Noise induced hearing loss (NIHL) is a significant problem in the United States, affecting ~15 percent of individuals from all age groups. These individuals are exposed to loud noise in their workplace or during leisure activities. A recent report by the National Institute of Deafness and Communicative Disorder indicated that 30 million Americans are exposed to hazardous levels of noise regularly. Chronic noise exposure leads to irreversible damage to inner ear structures and hearing loss. There are no known treatments available for NIHL, suggesting that it is imperative to develop effective treatment options. Recent data from our laboratory, indicate increased reactive oxygen species (ROS) generation and increased inflammatory mediators in the cochlea after noise trauma. Thus we hypothesize that NIHL is initiated by the generation of ROS in the cochlea which promote coclear inflammation, leading to damage and death of cells in the inner ear. Mediators of this inflammatory response include the cochlear specific NADPH oxidase, NOX3 (a primary source of ROS generation) and transient receptor potential V1 (TRPV1), a nonspecific cation channel, which is induced by ROS and participates in the cochlear inflammation. Thus, ROS serve as common mediator of cochlear inflammation in response to noise trauma. As such, targeting NOX3 and/or TRPV1 for inhibition would constitute treatment options for NIHL. We have identified a novel agent, transplatin, which ameliorates NIHL by inhibiting TRPV1, NOX3 and inflammatory mediators. The overall goal of this project is to examine the role of ROS mediated inflammation in NIHL and to determine if inhibition of these pro- inflammatory mediators by transplatin provides otoprotection.
Specific aim 1 (sub-aim 1A) will determine the effective doses of transplatin providing protection and examine the time-window for this drug to be effective prophylactically and as a rescue agent after noise trauma. Sub-aim 1B will determine whether administration of transplatin following noise exposure would provide otoprotection. The efficacy of both trans-tympanic and intraperitoneal routes of administration will be assessed by auditory brainstem responses (ABRs) and scanning electron microscopy (SEM).
Specific aim 2 will assess the molecular basis of transplatin otoprotection. Specifically, sub-aim 2A will determine the gene expression profile of the cochlea after noise and/or transplatin, compared to control, using whole transcript microarrays. Target gene/miRNA validation will be performed by quantitative PCR and Western blotting. Sub-aim 2B will focus on cochlear pro-inflammatory gene pathways identified by microarray of the cochlea after noise trauma. Overall, this study will provide comprehensive data regarding gene expression profile of the cochlea in NIHL and provide a more complete picture of the efficacy and mechanism of action of transplatin against NIHL. This information could highlight potentially new signaling pathways mediating NIHL and provide novel drug treatment targets. A successful outcome of this approach in the animal studies is expected to have direct translational application for the treatment of NIHL in human.
Noise induced hearing loss (NIHL) is a significant problem in industrialized countries. In the United States, it is estimated that 30 million people are exposed to high noise levels on a daily basis. Loss of hearing prevents effective communication and decreases social interaction and the quality of life of affected individuals. Since there are currently no treatments available for NIHL, research aimed at developing novel treatments is essential. This study will assess the effectiveness of transplatin (an inactive analog of cisplatin, which has been shown to be effective against drug-induced hearing loss and in preliminary studies of NIHL. We will test the efficacy of transplatin as a prophylatctic and as a rescue agent to treat NIHL in a rat model.
|Sheehan, Kelly; Sheth, Sandeep; Mukherjea, Debashree et al. (2018) Trans-Tympanic Drug Delivery for the Treatment of Ototoxicity. J Vis Exp :|
|Mukherjea, Debashree; Ghosh, Sumana; Bhatta, Puspanjali et al. (2015) Early investigational drugs for hearing loss. Expert Opin Investig Drugs 24:201-17|
|Sheth, Sandeep; Brito, Rafael; Mukherjea, Debashree et al. (2014) Adenosine receptors: expression, function and regulation. Int J Mol Sci 15:2024-52|
|Brito, Rafael; Sheth, Sandeep; Mukherjea, Debashree et al. (2014) TRPV1: A Potential Drug Target for Treating Various Diseases. Cells 3:517-45|
|Jajoo, Sarvesh; Mukherjea, Debashree; Kaur, Tejbeer et al. (2013) Essential role of NADPH oxidase-dependent reactive oxygen species generation in regulating microRNA-21 expression and function in prostate cancer. Antioxid Redox Signal 19:1863-76|
|Sheth, Sandeep; Jajoo, Sarvesh; Kaur, Tejbeer et al. (2012) Resveratrol reduces prostate cancer growth and metastasis by inhibiting the Akt/MicroRNA-21 pathway. PLoS One 7:e51655|
|Rybak, Leonard P; Mukherjea, Debashree; Jajoo, Sarvesh et al. (2012) siRNA-mediated knock-down of NOX3: therapy for hearing loss? Cell Mol Life Sci 69:2429-34|