Characterization and Contextualization of Modifier Genes Affecting ER Stress

内质网(ER)应激反应是多种人类疾病的基础-从糖尿病到 神经退行性变。内质网应激导致有利于生存或促进凋亡的结果取决于 压力的严重程度。鉴于内质网应激对人类疾病的影响，以及相反的可能 从其激活的结果来看，迫切需要创造能够针对内质网应激反应的治疗方法 在人类身上特地激活正确的结果。尽管它与健康相关且高度进化 保守的内质网应激反应仍然受制于自然遗传变异--影响 可以极大地改变其反应幅度的途径。修饰基因是很好的靶点 治疗，因为它们是主要的内质网应激途径的外围，通常服从于大量表达 没有太多次要影响的变化。Chow实验室已经对遗传修饰物进行了两次筛选， 影响内质网应激，现在已经有已知的&gt；100候选修饰基因。这项建议的第一个目的是 使用这些完整的筛查来快速表征与人类健康最相关的顶级候选基因 它们在内质网应激反应中的作用和机制。这一特征利用了果蝇的基因 工具，内质网应激诱导转基因模型和药物，以及内质网应激途径的荧光标记物。 了解每个基因的功能对于了解它是否是合适的治疗靶点至关重要。第二 这项提案的目的是与哈佛医学院合作，进行全基因组CRISPR 筛选额外的内质网应激候选基因-不同于以前的筛选，专门为寻找基因而设计 这赋予了内质网抵抗压力的能力。目标2还涉及创建所有已知的基因相互作用网络 候选基因，还将包括基因表达和本体分析。这个基因网络将被用来 作为一种工具来框定未来的研究，并帮助寻找治疗靶向的最佳途径，以便 目标是更理想的或最小的总路径。总之，影响基因的修饰基因的特征 目标1中的内质网压力，以及目标2中它们在基因相互作用网络中的语境化，将大大 帮助未来针对人类疾病的内质网应激反应的治疗方法的创造。考虑到庞大的基因组 作为这项提议的组成部分，犹他大学人类遗传学系是一个完美的环境 完成这次训练。这里有许多遗传学方面的专家，包括许多从事 果蝇，这为博士后培养了一个强有力的培训环境。赞助商克莱门特·周博士一直在努力 研究修饰基因多年，他最初发现了大量与内质网应激相关的修饰候选基因 在这里工作。共同发起人卡尔·图梅尔博士是世界知名的果蝇遗传学领导者 并拥有培养成功博士后的丰富历史。本培训计划旨在让受训人员 产生高质量的以人类健康为导向的研究，变得对果蝇和 并获得独立研究事业所需的经验。

The endoplasmic reticulum (ER) stress response underlies multiple human diseases – from diabetes to neurodegeneration. ER stress results in either a pro-survival or pro-apoptotic outcomes depending on the severity of the stress. Given the impact ER stress has on human diseases, as well as the opposite possible outcomes from its activation, there is a strong need to create therapeutics that can target the ER stress response to specifically activate the correct outcome in humans. Despite its health relevance and high evolutionary conservation, the ER stress response is still subject to natural genetic variation – modifier genes affecting the pathway that can drastically alter the magnitude of its response. Modifier genes are excellent targets for therapeutics as they are peripheral to the main ER stress pathway and are often amenable to large expression changes without many secondary effects. The Chow lab has performed two screens for genetic modifiers that impact ER stress, and there are now >100 candidate modifier genes known. The first Aim of this proposal is to use these completed screens to rapidly characterize the top, most human health-relevant candidate genes for their role and mechanism in the ER stress response. This characterization makes use of Drosophila genetic tools, ER stress-inducing transgenic models and drugs, as well as fluorescent markers for ER stress pathways. Knowing the function of each gene is crucial to knowing if it is an appropriate target for therapeutics. The second Aim of this proposal involves a collaboration with Harvard Medical School to perform a genome-wide CRISPR screen for additional ER stress candidate genes – unlike previous screens, specifically designed to find genes that confer ER stress resistance. Aim 2 also involves the creation of gene interaction network of all known candidate genes, which will also include gene expression and ontology analysis. This gene network will be used as a tool to frame future research and aid in finding the best pathways to target with therapeutics in order to target more desirable or the smallest total of pathways. Together, the characterization of modifier genes affecting ER stress in Aim 1, along with the contextualization of them in a gene interaction network in Aim 2, will greatly aid future creation of therapeutics targeting the ER stress response in human diseases. Given the large genomic component to this proposal, the Department of Human Genetics at the University of Utah is the perfect setting for completing this training. There are a multitude of experts in genetics here, including many who work with Drosophila, that foster a strong training environment for postdocs. The sponsor, Dr. Clement Chow, has worked with modifier genes for years, and he originally found the bulk of ER stress-related modifier candidate genes being worked on here. The co-sponsor, Dr. Carl Thummel, is a world renowned leader in Drosophila genetics and has extensive history of training successful postdocs. This training plan is designed to have the trainee produce quality human health-oriented research, become extremely knowledgeable in both Drosophila and genetic tools, and attain the experience necessary for an independent research career.