Heat shock proteins in the nervous system

在应激刺激下，细胞激活高度保守的“热休克反应”，其中诱导一组热休克蛋白（Hsps）。这些热休克蛋白参与修复和保护机制，使细胞能够在通常会杀死它们的温度冲击中存活下来。我们已经证明，这种反应是生理相关的热休克蛋白是迅速诱导神经系统在发热样的压力或组织损伤。虽然这种反应的分子生物学已经研究了很多年，但在Hsps在功能水平上保护神经细胞的机制方面几乎没有进展。本实验室在突触水平研究热休克蛋白的神经保护作用。研究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，在压力期间需要保持其功能，以防止通信中断。这项工作表明，先前的热休克，足以诱导热休克蛋白，保护神经系统的神经传递水平和热休克蛋白过表达增强突触保护的水平。我们的假设是，压力扰动突触蛋白和热休克蛋白结合到这些目标，以促进构象校正。热休克蛋白作为“蛋白质修复剂”，为易聚集蛋白质提供了一道防线。该研究计划的目标是：i）鉴定Hsps的突触结合配偶体，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的扰动的“薄弱环节”，但可以通过操纵应激反应进行修复和保护，（二）采用先进的“活-细胞成像来研究组织培养系统和完整动物中Hsps的表达及其与突触的关联。这项工作将推进我们对Hsps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购买的一系列新技术中受益匪浅，这些新技术是由CFI/ORF基础设施奖励580万美元。NSERC发现赠款的支持促进了为2009年基础设施奖提供杠杆作用的方案基础。

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.