Heat shock proteins in the nervous system

作为对应激刺激的响应，细胞激活一种高度保守的‘热休克反应’，在其中诱导一系列热休克蛋白(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幸存下来。我们已经证明，这种反应是生理学上相关的，因为热休克蛋白在神经系统中快速诱导，对发烧样的压力或组织损伤做出反应。虽然这种反应的分子生物学已经被研究了很多年，但关于热休克蛋白在功能水平上保护神经细胞的机制研究进展很少。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。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，在应激期间需要保留它们的功能，以防止沟通中断。这项工作表明，先前的热休克足以诱导热休克，在神经传递水平上保护神经系统，热休克蛋白的过度表达提高了突触保护水平。我们的假设是，应激扰乱突触蛋白，热休克蛋白与这些靶点结合以促进构象校正。热休克蛋白是一种“蛋白质修复剂”，提供了一道防御容易聚集的蛋白质的防线。该研究计划的目标是-i)确定HSPs的突触结合伙伴，以表征神经传递级联中的关键蛋白质，这些蛋白质容易受到应激诱导的干扰，但可以通过操纵应激反应进行修复和保护；ii)利用先进的‘活细胞成像’来研究HSPs的表达及其与组织培养系统和完整动物中突触的关系。这项工作将促进我们对热休克蛋白如何在功能水平上保护神经系统的了解。参加该计划的学员将从CFI/ORF基础设施大奖580万美元购买的一系列新技术中受益匪浅。NSERC Discovery Grants的支持培育了为2009年基础设施奖提供筹码的计划基础。

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.