能力。候选人还将获得神经生物学基础的重要实验和理论知识，以从事神经科学的职业生涯。爱德华·齐夫博士将建议和指导候选人成为一名独立的科学家。Ziff博士以前曾培训过许多非常成功的研究人员，包括Michael Greenberg博士和托马斯Kouzarides博士。此外，Moses Chao博士、Bernardo Rudy博士和托马斯Neubert wilf博士担任共同导师，并在整个提案期间提供一般和具体指导。纽约大学医学中心和爱德华·齐夫博士提供了一个示范性的环境，进行研究的候选人获得进一步的培训。 在大多数兴奋性突触中，一种被称为PSD的特殊细胞结构与活性区直接并列。在PSD处组装的是介导和传递突触前输入的蛋白质，例如离子型谷氨酸受体、支架蛋白和激酶以及磷酸酶。然而，最近的蛋白质组学研究表明，PSD比以前认为的要复杂得多。这项资助的长期目标是探索PSD的分子组成，并确定调节突触功能的新成分。初步工作已经从从全脑纯化的PSD中鉴定出452种蛋白质。这项工作发现了一组具有核定位信号的新型蛋白质，这些蛋白质高度富集于PSD中。其中之一可以响应于NMDA受体刺激而快速穿梭进入细胞核。具体目的是1）-通过液相色谱和质谱法鉴定来自海马、纹状体和小脑的纯化PSD的PSD组成的区域特异性差异。2)-通过化学和电刺激，在分离的神经元和切片培养物中表征我们鉴定的靶点的核转位3）-探索响应于突触刺激的核转位的机制和组分，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，该项目还将分析能够响应突触刺激而穿梭到细胞核的新型蛋白质。这项工作将增加我们对突触功能的理解，这在学习和记忆中至关重要。

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.