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: 7534030
• 负责人: SHERRI M JONES
• 金额: $ 27.61万
• 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/7534030
• 关键词: Acceleration; Adult; Affect; Afferent Neurons; Age; Age-Months; Anatomy; Animals; Auditory; Auditory Brainstem Responses; Backcrossings; Behavior; Chronic; Cochlea; Complement; Crista ampullaris; Data; Databases; Defect; Deformity; Development; Diagnosis; Disease; Dizziness; Elderly; Electron Microscopy; Elements; Embryonic Ear; Equilibrium; Evoked Potentials; Evoked Potentials, Auditory, Brain Stem; Exhibits; Force of Gravity; Functional disorder; Future; Gene Mutation; Genes; Genetic; Growth; Hair Cells; Head; Hearing; Heterozygote; Histology; Homologous Gene; Homozygote; Human; Immunohistochemistry; Impairment; Inbred Strain; Inbred Strains Mice; Individual; Inherited; Knowledge; Labyrinth; Lead; Learning; Location; Maps; Measures; Modeling; Morphology; Mouse Strains; Mus; Mutant Strains Mice; Mutation; Nature; Neural Pathways; Neurons; Organ; Pathology; Pattern; Play; Population; Prevalence; Relative (related person); Research; Research Personnel; Role; Saccule and Utricle; Screening procedure; Semicircular canal structure; Severities; Shapes; Stereocilium; Structure; Synapses; System; Techniques; Temporal bone structure; Testing; Time; Variant; Vestibular Diseases; Vestibular loss; Work; base; cell type; deafness; early onset; experience; functional status; genetic linkage analysis; genome-wide linkage; hearing impairment; improved; interest; macula; morphometry; mutant; neuroepithelium; otoconia; programs; receptor; receptor function; relating to nervous system; sensory system; trend

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 1will 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.

3.4%的美国成年人口，或620万人，经历慢性头晕和/或失衡。 虽然这些情况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。 年龄头晕/不平衡的原因往往仍然未知，治疗可能往往不成功。 在这些个体中，头晕/失衡是否有遗传基础？虽然很多人 虽然我们了解了耳聋的遗传学，但对基因在前庭神经系统中的作用却知之甚少。 功能障碍（即，在没有显著听力损失的情况下发生的前庭损伤）。不是所有的遗传 突变会导致耳蜗和前庭异常。耳孢子缺陷小鼠（例如，het，tit）是 由于基因突变导致的选择性前庭损伤的例子。初步数据显示， 具有早发性、严重黄斑缺陷和正常听力的小鼠品系。我们的假设是， 存在突变，其产生选择性遗传性前庭损伤。此外，我们假设， 选择性前庭损害是由于耳锥丧失以外的缺陷。拟议的研究将 测试这些假设。具体目标1将确定近交系，表现出重力受体受损， 3个月大。我们将记录线性前庭诱发电位（VsEPs）和听觉脑干电位。 在年龄匹配的动物中进行ABR，以确定黄斑和听觉的功能状态。 器官，分别。具体目标2将描述重力感受器功能与年龄的关系， 在特定目标1中鉴定为前庭损伤的菌株。将在几个年龄段收集VsEP， 描述黄斑缺损的时间进程和性质。将收集ABR以确认不存在 严重的听力障碍。具体目标3将检查终末器官和初级传入解剖结构， 确定特定目标2中评估的功能缺陷的推定结构相关性。我们将研究 毛细胞静纤毛和毛束的形态特征，毛细胞类型的数量和分布， 突触的关键结构以及传入神经元的相对数量、大小和分布。具体目标4 将使用两个基因组的全基因组连锁分析来绘制导致重力感受器功能障碍的基因座， 近交系回交。这项研究将扩大我们对前庭个体发育和前庭神经发育的理解。 功能障碍此外，我们将确定遗传性前庭功能障碍的基因位点， 鉴定影响前庭系统的特定基因，以及潜在的人类前庭系统的遗传同源物。 前庭疾病这项工作可能会导致更好的诊断和治疗前庭损伤。