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

我的目标是了解在各种条件下控制有机体整个生命过程的健康过程的机制。动态平衡是指细胞、器官或有机体在一系列外部因素下产生并维持内部过程平衡的能力：我们使用创新的方法在常见的果蝇-黑腹果蝇身上探索这一点。 在开始我的团队之前，我证明了苍蝇体内中央亚细胞蛋白Akt1的丢失导致了广泛的细胞死亡。这是我的起点，并导致了对Akt1激酶和一种“主控制蛋白”--FOXO转录因子的探索。我的小组是许多小组中第一个报道果蝇体内FOXO的小组，我们研究了FOXO活动对饥饿的影响。最近，我们发现一些Akt1缺陷果蝇对FOXO引起的氨基酸饥饿有更强的耐受能力。这些突变体在发育过程中经历生长补偿。我们将继续探索生物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(小脑)在生长过程中影响FOXO活性并随着时间的推移调节退化的能力。有趣的是，迷你大脑是唐氏综合症候选基因的果蝇版本。第三，我们启动了蛋白质修饰因子阿托金与FOXO之间关系的研究。在脊椎动物中，阿托品可以在肌肉退化过程中发挥作用，并与FOXO因子有复杂的关系。阿托品不仅可以促进蛋白质的分解，而且用阿托品修饰FOXO可以提高活性。我们正在评估阿托金蛋白家族在细胞和生物生存中的作用。最后，我们已经开始研究FOXO和SPARGELL以及Parkin-PINK1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，包括在健康细胞和生物体中维持线粒体平衡。我们的研究目标是全面了解在各种压力条件下存活的机制，包括衰老对个体的“自然”影响。FOXO的精确控制可能会导致体内平衡水平的提高，即从各种压力的挑战中生存下来的能力，或许还会从中受益。总体而言，拟议的研究计划有望以一种变革性的方式帮助我们了解动态平衡的基本生物学机制，并在开发适用于广泛生物系统的创新概念方面有所应用。最后，在培训方面，这项研究计划的实施将有助于培训大量分子细胞生物学和遗传学的本科生和研究生，从而促进加拿大人在学术和应用科学方面的科学知识。

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.