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Characterization and Contextualization of Modifier Genes Affecting ER Stress

影响内质网应激的修饰基因的特征和背景

基本信息

批准号：
10312806
负责人：
Hans Martin Dalton
金额：
$ 6.98万
依托单位：
UNIVERSITY OF UTAH
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-01-15 至 2023-01-14
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10312806
关键词：
Affect Animal Model Apoptotic Biological Biological Process Biology CRISPR screen Candidate Disease Gene Cell Culture Techniques Cells Clustered Regularly Interspaced Short Palindromic Repeats Collaborations Collection Complex Data Diabetes Mellitus Disease Disease Outcome Drosophila genus Drug Targeting Drug usage Endoplasmic Reticulum Environment Fostering Future Gene Expression Genes Genetic Genetic Screening Genetic Techniques Genetic Transcription Genetic Variation Genomics Goals Grant Health Human Human Genetics Individual Knock-out Learning Modeling Nerve Degeneration Ontology Orthologous Gene Outcome Pathway interactions Peripheral Pharmaceutical Preparations Population Postdoctoral Fellow Recording of previous events Research Resistance Role Severities Specificity Stress Therapeutic Tissues Training Transgenic Model Tunicamycin Universities Utah Variant Work biological adaptation to stress career clinical application design endoplasmic reticulum stress experience gene function gene interaction gene network genome wide association study genome wide screen genome-wide human disease insight medical schools misfolded protein personalized therapeutic physiologic model resistance gene response success targeted treatment therapeutic target therapy development tool transcriptome whole genome

项目摘要

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.

内质网（ER）应激反应是多种人类疾病的基础-从糖尿病到糖尿病，神经变性ER应激导致促存活或促凋亡结果，这取决于压力的严重性。考虑到内质网应激对人类疾病的影响，由于其激活的结果，强烈需要创造可以靶向ER应激反应的治疗方法来激活人类的正确结果。尽管它与健康相关，保守，ER应激反应仍然受到自然遗传变异-修饰基因影响，这一途径可以极大地改变其反应的幅度。修饰基因是很好的靶点，因为它们是主要ER应激途径的外周，并且通常适合于大量表达，没有太多的副作用。Chow实验室已经对遗传修饰剂进行了两次筛选，影响ER应激，现在已知有>100个候选修饰基因。本建议的第一个目的是使用这些完整的筛选来快速表征最重要的，最与人类健康相关的候选基因，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遗传特性，工具，ER应激诱导转基因模型和药物，以及ER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治疗的合适靶点至关重要。第二该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ER应激候选基因-与以前的筛选不同，专门设计用于寻找基因赋予内质网应激抗性。目标2还涉及所有已知的基因相互作用网络的创建候选基因，这也将包括基因表达和本体分析。这个基因网络将被用于作为一种工具，以框架未来的研究，并帮助寻找最佳途径，以靶向治疗，目标更理想或路径总数最小。总之，修饰基因的表征影响目标1中的ER应激，沿着它们在目标2中的基因相互作用网络中的情境化，将极大地有助于将来创造靶向人类疾病中ER应激反应的治疗剂。鉴于大基因组作为这项提议的一个组成部分，犹他州大学的人类遗传学系是一个完美的环境完成这次训练。这里有许多遗传学专家，包括许多与果蝇，这为博士后培养了一个强大的培训环境。发起人周文健博士多年来，他一直在研究修饰基因，最初他发现了大部分与ER应激相关的修饰候选基因，在这里工作。共同发起人卡尔·图梅尔博士是世界著名的果蝇遗传学领导者并有培养成功博士后的广泛历史。本培训计划旨在让学员进行高质量的以人类健康为导向的研究，对果蝇和遗传工具，并获得独立研究生涯所需的经验。