Genetic basis for gravity receptor dysfunction in mice

小鼠重力感受器功能障碍的遗传基础

• 批准号: 7048133
• 负责人: SHERRI M JONES
• 金额: $ 30.62万
• 依托单位: EAST CAROLINA UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-12-15 至 2010-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7048133
• 关键词: afferent nerve; age difference; auditory cortex; cell morphology; cochlea; disease /disorder model; ear hair cell; electron microscopy; evoked potentials; gene mutation; genetic mapping; genetically modified animals; gravity; histology; immunocytochemistry; laboratory mouse; morphometry; neurogenetics; otocyst /otolith; proprioception /kinesthesia; protein structure function; receptor expression; semicircular duct; sensory disorders; vestibular apparatus; vestibular pathway

DESCRIPTION (provided by applicant): 3.4% of the US adult population, or 6.2 million individuals, experience chronic dizziness and/or imbalance. While the prevalence of these conditions is greater among older adults, balance problems can occur at any age. The cause of dizziness/imbalance often remains unknown and treatment may often be unsuccessful. Could there be a genetic basis for dizziness/imbalance in some of these individuals? While much is being learned about the genetics of deafness, relatively little is known about the role genes may play in vestibular dysfunction (i.e., vestibular impairment occurring in the absence of significant hearing loss). Not all genetic mutations produce both cochlear and vestibular abnormalities. Otoconia-deficient mice (e.g., het, tit) are examples of selective vestibular impairment due to genetic mutations. Preliminary data have identified inbred mouse strains with early onset, profound macular deficits and normal hearing. Our hypothesis is that genetic mutations exist, which produce selective, hereditary vestibular impairment. Furthermore, we hypothesize that the selective vestibular impairment is due to deficits other than otoconial loss. The proposed research will test these hypotheses. Specific Aim 1 will identify inbred strains that exhibit gravity receptor impairment by 3 months of age. We will record linear vestibular evoked potentials (VsEPs) and auditory brainstem responses (ABR) in age matched animals to determine the functional status of the macular and auditory organs, respectively. Specific aim 2 will characterize gravity receptor function in relation to age in those strains identified with vestibular impairment in specific aim 1. VsEPs will be collected at several ages to describe the time course and nature of the macular deficit. ABRs will be collected to confirm the absence of significant hearing impairment. Specific aim 3 will examine end organ and primary afferent anatomy to identify putative structural correlates for the functional deficits evaluated in specific aim 2. We will examine morphological features of hair cell stereocilia and bundles, the numbers and distributions of hair cell types, key structures at synapses and the relative number, size and distribution of afferent neurons. Specific aim 4 will map loci that contribute to gravity receptor dysfunction using genome-wide linkage analyses of two inbred strain backcrosses. This research will extend our understanding of vestibular ontogeny and vestibular dysfunction. In addition, we will identify loci for hereditary vestibular impairment providing the basis for identifying specific genes affecting the vestibular system and, potentially, genetic homologs for human vestibular disease. This work may lead to better diagnosis and treatment of vestibular impairment.

描述（由申请人提供）：3.4%的美国成年人口或620万人经历慢性头晕和/或失衡。虽然这些疾病在老年人中的患病率更高，但平衡问题可能发生在任何年龄。头晕/失衡的原因通常尚不清楚，治疗通常可能不成功。在这些个体中，头晕/失衡是否有遗传基础？虽然人们对耳聋的遗传学了解很多，但对基因在前庭功能障碍中的作用知之甚少（即，在没有显著听力损失的情况下发生的前庭损伤）。并不是所有的基因突变都会导致耳蜗和前庭异常。耳孢子缺陷小鼠（例如，Het，Titt）是由于基因突变而导致选择性前庭损伤的实例。初步数据已经确定了具有早发性、严重黄斑缺陷和正常听力的近交系小鼠品系。我们的假设是，存在基因突变，产生选择性，遗传性前庭障碍。此外，我们假设选择性前庭损害是由于其他缺陷耳锥损失。拟议的研究将检验这些假设。具体目标1将识别3个月大时表现出重力受体损伤的近交系。我们将在年龄匹配的动物中记录线性前庭诱发电位（VsEP）和听觉脑干反应（ABR），以分别确定黄斑和听觉器官的功能状态。具体目标2将描述在具体目标1中鉴定为前庭损伤的菌株中与年龄相关的重力感受器功能。将在几个年龄收集VsEP，以描述黄斑缺损的时间过程和性质。将收集ABR，以确认不存在显著听力损伤。具体目标3将检查终末器官和初级传入解剖结构，以确定具体目标2中评价的功能缺陷的推定结构相关性。我们将研究毛细胞静纤毛和束的形态特征，毛细胞类型的数量和分布，突触的关键结构和传入神经元的相对数量，大小和分布。具体目标4将使用两个近交系回交的全基因组连锁分析来绘制有助于重力受体功能障碍的基因座。这项研究将扩大我们对前庭个体发育和前庭功能障碍的理解。此外，我们将确定遗传性前庭功能障碍的基因座，为确定影响前庭系统的特定基因提供基础，并可能为人类前庭疾病提供遗传同源物。这项工作可能会导致更好的诊断和治疗前庭损伤。