Measuring the effect of environmental stress on checkpoint, genome instability and survival

测量环境压力对检查点、基因组不稳定性和生存的影响

• 批准号: RGPIN-2015-04405
• 负责人: Sabatinos, Sarah
• 金额: $ 2.33万
• 依托单位: Ryerson University
• 依托单位国家: 加拿大
• 项目类别: Discovery Grants Program - Individual
• 财政年份: 2016
• 资助国家: 加拿大
• 起止时间: 2016-01-01 至 2017-12-31
• 项目状态: 已结题
• 来源: https://www.nserc-crsng.gc.ca/ase-oro/Details-Detailles_eng.asp?id=612947
• 关键词: Measuring; effect; environmental; stress; checkpoint

Cells have a remarkable ability to survive toxic stress. Different kinds of stress –harmful drugs, UV light, heavy metals like mercury– have different outcomes. My work examines DNA damaging drugs. DNA determines how we grow, change, and how our children develop. When DNA is damaged by a drug, the cell activates a pathway that STOPS its growth. By STOPPING growth, a cell can assess damage, repair it and then resume healthy division. These STOP pathways are called “checkpoints.” I am interested in how checkpoints work and why they fail. A faulty checkpoint causes massive problems including DNA rearrangements and death. Many cancers are a direct result of checkpoint failures. Our work uses yeast. It is fast growing, inexpensive, and shares all the critical components of mammalian checkpoint pathways. Analyzing how yeast survives DNA damage helps us understand how the same kind of damage affects all life. Cells in the real world face changes in temperature, nutrition, pH, etc. These environmental stresses activate specific stress pathways to promote cellular survival. Lab conditions allow us to examine checkpoints without stresses, giving an initial picture of how the checkpoint works. We can then introduce stresses alone, or in combination, to measure their effect. Our core research questions are: Does a change in environmental stress have an effect on DNA damage checkpoint? Do cells survive? I previously found that environmental stress changes a cell’s ability to survive DNA damage. This NSERC research project will determine how environmental changes affect cell survival and DNA mutation. We ask whether the mutated cells are different from the original, and what this means to the whole animal/plant. We expect to find new checkpoint factors that improve health after DNA damage. A team of junior scientists and university students at Ryerson University will perform these experiments and accomplish our goals. These highly trained Canadians graduate with the skills and knowledge to tackle important questions in research and industry. Our collaborators at Ryerson, and internationally, will include ecologists, biologists and computer scientists. We will examine how entire organisms are affected in ageing and disease. Our preliminary evidence shows that cells change DNA damage checkpoints under stress. We do not know how it happens or the consequences. Our work testing multiple variables in yeast to predict consequences in other organisms is a powerful tool to understand how cells behave in the real world. We look to encourage discussion between academic, government, and private sectors. Canada’s leadership role in ecology, preservation and agriculture ensures that our work will impact research on changing environmental times.

细胞具有在毒性压力下存活的非凡能力。不同种类的压力--有害药物、紫外线、汞等重金属--会产生不同的结果。我的工作是研究破坏DNA的药物。DNA决定了我们如何成长，如何改变，以及我们的孩子如何发展。当DNA被药物破坏时，细胞会激活一条阻止其生长的途径。通过停止生长，细胞可以评估损伤，修复它，然后恢复健康的分裂。这些STOP路径被称为“检查点”。我对检查点是如何工作的以及它们为什么会失败很感兴趣。检查站故障会导致严重问题，包括DNA重排和死亡。许多癌症是检查点失败的直接结果。 我们的工作使用酵母。它生长迅速，价格低廉，并且共享哺乳动物检查点途径的所有关键组件。分析酵母如何在DNA损伤中幸存下来，有助于我们了解同样的损伤如何影响所有生命。 真实的世界中的细胞面临着温度、营养、pH值等的变化，这些环境压力会激活特定的压力通路，促进细胞存活。实验室条件允许我们在没有压力的情况下检查检查点，从而初步了解检查点的工作原理。然后，我们可以单独或组合引入应力，以测量它们的效果。我们的核心研究问题是：环境压力的变化对DNA损伤检查点有影响吗？细胞能存活吗？ 我以前发现，环境压力改变了细胞在DNA损伤中生存的能力。NSERC的研究项目将确定环境变化如何影响细胞存活和DNA突变。我们问突变的细胞是否与原始细胞不同，以及这对整个动物/植物意味着什么。我们希望找到新的检查点因素，改善DNA损伤后的健康状况。 瑞尔森大学的一个由年轻科学家和大学生组成的团队将执行这些实验并实现我们的目标。这些训练有素的加拿大人毕业时拥有解决研究和工业中重要问题的技能和知识。我们在瑞尔森和国际上的合作者将包括生态学家，生物学家和计算机科学家。我们将研究整个生物体在衰老和疾病中是如何受到影响的。 我们的初步证据表明，细胞在压力下会改变DNA损伤检查点。我们不知道它是如何发生的或后果。我们在酵母中测试多个变量以预测其他生物体中的结果的工作是了解细胞在真实的世界中如何行为的有力工具。我们希望鼓励学术界、政府和私营部门之间的讨论。加拿大在生态学、保护和农业方面的领导作用确保了我们的工作将对不断变化的环境时代的研究产生影响。