The Office of Dietary Supplements (ODS) of the National Institutes of Health (NIH)
Click to access mobile menu

Grant Abstract: Deciphering the Usher I protein interactome using a genetic approach

Grant Number: 1R01DC015111-01
PI Name: Zheng
Project Title: Deciphering the Usher I protein interactome using a genetic approach

Abstract: Abstract: DESCRIPTION (provided by applicant): Usher Syndrome (USH) accounts for 6% of the congenitally deaf population and more than 50% of the deaf-blind population. Mutations of the CDH23 gene can cause three kinds of hearing loss including Usher Syndrome 1D (USH1D), deafness, autosomal recessive 12 (DFNB12) and age-related hearing loss (HL). Discovery of therapeutic targets that prevent hair cell death is the key to helping Usher 1 patients to respond to cochlear implants and other treatment options successfully. We have developed a HL mouse model named Erlong (erl) with a missense mutation in Cdh23 gene. In our approved parent R01DC015111 (Title: Deciphering the Usher I Protein Interactome Using a Genetic Approach), we proposed to test the hypothesis that the erl mutation causes CDH23 protein retention in the endoplasmic reticulum (ER), thus inducing the Unfolded Protein Response (UPR). The UPR is a set of cellular signaling pathways in mammalian cells that detect unfolded proteins in the ER and direct cellular responses. Accumulation of unfolded and misfolded proteins in the ER lumen was followed by induction of ER stress. ER stress, in turn can induce apoptosis. Tauroursodeoxycholic Acid (TUDCA) is a water soluble bile acid dietary supplement and widely used in clinical and experimental research to treat liver disease, diabetes, and neurodegeneration diseases as healthy liver functions and detoxification. Previous studies have demonstrated TUDCA modulate ER function, protecting against ER stress-induced apoptosis. Given TUDCA’s cell-protective effects in disorders associated with apoptosis and its clinical safety, in response to PA-15-258, we hypothesize that orally administering with TUDCA can significantly alleviate hearing loss and suppress hair cell death in erl/erl mice . Thus, under the scope of the approved parent project we propose the following experiments: 1) Test the hypothesis that CDH23erl accumulates in the ER of cochlear HCs but not vestibular HCs, thus causing ER stress (ERS) and progressive HL without circling behavior. 1) a. TUDCA inhibit hair cells (HCs) apoptosis in the basal turn of cochlear. 1) b. TUDCA prevents CDH23erl protein from accumulating in the ER area of cochlear HCs. 2) Test the hypothesis that the PERK - eIF2? signaling of the UPR is activated in the cochlear HC but not in the vestibular apparatus of the Cdh23erl/erl mice. 2) a. TUDCA suppresses apoptosis-related genes and caspase-3 activation in erl/erl mice . 2) b. TUDCA, a inhibitor of eIF2? dephosphorylation (in the UPR pathway) can prevent HL and HC loss in the Cdh23erl/erl mice. 3) Test the hypothesis that the delayed onset of HL is due to (a) over-adaptation and increased protein synthesis rates in response to the CDH23erl-induced ERS in HCs and (b) increased sensitivity of HCs to additional stress challenges, like oxidative stress during postnatal life. Once we achieve the above goal, we will enhance the parent R01 for all of the aims, to conclude that ER stress is the underlying the mechanism of action plus this will help to translate to clinical studies.

Back to Grants Page