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LincRNAs Regulate Atp2b2, Potentially Determining PMCA2 Quantity in Stereocilia

LincRNA 调节 Atp2b2，可能决定立体纤毛中 PMCA2 的数量

基本信息

批准号：
9098685
负责人：
BRUCE L TEMPEL
金额：
$ 22.23万
依托单位：
UNIVERSITY OF WASHINGTON
依托单位国家：
美国
项目类别：
财政年份：
2015
资助国家：
美国
起止时间：
2015-07-01 至 2017-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9098685
关键词：
5&apos Untranslated Regions Auditory Auditory system Binding Brain Stem CDH23 gene Ca(2+)-Transporting ATPase Calcium Cell Line Cell membrane Cells Chromosomes Cochlea Complex Congenic Mice Congenic Strain DNA Sequence Alteration Data Down-Regulation Exhibits Exons Gene Expression Gene Targeting Genes Genetic Transcription Genetic study Haplotypes Health Hearing Homologous Gene Human Link Mammalian Cell Measures Monitor Mus Mutation Open Reading Frames Organ of Corti Outer Hair Cells Peripheral Phenotype Play Presbycusis Process Proteins RNA Regulation Regulator Genes Regulatory Element Reporter Research Role Sampling Scientist Sensory Stereocilium Testing Transcript Transcriptional Regulation Translating Untranslated RNA Western Blotting Work deafness hearing impairment inhibitor/antagonist interest knock-down link protein overexpression promoter protein expression research study response vector

项目摘要

DESCRIPTION (provided by applicant): C57BL/6J (B6) mice have a well-characterized age-related hearing loss (AHL) phenotype. A recent study has shown that this loss is only partially caused by mutations in the Cadherin 23 (Cdh23) gene which encodes the tip link protein CDH23 (Kane et al., 2011). In mice and in humans, mutations in Cdh23 are exacerbated by mutations in the plasma membrane Ca2+ ATPase 2 (PMCA2) protein, which regulates intracellular Ca2+ levels (Noben-Trauth et al., 1997 and Schultz et al., 2007). This interaction is likely due to the necessity of Ca2+ in maintaining the structural integrity of CDH23 (Sotomayor et al., 2010). There are no mutations in the B6 Atp2b2 gene, which encodes PMCA2. However, two discreet measures of gene expression show that there is down-regulation of Atp2b2 transcript in B6 compared to the good-hearing strain CBA/CaJ (CBA). Studies of the deafwaddler mutations in Atp2b2 demonstrate that the auditory system is highly sensitive to small changes in Atp2b2. These mice exhibit changes in hearing sensitivity that can be correlated to changes in regulation, function and expression of Atp2b2 (McCullough and Tempel, 2004; Watson and Tempel, 2013). All of this evidence suggests that the down-regulation of Atp2b2 in B6 is a likely contributor to the age-related hearing loss phenotype in these mice. As there are no mutations in the protein coding region of Atp2b2 but changes in transcript expression, transcriptional processes are likely involved in the down-regulation of Atp2b2 in B6. Recent experiments in the Tempel lab have confirmed the presence of a long intergenic non-coding RNA (lincRNA-83) that is in the intronic regions of the mouse Atp2b2 gene. Expression studies indicate that this gene is misregulated in the brainstem and the cochlea of B6 mice. Importantly, lincRNAs are emerging as key players in transcriptional regulation of nearby genes (Wang and Chang, 2011). The over-arching hypothesis in this proposal is that Atp2b2 misregulation in B6 contributes to AHL in this strain. We propose two aims to better understand the: 1) degree of expression differences between B6 and CBA, and 2) the extent to which non-coding RNAs regulate the Atp2b2 gene.