Heat shock proteins in the nervous system

神经系统中的热休克蛋白

• 批准号: 6721-2010
• 负责人: Brown, Ian
• 金额: $ 5.68万
• 依托单位: University of Toronto
• 依托单位国家: 加拿大
• 项目类别: Discovery Grants Program - Individual
• 财政年份: 2010
• 资助国家: 加拿大
• 起止时间: 2010-01-01 至 2011-12-31
• 项目状态: 已结题
• 来源: https://www.nserc-crsng.gc.ca/ase-oro/Details-Detailles_eng.asp?id=450020
• 关键词: Heat; shock; proteins; nervous; system

In response to stressful stimuli, cells activate a highly conserved 'heat shock response' in which a set heat shock proteins (Hsps) are induced. These Hsps are involved in repair and protective mechanisms that permit cells to survive temperature shocks that would normally kill them. We have demonstrated that this response is physiologically relevant as Hsps are rapidly induced in the nervous system in response to fever-like stress or tissue injury. Although the molecular biology of this response has been investigated for many years, little progress has been made on the mechanisms by which Hsps protect neural cells at the functional level. Our laboratory studies neuroprotective effects of Hsps at the level of the synapse. The rationale for looking at synaptic function is that synapses are critical points of information transfer in the nervous system and their functionality needs to be preserved during periods of stress to prevent communication breakdown. This work demonstrates that prior heat shock, sufficient to induce Hsps, protects the nervous system at the level of neurotransmission and that Hsp overexpression enhances the level of synaptic protection. Our hypothesis is that stress perturbs synaptic proteins and that Hsps bind to these targets to facilitate conformational correction. Hsps serve as 'protein repair agents' that provide a line of defense against aggregation-prone proteins. The objectives of the research plan are- i) identify the synaptic binding partners of Hsps to characterize key proteins in the neurotransmission cascade that are 'weak links' susceptible to stress-induced perturbation yet amenable to repair and protection by manipulation of the stress response, ii) employ advanced 'live-cell imaging' to investigate the expression of Hsps and their association with synapses in tissue culture systems and in the intact animal. The work will advance our knowledge of how Hsps protect the nervous system at a functional level. Trainees participating in this program will greatly benefit from the array of new technology purchased with a major CFI/ORF infrastructure award of $5.8 million. Support from NSERC Discovery Grants fostered the programmatic foundation that provided the leverage for the 2009 infrastructure award.

在应激刺激下，细胞会激活一种高度保守的“热休克反应”，在这种反应中，一组热休克蛋白（Hsps）被诱导。这些热休克蛋白参与修复和保护机制，使细胞在通常会杀死它们的温度冲击中存活下来。我们已经证明，这种反应在生理学上是相关的，因为热休克蛋白在神经系统中被迅速诱导，以应对类似发烧的应激或组织损伤。尽管这种反应的分子生物学研究已经进行了多年，但热休克蛋白在功能水平上保护神经细胞的机制却进展甚微。我们的实验室在突触水平上研究热休克蛋白的神经保护作用。观察突触功能的基本原理是，突触是神经系统中信息传递的关键点，在压力时期，它们的功能需要保持，以防止通信中断。本研究表明，先前的热休克足以诱导热休克蛋白，在神经传递水平上保护神经系统，热休克蛋白过表达增强了突触保护水平。我们的假设是，压力扰乱了突触蛋白，热休克蛋白与这些目标结合以促进构象纠正。热休克蛋白充当“蛋白质修复剂”，为易聚集的蛋白质提供一道防线。研究计划的目标是：1)确定热休克蛋白的突触结合伙伴，以表征神经传递级联中的关键蛋白，这些蛋白是易受应激诱导扰动的“薄弱环节”，但可以通过操纵应激反应来修复和保护；2)采用先进的“活细胞成像”来研究热休克蛋白的表达及其与组织培养系统和完整动物突触的关联。这项工作将推进我们对热休克蛋白如何在功能水平上保护神经系统的认识。参加该计划的学员将从CFI/ORF基础设施580万美元的重大奖励中购买的一系列新技术中受益匪浅。NSERC发现基金的支持促进了项目基础，为2009年基础设施奖提供了杠杆作用。