Signalling mechanisms integrating cell survival, organismal growth and stress-resistance in Drosophila

果蝇中整合细胞存活、有机体生长和抗应激的信号机制

• 批准号: RGPIN-2016-04828
• 负责人: Staveley, Brian
• 金额: $ 2.26万
• 依托单位: Memorial University of Newfoundland
• 依托单位国家: 加拿大
• 项目类别: Discovery Grants Program - Individual
• 财政年份: 2020
• 资助国家: 加拿大
• 起止时间: 2020-01-01 至 2021-12-31
• 项目状态: 已结题
• 来源: https://www.nserc-crsng.gc.ca/ase-oro/Details-Detailles_eng.asp?id=709107
• 关键词: Signalling; mechanisms; integrating; cell; survival

My goal is to understand the mechanisms that control healthy processes throughout the life of the organism under various conditions. Homeostasis is the ability of a cell, an organ or an organism to generate and maintain a balance of internal processes to function under a range of external factors: we use innovative approaches to explore this in Drosophila melanogaster, the common fruit fly. Prior to starting my group, I demonstrated that loss of a central sub-cellular protein, Akt1, in flies led to widespread cell death. This was my starting point and led to the exploration of the Akt1 kinase and a “master control protein” the foxo transcription factor. My group was the first, of many, to report on foxo in flies and we have examined the effects of foxo activities in response to starvation. Recently, we found that some Akt1 defective flies have an enhanced ability to endure amino-acid starvation due to foxo. These mutants undergo growth compensation during development. We will continue to explore organismal growth and survivability under stress. Secondly, we have evaluated the ability of another sub-cellular protein (minibrain) to influence foxo activity during growth and to regulate degeneration over time. Interestingly, minibrain is the Drosophila version of a Down Syndrome candidate gene. Thirdly, we have initiated the study of the relationship between a protein modification factor atrogin and foxo. In vertebrates, atrogin can act during muscle degeneration and has a complex relationship with the foxo factors. Not only can atrogin contribute to protein breakdown, modification of foxo by atrogin can increase activity. We are evaluating the atrogin protein family in cell and organismal survival. Finally, we have started to examine the relationship between foxo and spargel along with other members of the parkin-Pink1 pathway. Through the work described here, we will focus upon a number of processes including the maintenance of the mitochondrial balance in healthy cells and organisms. Our research goal to develop a full understanding of the mechanisms that lead to survivorship under various stress conditions, including the “natural” effects of ageing upon an individual. It is possible that the precise control of foxo may lead to an enhanced level of homeostasis, the ability to survive, and perhaps benefit, from the challenges of various stress. Overall, the proposed research program is expected to contribute in a transformative manner to our knowledge of the fundamental biological mechanisms of homeostasis and have applications in the development of innovative concepts applicable to a wide range of biological systems. Finally, in terms of training, implementation of this research program will help train a substantial number of undergraduate and graduate students in molecular cellular biology and genetics thus contributing to the scientific knowledge of Canadians in academics and applied sciences.

我的目标是了解在各种条件下控制有机体整个生命过程中健康过程的机制。稳态是细胞、器官或生物体在一系列外部因素下产生和维持内部过程平衡的能力：我们使用创新方法在果蝇（Drosophila melanogaster）中探索这一点。 在开始我的小组之前，我证明了果蝇中一种中心亚细胞蛋白Akt 1的丢失导致了广泛的细胞死亡。这是我的出发点，并导致了对Akt 1激酶和“主控蛋白”foxo转录因子的探索。 我的小组是第一个报告苍蝇体内foxo的小组，我们已经研究了饥饿对foxo活性的影响。最近，我们发现一些Akt 1缺陷的果蝇具有增强的耐受由于foxo引起的氨基酸饥饿的能力。这些突变体在发育过程中进行生长补偿。我们将继续探索有机体在压力下的生长和生存能力。其次，我们评估了另一种亚细胞蛋白（minibrain）在生长过程中影响foxo活性和随时间调节退化的能力。有趣的是，minibrain是唐氏综合症候选基因的果蝇版本。第三，我们开始了蛋白质修饰因子atrogin与foxo关系的研究。 在脊椎动物中，atrogin可在肌肉退化过程中起作用，并与foxo因子有着复杂的关系。atrogin不仅可以促进蛋白质分解，而且通过atrogin修饰foxo可以增加活性。我们正在评估atrogin蛋白家族在细胞和生物体存活中的作用。最后，我们已经开始研究foxo和spargel沿着与parkin-Pink 1通路的其他成员之间的关系。 通过这里描述的工作，我们将专注于一些过程，包括健康细胞和生物体中线粒体平衡的维持。 我们的研究目标是全面了解导致在各种压力条件下生存的机制，包括衰老对个体的“自然”影响。 对foxo的精确控制可能会导致体内平衡水平的提高，从而提高生存能力，并可能从各种压力的挑战中受益。 总的来说，拟议的研究计划预计将有助于以变革的方式，我们的知识的基本生物机制的稳态，并在开发适用于广泛的生物系统的创新概念的应用。最后，在培训方面，该研究方案的实施将有助于在分子细胞生物学和遗传学方面培训大量本科生和研究生，从而有助于加拿大人在学术和应用科学方面的科学知识。