An innate immune response to viral double-stranded RNA (dsRNA) is activated upon binding by sensor dsRNA binding proteins (dsRBPs). However, dsRBP-dependent activation of innate immunity in the absence of pathogen has been observed in some human diseases, suggesting that an unrecognized source of cellular dsRNA is involved. Using the genetically tractable model organism C. elegans, I will investigate this novel function of cellular dsRNAs, wherein changes in cellular dsRNA levels are sensed by dsRBPs and lead to downstream changes in gene expression.
In Aim 1, I will identify genes and pathways affected by altered cellular dsRNA levels by comparing gene expression profiles of C. elegans strains in which genes encoding dsRNA are overexpressed or deleted.
In Aim 2, I will identify genomic loci encoding cellular dsRNA using high- throughput sequencing of samples coimmunoprecipitated with dsRBPs. Common genomic regulatory elements of dsRNA loci identified using bioinformatics approaches will provide information regarding the regulation and biological function of these dsRNAs. Finally, in Aim 3 I will utilize both genome-wide RNAi screens and targeted genetic studies to identify cellular mechanisms regulating dsRNA expression. These studies will advance our understanding of dsRNA's role in the cell, and furthermore, have the potential to reveal dsRNA as a new target in the treatment of human diseases including cancer.

Public Health Relevance

Inflammation, a normal feature of the innate immune response to pathogens, is also a common symptom of many human diseases, including obesity, cancer and Alzheimer's. In these diseases, the induction of an inflammatory innate immune response is linked to the activation of pathogen-sensing dsRNA binding proteins in the absence of a discernible infection, suggesting that cellular dsRNA may play a role in the pathogenesis. This project will investigate the role of long cellular dsRNA as a signaling molecule that mediates responses to stress in the cell, providing new insights into the impact of noncoding RNA on human diseases.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Postdoctoral Individual National Research Service Award (F32)
Project #
1F32GM106539-01
Application #
8525045
Study Section
Special Emphasis Panel (ZRG1-F08-Q (20))
Program Officer
Reddy, Michael K
Project Start
2013-04-01
Project End
2015-03-31
Budget Start
2013-04-01
Budget End
2014-03-31
Support Year
1
Fiscal Year
2013
Total Cost
$49,214
Indirect Cost
Name
University of Utah
Department
Biochemistry
Type
Schools of Medicine
DUNS #
009095365
City
Salt Lake City
State
UT
Country
United States
Zip Code
84112