The genetics of the Drosophila IIS pathway response to changing nutrition

描述（由申请人提供）：现代人群的饮食和活动水平发生了变化，导致代谢紊乱增加。众所周知，IIS通路影响生长、代谢和寿命的许多方面，但对该通路中持续变异的遗传基础知之甚少。该项目的目标是研究胰岛素/胰岛素样信号（IIS）通路中自然遗传变异的遗传基础。该项目将利用新开发的资源进行复杂性状的遗传分析，即果蝇合成种群资源（DSPR）。将在三种不同的营养条件下测量IIS途径中每个基因的基因表达水平，并绘制影响这些基因表达水平的QTL。该项目将确定IIS中自然遗传变异的来源，并确定遗传变异是否与编码途径中主要蛋白质的基因共定位。将在多种营养环境中鉴定影响基因表达的基因，从而可以确定在不同环境中是否有相同或不同的变体控制IIS途径。此外，该项目将解决是否相同的“主基因”控制IIS途径的几个组成部分。该项目还将使用系统生物学方法回答有关IIS途径组件之间相互作用的性质的广泛问题。利用DSPR，本项目将能够将影响IIS途径的QTL定位到1-2厘摩，估计这些QTL的效应和频率，并确定潜在的致病位点。IIS途径在黑腹果蝇和人类之间高度保守，因此，识别控制果蝇中IIS信号传导的基因可以直接识别药物干预的靶点，特别是在识别出“主基因”的情况下。最终，该项目将表征一个中央内分泌途径的遗传基础，这对我们理解新陈代谢和内部资源分配有直接影响。 公共卫生相关性：肥胖和2型糖尿病在现代人群中正以惊人的速度增加。该项目旨在确定一个中心代谢途径的遗传基础，即多种营养环境中的胰岛素/胰岛素样信号通路，以更好地了解代谢紊乱的遗传基础。

DESCRIPTION (provided by applicant): Modern human populations have experienced changes in diet and activity levels, leading to an increase in metabolic disorders. The IIS pathway is known to influence many aspects of growth, metabolism, and longevity but little is known about the genetic basis of standing variation in the pathway. The goal of this project is to examine the genetic basis of natural genetic variation in the insulin/insulin-like signaling (IIS) pathway. The project will utilize a newly developed resource for the genetic analysis of complex traits, the Drosophila Synthetic Population Resource (DSPR). Gene expression levels for every gene in the IIS pathway will be measured in three different nutritional conditions and QTL influencing these gene expression levels will be mapped. The project will identify the source of natural genetic variation in IIS and determine if genetic variants co-localize with the genes encoding major proteins in the pathway. Genes influencing gene expression will be identified in multiple nutritional environments, making it possible to determine if the same or different variants control the IIS pathway in different environments. In addition, the project will address whether the same "master genes" control several components of the IIS pathway. The project will also answer broad questions about the nature of the interactions between components of the IIS pathway using systems biology approaches. By using the DSPR, this project will be able to map QTL influencing the IIS pathway to 1-2 centiMorgans, estimate both the effect and frequency of those QTL and identify potentially causative sites. The IIS pathway is highly conserved between Drosophila melanogaster and humans and therefore, identifying the genes controlling IIS signaling in Drosophila may directly identify targets for pharmacological intervention, particularly if "master genes" are identified. Ultimately, this project will characteize the genetic basis of a central endocrine pathway that has direct implications for our understanding of metabolism and the internal allocation of resources. PUBLIC HEALTH RELEVANCE: Obesity and type 2 diabetes are increasing at alarming rates in modern human populations. This project aims to determine the genetic basis of a central metabolic pathway, the insulin/insulin-like signaling pathway in multiple nutritional environments to better understand the genetic basis of metabolic disorders.