The ultimate goal of project 2 is the discovery of the genes that drive prostate cancer pathogenesis. Since most of the risk variants discovered to date reside outside of known protein coding regions (i.e., intronic and intergenic), systematic approaches are required to reveal the connection between the risk allele and the gene that it influences. The primary hypotheses that we are comprehensively testing are that the risk regions harbor an as yet undiscovered transcript and/or that the risk regions are functional elements (e.g., promoters and enhancers) that influence gene expression. A range of complementary techniques is proposed that will thoroughly address these hypotheses. The prostate transcriptome will be sequenced to derive an unbiased census of coding and non-coding transcripts and alternative splicing. Functionally relevant elements within the prostate cancer risk loci regions will be annotated using the techniques of chromatin immunoprecipitation and DNase hypersensitivity. Finally, methods will be employed to functionally characterize each of the risk loci, including chromosome conformation capture to identify all other genomic regions that are interacting with the risk region, gene perturbation (e.g., knockdown and overexpression) experiments of candidate genes surrounding the risk regions, and evaluating associations between the risk alleles and transcript abundance across candidate genes. Understanding the biologic pathways driving prostate cancer provides a sound basis for rational intervention in disease prevention and treatment.

Public Health Relevance

This ultimate goal of Project 2 is to understand the genes that the non-protein coding risk alleles are influencing to cause disease. A variety of complementary and coordinated approaches will be implemented to tackle this question. A deeper understanding of the biology of prostate cancer pathogenesis will inform how to better prevent and treat this disease

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Program--Cooperative Agreements (U19)
Project #
5U19CA148537-04
Application #
8540138
Study Section
Special Emphasis Panel (ZCA1-SRLB-4)
Project Start
Project End
Budget Start
2013-07-01
Budget End
2014-06-30
Support Year
4
Fiscal Year
2013
Total Cost
$704,174
Indirect Cost
Name
University of Southern California
Department
Type
DUNS #
072933393
City
Los Angeles
State
CA
Country
United States
Zip Code
90089
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