MicroRNA-mediated genomic stability and NIHL susceptibility.
Abstract
We propose to develop a computational tool to detect and map genetic features associated with NIHL susceptibility using DNA from saliva samples of the Marine recruit archive. This tool will identify genomic instability associated with DNA structural variants to include CNVs and SNPs and map them at the individual level. This proposal addresses advancement in signal detection of NIHL suscepti"bility in Warfighters arising from structural features of DNA. Recently, it has become evident that genetic factors critically influ"ence the activity and threshold response of NIHL-associated molecular pathways in a way that defines the susceptibility of individua"ls to noise. These factors include single nucleotide polymorphisms (SNP) and more recently discovered copy number variants (CNV), w"hich are both DNA structural variants that contribute to the gene expression variability between individuals. Our increased capability to detect changes in these key elements of DNA becomes critical in preventing NIHL. We have identified SNPs associated with NIH"L in the nucleolin gene of Marine recruits exposed to noise. In a database analysis, we also found that many of the NIHL-associated"" genes contained CNVs. Nucleolin is a multifunctional protein that contributes to oxidative stress, DNA damage responses, and apopto"sis through mRNA and microRNA-mediated mechanisms. Nucleolin also binds with high affinity to specific DNA and RNA structures called G-quadruplexes. These structures are a source of genetic instability and are associated with formation of CNVs. We propose to detect genomic instability associated with nucleolin dysregulation in the cochlea as a key driver of NIHL susceptibility. Nucleolin dys"regulation alters DNA damage response and DNA repair pathways, via miRNA, producing genomic instability that leads to increased cell"" damage and death. In the context of hearing loss, this genomic instability is likely associated with oxidative stress. Our statemen"t of works includes: Identify changes in CNV distribution associated with NIHL susceptibility in Marine Recruits; Investigate the impact of nucleolin dysregulation on genomic stability in cochlear cells; Investigate the effect of nucleolin expression on the regulation of programmed cell death mediated by miRNA under oxidative stress in cochlear cells.This computational tool will be used to independently validate the impact of nucleolin dysregulation on genomic stability and regulation of programmed cell death mediated by microRNA under oxidative stress in cochlear cells.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Jul 07, 2017
- Source ID
- N000141712647
Entities
People
- Yohann Grondin
Organizations
- Office of Naval Research
- President and Fellows of Harvard College
- United States Navy