Ubiquitin proteasome system regulation of synaptic function

申请人描述(由申请人提供)：申请人是一名内科科学家，已完成神经学住院医师和临床癫痫研究员学位，最近被任命为范德比尔特大学神经病学系终身教职助理教授。申请者将利用导师职业发展奖(K08)提供的五年支持，成为一名独立的研究员，作为突触生理学家工作，目标是了解癫痫发生和神经退化的分子机制。本研究以果蝇神经肌肉接头(NMJ)和培养的海马神经元为突触模型系统，重点了解泛素蛋白酶体系统(UPS)在调节谷氨酸能突触传递中的作用。小蛋白泛素的共价加成针对蛋白酶体在细胞内的运输和降解。最近，UPS已被证明在突触局部发挥作用，并调节突触的可塑性，但关于特定泛素连接酶、蛋白质靶点和调节发生的时间尺度的机制细节才刚刚开始解决。来自果蝇NMJ的初步数据表明，UPS调节关键的突触后密度组织蛋白的丰度，盘大，还调节对维持内稳态突触可塑性重要的逆行信号通路。了解UPS对这些基本突触通路的调节机制可能对理解学习和记忆过程中突触强度的生理变化以及癫痫和神经退行性疾病中发生的病理变化具有广泛的意义。拟议的研究将在史蒂文森神经生物学教授肯德尔·布罗迪博士和范德比尔特神经科主任罗伯特·麦克唐纳博士的指导下进行，后者在培训研究癫痫基本机制的内科科学家方面有着杰出的记录。了解癫痫和神经退行性疾病中发生的长期突触变化的机制是开发这些疾病的新的和更好的治疗方法的基础。鉴于基因组中编码的大量UPS调节蛋白，识别特定的突触UPS通路为开发有针对性的干预措施预防和治疗这些疾病提供了希望。

DESCRIPTION (provided by applicant): The applicant is a physician scientist who has completed a neurology residency and a clinical epilepsy fellowship and is a recently appointed tenure-track Assistant Professor in the Vanderbilt University Neurology Department. The five year support from a Mentored Career Development Award (K08) would be used by the applicant to become established as an independent investigator working as a synaptic physiologist with the goal of understanding molecular mechanisms of epileptogenesis and neurodegeneration. This proposal focuses on understanding the role of the ubiquitin proteasome system (UPS) in regulating glutamatergic synaptic transmission, using the Drosophila neuromuscular junction (NMJ) and cultured hippocampal neurons as model synaptic systems. The covalent addition of the small protein, ubiquitin, targets proteins for intracellular trafficking and degradation by the proteasome. Recently, the UPS has been demonstrated to function locally at the synapse and regulate synaptic plasticity, but the mechanistic details about the specific ubiquitin ligases, protein targets, and the time scale over which the regulation occurs have just begun to be addressed. Preliminary data from the Drosophila NMJ suggests that the UPS regulates the abundance of the key postsynaptic density organizing protein, discs large, and also regulates a retrograde signaling pathway important for maintaining homeostatic synaptic plasticity. Understanding the mechanisms of UPS regulation of these fundamental synaptic pathways will likely have widespread implications for understanding the physiological changes in synaptic strength that occur during learning and memory as well as pathological changes that occur in epilepsy and neurodegenerative diseases. The proposed research will be performed under the guidance of Dr. Kendal Broadie, Stevenson Professor of Neurobiology, and Dr. Robert Macdonald, Chair of the Vanderbilt Neurology Department, who has a distinguished record of training physician scientists investigating basic mechanisms of epilepsy. Understanding the mechanisms of long-term synaptic changes that occur in epilepsy and neurodegenerative diseases is fundamental to developing new and better treatments for these diseases. Given the large complement of UPS regulatory proteins encoded in the genome, identifying specific synaptic UPS pathways offers the hope of developing targeted interventions for prevention and treatment of these diseases.