Ion Channel Function in Auditory & Vestibular Hair Cells

听觉中的离子通道功能

• 批准号: 7871614
• 负责人: JEFFREY R HOLT
• 金额: $ 18.36万
• 依托单位: UNIVERSITY OF VIRGINIA
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-07-17 至 2011-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7871614
• 关键词: Acute; Adenovirus Vector; American; Auditory; Basic Science; Biological Assay; Blindness; Cadherins; Candidate Disease Gene; Cardiac; Cell physiology; Chronic; Complex; Development; Dominant-Negative Mutation; Ear; Epilepsy; Equilibrium; Family; Family member; Functional disorder; Future; Gene Deletion; Gene Expression; Gene Family; Gene Proteins; Generations; Genes; Genetic; Glycine; Goals; Hair; Hair Cells; Hearing; Human Genome Project; Inherited; Investigation; Ion Channel; Labyrinth; Link; Maps; Measures; Mediating; Membrane Potentials; Molecular; Molecular Motors; Mus; Mutant Strains Mice; Mutate; Mutation; Myosin ATPase; Natural regeneration; Outer Hair Cells; Physiological; Play; Positioning Attribute; Proteins; Research; Rest; Role; Sensory; Sensory Hair; Signal Transduction; Small Interfering RNA; Stereocilium; Techniques; Testing; Tissues; Tyrosine; Usher Syndrome; Vestibular Hair Cells; Work; analog; base; cellular transduction; chemical genetics; deafness; design; equilibration disorder; experience; gene function; gene replacement; human CDH23 protein; human disease; inner ear diseases; interest; member; novel strategies; response

DESCRIPTION (provided by applicant): The studies proposed here focus on several distinct, yet equally significant lines of inner ear research. The overall goal is to identify the genes and proteins in sensory hair cells that are responsible for the generation and propagation of sensory information in the ear. Each family of genes that will be investigated is associated with inherited human disease and members of each family are expressed in inner ear hair cells. Some of the genes we will investigate are known to cause deafness and/or balance disorders when mutated. Others are candidate deafness genes because they are expressed in hair cells and because known mutations in those genes cause dysfunction in other body tissues. As such, mutations in the candidate genes may cause previously unrecognized forms of genetic auditory and vestibular dysfunction. Broadly, we aim to understand three critical hair cell functions and identify the genes and proteins that underlie those functions. 1) We will examine ion channel genes that determine the hair cell resting potential. Because these proteins are active at rest, i.e., in the absence of stimulation, they have a major impact on how hair cells respond to stimulation. We want to identify exactly which ion channel genes contribute to this function and have selected three families for investigation: the KCNQ family, the HCN family and the Kir2 family. Mutations in KCNQ genes cause deafness and epilepsy, while mutations in HCN and Kir2 genes cause cardiac problems. Members of each of these families are expressed in hair cells, but their precise contributions to hair cell conductances and hair cell function have not been determined. 2) We are also interested to identify the genes that mediate sensory adaptation in hair cells. In response to sustained hair bundle deflections, hair cells adapt which results in a decline in their response. Molecular motors, probably myosin molecules, have been hypothesized to play a role in this function. Furthermore, mutations in several members of the myosin family cause deafness. We will focus on one myosin in particular, Myosin 1c, and use a chemical-genetic strategy to inhibit its function. We will deflect hair bundles and measure their response to determine the contribution of Myosin 1c to adaptation in auditory hair cells. 3) Lastly, we are interested to identify the molecules that contribute to the development and regeneration of sensory transduction in hair cells. We hypothesize that the myosin and cadherin families may contribute to this function. Mutations in members of both families cause Usher's syndrome, characterized by deafness and blindness. We will use chronic inhibition of myosin and cadherin function to investigate the specific contributions of members of these families to development and regeneration of the transduction complex in sensory hair cells. Through these three lines of research we aim to identify several molecules that contribute to normal function of hair cells. Because deficiencies with these critical functions cause deafness and balance disorders, the information gained through these studies will facilitate design of rational strategies to treat genetic inner ear disorders. This project will study some of the genetic causes of inherited deafness and balance disorders. We will investigate a handful of genes, of the approximately 26,000 identified through the human genome project, that we suspect are critical for normal hearing and balance. We expect that this project will produce information that will form the basis for development of future strategies to treat deafness and balance problems in some of the ~28 million Americans who suffer from inner ear disorders.

描述（由申请人提供）：这里提出的研究重点关注内耳研究的几个不同但同样重要的领域。总体目标是识别感觉毛细胞中负责耳内感觉信息生成和传播的基因和蛋白质。将要研究的每个基因家族都与遗传性人类疾病相关，并且每个家族的成员在内耳毛细胞中表达。我们将研究的一些基因在突变时会导致耳聋和/或平衡障碍。其他基因是候选耳聋基因，因为它们在毛细胞中表达，并且这些基因的已知突变会导致其他身体组织功能障碍。因此，候选基因的突变可能会导致以前未被识别的遗传性听觉和前庭功能障碍。从广义上讲，我们的目标是了解三种关键的毛细胞功能，并识别这些功能背后的基因和蛋白质。 1) 我们将检查决定毛细胞静息电位的离子通道基因。由于这些蛋白质在休息时（即在没有刺激的情况下）处于活跃状态，因此它们对毛细胞对刺激的反应具有重大影响。我们想要准确确定哪些离子通道基因有助于此功能，并选择了三个家族进行研究：KCNQ 家族、HCN 家族和 Kir2 家族。 KCNQ 基因突变会导致耳聋和癫痫，而 HCN 和 Kir2 基因突变会导致心脏问题。每个家族的成员均在毛细胞中表达，但它们对毛细胞电导和毛细胞功能的精确贡献尚未确定。 2）我们也有兴趣识别介导毛细胞感觉适应的基因。为了应对持续的发束偏转，毛细胞会进行适应，从而导致其反应下降。分子马达，可能是肌球蛋白分子，已被假设在该功能中发挥作用。此外，肌球蛋白家族的一些成员的突变会导致耳聋。我们将重点关注一种肌球蛋白，特别是肌球蛋白 1c，并使用化学遗传策略来抑制其功能。我们将偏转毛束并测量它们的反应，以确定肌球蛋白 1c 对听觉毛细胞适应的贡献。 3）最后，我们有兴趣识别有助于毛细胞感觉转导发育和再生的分子。我们假设肌球蛋白和钙粘蛋白家族可能有助于此功能。两个家族成员的突变都会导致亚瑟综合症，其特征是耳聋和失明。我们将利用肌球蛋白和钙粘蛋白功能的慢性抑制来研究这些家族成员对感觉毛细胞中转导复合物的发育和再生的具体贡献。通过这三方面的研究，我们的目标是确定几种有助于毛细胞正常功能的分子。由于这些关键功能的缺陷会导致耳聋和平衡障碍，因此通过这些研究获得的信息将有助于设计合理的策略来治疗遗传性内耳疾病。该项目将研究遗传性耳聋和平衡障碍的一些遗传原因。我们将研究人类基因组计划确定的大约 26,000 个基因中的少数基因，我们怀疑这些基因对于正常听力和平衡至关重要。我们预计该项目将产生的信息将成为制定未来策略的基础，以治疗大约 2800 万患有内耳疾病的美国人中的一些人的耳聋和平衡问题。