Molecular regulation of Insulin signaling in nutrient stress response in Drosophila.

果蝇营养应激反应中胰岛素信号的分子调节。

• 批准号: 2115690
• 负责人: Jianzhong Yu
• 金额: $ 67.34万
• 依托单位: University of Connecticut
• 依托单位国家: 美国
• 项目类别: Continuing Grant
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-10-01 至 2024-06-30
• 项目状态: 已结题
• 来源: https://www.nsf.gov/awardsearch/showAward?AWD_ID=2115690&HistoricalAwards=false
• 关键词: Molecular; regulation; Insulin; signaling; nutrient

Organ growth is one of the most fundamental biological processes during metazoan development and is tightly regulated by multiple mechanisms. A key factor that determines adult size in the fruit fly Drosophila is nutrient availability during the larval growth phase. Reduced nutrition decreases larval growth, and eventually the final size of an adult fly. This research project aims to understand how animals adjust their growth rate in response to nutrient availability. It will provide new insights into the molecular mechanisms underlying nutrient stress response during animal development. In addition, this project will provide a platform for broadening participation of students under-represented in STEM fields at multiple levels. The results of this research will be integrated into workshops, seminars, and courses for undergraduate and graduate students, which will inspire prospective students to pursue education and careers in biological research.The insulin signaling pathway plays critical roles in controlling cell growth, proliferation and metabolism in response to intracellular and extracellular stimuli. In Drosophila, PTEN mutant cells showed a strong growth advantage under nutrient starvation conditions. Strikingly, while the increase of PTEN mutant eye size was mainly caused by enlarged cell size under nutrient rich conditions, the overgrowth of the PTEN mutant eye under nutrient starvation conditions was largely due to massively increased cell number. How reduced nutrition primarily affects the proliferation potential of PTEN mutant cells remains unclear. Drosophila Headcase (Hdc) is a nutrient stress specific growth regulator that regulates cell cycle progression. Hdc genetically interacts with multiple insulin signaling pathway components. In addition, Hdc protein is phosphorylated by Akt, a key protein kinase of the insulin signaling pathway. The central hypothesis of this project is that Hdc functions as a novel downstream regulator of the insulin signaling pathway and mediates PTEN regulated nutrient stress response. This hypothesis will be tested by three specific aims: (1) define the upstream signal that links nutritional status to Hdc growth inhibition function, (2) investigate the molecular regulation of Hdc by Akt induced phosphorylation, and (3) determine the role of Hdc in PTEN mediated nutrient stress response. The proposed research is expected to reveal novel molecular architecture of the insulin signaling pathway in nutrient stress response. This project will provide a platform for broadening participation of students that are under-represented in STEM fields.This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.

器官生长是后生动物发育过程中最基本的生物过程之一，并受到多种机制的严格调控。决定果蝇成虫大小的一个关键因素是幼虫生长阶段的营养可用性。营养减少会降低幼虫的生长，并最终降低成年苍蝇的最终尺寸。该研究项目旨在了解动物如何根据营养供应情况调整生长速度。它将为动物发育过程中营养应激反应的分子机制提供新的见解。此外，该项目还将提供一个平台，扩大 STEM 领域中代表性不足的学生在多个层面的参与。这项研究的结果将被纳入本科生和研究生的讲习班、研讨会和课程中，这将激励未来的学生继续从事生物学研究的教育和职业。胰岛素信号通路在控制细胞生长、增殖和代谢中发挥着关键作用对细胞内和细胞外的刺激做出反应。在果蝇中，PTEN突变细胞在营养饥饿条件下表现出强大的生长优势。引人注目的是，虽然PTEN突变体眼睛尺寸的增加主要是由于营养丰富条件下细胞尺寸增大引起的，但PTEN突变体眼睛在营养匮乏条件下的过度生长主要是由于细胞数量大量增加所致。营养减少主要如何影响 PTEN 突变细胞的增殖潜力仍不清楚。果蝇头壳 (Hdc) 是一种营养应激特异性生长调节剂，可调节细胞周期进程。 Hdc 在基因上与多种胰岛素信号通路成分相互作用。此外，Hdc 蛋白被 Akt 磷酸化，Akt 是胰岛素信号通路的关键蛋白激酶。该项目的中心假设是 Hdc 作为胰岛素信号通路的新型下游调节剂发挥作用，并介导 PTEN 调节的营养应激反应。该假设将通过三个具体目标进行检验：(1) 定义将营养状况与 Hdc 生长抑制功能联系起来的上游信号，(2) 研究 Akt 诱导的磷酸化对 Hdc 的分子调节，以及 (3) 确定 Hdc 的作用PTEN 介导的营养应激反应。拟议的研究有望揭示营养应激反应中胰岛素信号通路的新颖分子结构。该项目将为扩大 STEM 领域代表性不足的学生的参与提供一个平台。该奖项反映了 NSF 的法定使命，并通过使用基金会的智力价值和更广泛的影响审查标准进行评估，被认为值得支持。