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.
The response to endoplasmic reticulum (ER) stress is a fundamental biological process that underlies numerous human diseases, including diabetes and neurodegeneration. Despite its importance and evolutionary conservation, natural genetic variation can cause massive differences in how individuals respond to ER stress. Due to its role in multiple diseases, the goal of this research is to develop more personalized therapeutics targeting the ER stress response by understanding how variable modifier genes influence the differences in its response.
