Heat Shock Proteins and Motoneuron Survival

热激蛋白和运动神经元存活

• 批准号: 7337321
• 负责人: Carol Milligan
• 金额: $ 31.46万
• 依托单位: WAKE FOREST UNIVERSITY HEALTH SCIENCES
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-12-15 至 2009-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7337321
• 关键词: Address; Affect; Amyotrophic Lateral Sclerosis; Astrocytes; Cell Death; Cells; Central Nervous System Diseases; Cessation of life; Condition; Culture Media; Data; Development; Disease; Disease Progression; Event; Extracellular Protein; Future; Glucose; Glutamates; Heat shock proteins; Heat-Shock Proteins 70; In Vitro; Injury; Knowledge; Laboratories; Link; Mediating; Metabolic; Methods; Molecular; Motor Neurons; Nature; Nerve Degeneration; Neuraxis; Neurodegenerative Disorders; Neuroglia; Neurons; Pathology; Phase; Physiological; Population; Process; Production; Protein Overexpression; Proteins; Purpose; Role; Role playing therapy; Source; Spinal; Spinal Cord; Starvation; Stimulus; Stress; Testing; Tissues; Toxic effect; Work; base; excitotoxicity; extracellular; in vivo; neuron loss; neuronal survival; neuroprotection; prevent; research study; response; uptake

DESCRIPTION (provided by applicant): In diseases of the Central Nervous System, the culmination of ineffective responses to stressful stimuli appear to trigger neurodegeneration. The specific reason why selective neuronal populations die in these disorders is unknown. Stressful stimuli can include, excessive changes in metabolic activity, excitotoxicity, toxic insults, or, similar to developmental cell death, loss of or inadequate trophic support. Many of these factors have been hypothesized to contribute to motoneuron death in amyotrophic lateral sclerosis (ALS), a disease characterized by motoneuron injury and death. Furthermore, there also appears to be altered or ineffective responses to stressful stimuli by the glial cells in affected tissue, implying a decline in glial function. In this proposal, we plan to examine the role of glia in neuroprotection following stress. This potentially critical neuronal-glial interaction involves production and secretion of heat shock proteins (Hsps) by glia, and utilization of these exogenous proteins by neurons. Our preliminary data indicate that motoneurons deprived of trophic factors show no detectable change in endogenous heat shock proteins as compared to healthy spinal motoneurons. Interestingly, the addition of exogenous heat shock proteins to the culture medium is extremely effective at promoting motoneuron survival in the absence of trophic support. There are two central hypotheses of this proposal. The first is that extracellular heat shock proteins promote motoneuron survival following stressful stimuli in vivo. The second hypothesis is that glial cells secrete these proteins. The purpose of this proposal is to test this hypothesis by examining neurons and glia in culture under stress conditions, and determining the role of heat shock proteins in neuronal survival. The first Aim of this proposal will serve to first gather appropriate baseline data for Hsp expression in spinal motoneurons subjected to stressful stimuli in culture. The second Aim will address the role played by Hsps from an extracellular source in neuroprotection following stress. The third Aim will establish the connection in vitro between Hsps secreted by astrocytes and neuronal protection from stressful stimuli. Taken together, these experiments will form a strong basis both for future experiments exploring the fundamental nature of the interactions of neurons and glia, and on ways to exploit that knowledge for the treatment of neurodegenerative diseases.

描述（由申请人提供）：在中枢神经系统疾病中，对压力刺激的无效反应的顶点似乎引发神经变性。选择性神经元群体在这些疾病中死亡的具体原因尚不清楚。应激刺激可以包括代谢活性的过度变化、兴奋性毒性、毒性损伤，或者类似于发育性细胞死亡、营养支持的丧失或不足。这些因素中的许多已被假设为有助于肌萎缩侧索硬化症（ALS），一种以运动神经元损伤和死亡为特征的疾病中的运动神经元死亡。此外，似乎也有改变或无效的反应，受影响的组织中的神经胶质细胞的应激刺激，这意味着神经胶质功能的下降。在这个提议中，我们计划研究神经胶质细胞在应激后的神经保护中的作用。这种潜在的关键神经元-胶质细胞相互作用涉及胶质细胞产生和分泌热休克蛋白（Hsps），以及神经元对这些外源蛋白的利用。 我们的初步数据表明，运动神经元剥夺营养因子显示没有检测到的变化，内源性热休克蛋白相比，健康的脊髓运动神经元。有趣的是，在缺乏营养支持的情况下，向培养基中加入外源性热休克蛋白对促进运动神经元存活非常有效。这一提议有两个核心假设。第一个是细胞外热休克蛋白促进运动神经元在体内应激刺激后的存活。第二个假设是神经胶质细胞分泌这些蛋白质。本提案的目的是通过检查应激条件下培养的神经元和神经胶质细胞来验证这一假设，并确定热休克蛋白在神经元存活中的作用。 本建议的第一个目的将首先收集适当的基线数据，脊髓运动神经元受到应激刺激的文化中的热休克蛋白表达。第二个目标将解决的作用，从细胞外来源的热休克蛋白在神经保护应激。第三个目标是在体外建立星形胶质细胞分泌的热休克蛋白和神经元保护应激刺激之间的联系。总之，这些实验将为未来探索神经元和神经胶质相互作用的基本性质的实验以及利用这些知识治疗神经退行性疾病的方法奠定坚实的基础。