Characterization and Contextualization of Modifier Genes Affecting ER Stress - 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.
