Biological Amyloid Aggregation as a Post-Translational Regulatory Pathway

生物淀粉样蛋白聚集作为翻译后调节途径

• 批准号: RGPIN-2017-04998
• 负责人: Audas, Timothy
• 金额: $ 2.4万
• 依托单位: Simon Fraser University
• 依托单位国家: 加拿大
• 项目类别: Discovery Grants Program - Individual
• 财政年份: 2017
• 资助国家: 加拿大
• 起止时间: 2017-01-01 至 2018-12-31
• 项目状态: 已结题
• 来源: https://www.nserc-crsng.gc.ca/ase-oro/Details-Detailles_eng.asp?id=629948
• 关键词: Biological; Amyloid; Aggregation; Post; Translational

Under normal environmental situations, biological molecules perform the basic tasks necessary to maintain human cells. However, exposure to harsh and stressful conditions, such as high temperature, acidity, and UV radiation, can disrupt the function of these biological molecules and damage cellular components. This requires the activation of repair pathways, which attempt to compensate for the harmful effects of an environmental stressor. The success or failure of these cellular countermeasures ultimately determines whether a cell and/or organism survives exposure. Recently, we identified a new biological pathway that enhances survival during periods of cellular stress. Through the reversible formation of dense, insoluble, and fibrous protein clumps (termed amyloids) a cell can rapidly shut down non-essential functions, to focus on repairing the damaged components. What is particularly striking about these biological amyloids is their close resemblance to the toxic plaques found in patients with neurological disorders (such as Alzheimer’s, Parkinson’s and mad cow diseases). This suggests that this natural pathway may be one of the first examples of a biological counterpart to the disease-associated plaques. The goal of this research program is to enhance our understanding of this newly discovered biological phenomenon. How natural amyloid aggregates form and disassemble, what environmental stressors activate this process, and why it is protective to the cell are long-term questions that we hope to address. Specifically in the next 5 years, we will focus our efforts on the following three aims.

在正常的环境条件下，生物分子执行维持人体细胞所必需的基本任务。然而，暴露于苛刻和压力条件下，如高温，酸性和紫外线辐射，会破坏这些生物分子的功能并损害细胞成分。这需要激活修复途径，试图补偿环境压力的有害影响。这些细胞对抗措施的成功或失败最终决定了细胞和/或生物体是否能在暴露后存活。最近，我们发现了一种新的生物学途径，可以提高细胞应激期间的存活率。通过可逆地形成致密的、不溶性的和纤维状的蛋白质团块（称为淀粉样蛋白），细胞可以迅速关闭非必需的功能，专注于修复受损的成分。这些生物淀粉样蛋白特别引人注目的是，它们与神经系统疾病患者（如阿尔茨海默氏症，帕金森氏症和疯牛病）中发现的有毒斑块非常相似。这表明，这种天然途径可能是疾病相关斑块的生物学对应物的第一个例子之一。这项研究计划的目的是加强我们对这一新发现的生物现象的理解。天然淀粉样蛋白聚集体是如何形成和分解的，什么样的环境压力激活了这一过程，以及为什么它对细胞有保护作用，这些都是我们希望解决的长期问题。具体来说，在未来五年，我们将集中力量实现以下三个目标。