Auditory Neurogenetics

听觉神经遗传学

基本信息

批准号：
7150627
负责人：
BRUCE L TEMPEL
金额：
$ 37.79万
依托单位：
UNIVERSITY OF WASHINGTON
依托单位国家：
美国
项目类别：
财政年份：
1995
资助国家：
美国
起止时间：
1995-08-01 至 2008-11-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7150627
关键词：
3p25.3 Accounting Address Adult Affect Age Aging Alleles Auditory Bilateral Hearing Loss Calcium Cell physiology Cochlea Data Drops Equilibrium Frameshift Mutation Frequencies Funding Gene Expression Gene Expression Regulation Genes Hair Cells Hearing Hearing Impaired Persons Heterozygote High-Frequency Hearing Loss Human Indium Knockout Mice Labyrinth Localized Measures Molecular Mus Mutant Strains Mice Mutation Neurons Noise Noise-Induced Hearing Loss Outer Hair Cells Parkinson Disease Patients Pattern Phenotype Population Presbycusis Process Promoter Regions Protein Isoforms Proteins Research Personnel Resistance Severities Single Nucleotide Polymorphism Stereocilium Techniques Temporal bone structure Testing Transgenic Mice base cohort deafness early onset functional disability hearing impairment man mouse model mutant neurogenetics otoacoustic emission positional cloning prevent programs promoter

项目摘要

DESCRIPTION (provided by applicant): Hearing loss is debilitating and permanent, affecting < 66% of the population over age 70 (Cruickshanks et al., Am. J. Epidemiol., 1998), causing interpersonal isolation and having significant financial impact. During the previous funding period, we used positional cloning techniques to identify mutations in Atp2b2 and Spnb4 in the mouse mutant's deafwaddler and quivering, respectively (Street ea, 1998; Parkinson ea, 2001). For each locus we identified multiple alleles with different degrees of functional impairment. For deafwaddler, the dfw allele is a hypomorph with function reduced to 30% (Penheiter ea) while dfw 2J and dfvv 3J are apparent null alleles with frameshift mutations yielding no detectable protein. We have found that homozygous mutants of all alleles are deaf (Konrad-Martin, 2001 ; Mccullough and Tempel, submitted). Further studies have shown that in homozygous null mice (dfw2J/dfw 2J) endolymphatic calcium concentration drops from 23 mu/M in control to 6 mu/M (Wood et al., 2004). This significant drop in endolyphatic calcium may be causally related to profound deafness, to the degeneration and loss of otoconia (Fonseca-Burke et al., in prep.), as well as to hair cell loss (Pujol et al., 2001) in homozygous null deafwaddler alleles. In heterozygotes no hair cell loss is seen yet hearing loss occurs at high frequencies (Konrad-Martin, 2001; McCullough and Tempel, submitted). These data suggest that calcium is tightly regulated in the inner ear and that PMCA2 (the protein product of the Atp2b2 locus) is a critical player in maintaining calcium balance. Here we propose to extend our studies on deafwaddler by examining its contribution to age-related hearing loss (AHL) and noise-induced hearing loss (NIHL) in mice with graded reductions in Atp2b2 expression. To establish a rationale for comparing man with mouse, we will examine the distribution of PMCA2 in human temporal bone and ask whether patients carrying a deletion of the ATP2B2 locus show hearing loss. Toward identifying pharmacological strategies for preventing hearing loss, we will examine the molecular basis of Atp2b2 gene regulation and ask whether increased levels of expression of Atp2b2 can prevent AHL in mice and protect them from NIHL.

描述（由申请人提供）：听力损失是令人衰弱和永久性的，影响了70岁以上人口的66％（Cruickshanks等人，Am。J。Epidemiol。，1998），导致人际隔离并产生重大的财务影响。在上一个资金期间，我们分别使用位置克隆技术来鉴定小鼠突变体聋人和颤抖中的ATP2B2和SPNB4中的突变（Street EA，1998; Parkinson EA，2001）。对于每个基因座，我们确定了具有不同功能障碍程度的多个等位基因。对于Deafwaddler，DFW等位基因是功能降低至30％（Penheiter EA）的hypomorph，而DFW 2J和DFVV 3J是明显的无效突变的无效突变，没有可检测到的蛋白质。我们发现所有等位基因的纯合突变体都是聋（Konrad-Martin，2001； McCullough and Tempel，已提交）。进一步的研究表明，在纯合无零小鼠（DFW2J/DFW 2J）中，内淋巴钙浓度从对照的23 mU/m到6 mu/m（Wood等，2004）。内态钙的这种显着下降可能与深度耳聋，与奥托可尼症的变性和丧失（Fonseca-Burke等人，预备术中）以及毛细胞损失（Pujol等人，2001年）在纯合无效的聋人聋哑人中（Pujol等，2001）。在杂合子中，没有看到毛细胞损失，但在高频下发生听力损失（Konrad-Martin，2001； McCullough和Tempel，提交）。这些数据表明钙在内耳中受到严格调节，PMCA2（ATP2B2基因座的蛋白质产物）是维持钙平衡的关键参与者。在这里，我们建议通过研究其对年龄相关的听力损失（AHL）和噪声诱导的听力损失（NIHL）的贡献，以扩展对聋人的研究，并在ATP2B2表达中分级降低的小鼠中降低了听力损失（NIHL）。为了建立将人与小鼠进行比较的基本原理，我们将检查PMCA2在人类颞骨中的分布，并询问携带ATP2B2基因座缺失的患者是否显示出听力损失。为了确定预防听力损失的药理策略，我们将检查ATP2B2基因调节的分子基础，并询问ATP2B2表达水平的增加是否可以防止小鼠AHL并保护它们免受NIHL的侵害。