The roles of gasdermins in progressive hearing loss

Gasdermin 在进行性听力损失中的作用

• 批准号: 8874952
• 负责人: Martin Schwander
• 金额: $ 38.31万
• 依托单位: RUTGERS, THE STATE UNIV OF N.J.
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-07-01 至 2016-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8874952
• 关键词: Ablation; Acoustics; Actins; Adult; Affect; Afferent Neurons; Alleles; American; Apoptosis; Auditory; Auditory system; Binding; Biochemical Pathway; Candidate Disease Gene; Cell Differentiation process; Cell Survival; Cell physiology; Cells; Clinical; Cochlear Hearing Loss; Complex; Cytoskeleton; Data; Defect; Development; Disease; Elderly; Electron Microscopy; Epithelium; Evaluation; Functional disorder; Gene Family; Gene Silencing; Genes; Genetic; Genetic Models; Goals; Hair; Hair Cells; Health; Histology; Human; Immune Sera; Immunoelectron Microscopy; Immunofluorescence Microscopy; Immunohistochemistry; Knockout Mice; Knowledge; Labyrinth; Lead; Lesion; Link; Maintenance; Maps; Mechanics; Mediating; Microtubules; Molecular; Mus; Mutant Strains Mice; Mutation; Neurons; Neuropathy; Newborn Infant; Pathogenesis; Pathway interactions; Patients; Phenotype; Physiological; Physiology; Population; Presbycusis; Process; Protein Family; Proteins; Proteomics; Quality of life; Research; Role; Sensory; Sensory Hair; Signal Pathway; Signal Transduction; Signaling Protein; Site; Speech; Stereocilium; Structural Protein; System; Techniques; Tertiary Protein Structure; Therapeutic; Time; Transfection; Work; aging population; base; cDNA Library; deafness; disease-causing mutation; hearing impairment; in vivo Model; insight; mechanical behavior; member; novel; novel therapeutics; overexpression; postnatal; prenatal; prevent; response; response to injury; screening; sound; yeast two hybrid system

DESCRIPTION (provided by applicant): Deafness is an extremely common and disabling disorder affecting 1 in 1000 newborns in the US, with half of these cases being of genetic origin. Genetic defects are also important for progressive and age-related hearing loss, which significantly impair the quality of life of a large fraction of the aging population. Despite its clinical importance, the molecular pathogenesis of progressive hearing loss is not well understood. We and others have linked mutations in DFNB59 (encoding pejvakin) and DFNA5, two members of the gasdermin family of genes, to progressive hearing loss in humans. Depending on the type of mutation DFNB59 patients develop either progressive hearing loss with cochlear dysfunction or non-progressive auditory neuropathy. However, the precise site of the lesion underlying hearing loss and the physiological function of pejvakin and DFNA5 in the inner ear are still unknown. We hypothesize that these gasdermins regulate a cytoskeleton-associated signaling pathway at the stereocilia base that is important for the differentiation and survival of hair cells. In our preliminary data, we have generated a pejvakin conditional allele in mice and show that pejvakin regulates hair cell function in a cell-autonomous manner. We have employed immunohistochemical and hair cell transfection techniques and identified a unique subcellular distribution of pejvakin and DFNA5 at the base of the hair bundle consistent with a role for these proteins in the assembly or function of stereociliary rootlets. In addition, we have uncovered novel binding partners for gasdermins that are key components of signaling pathways that regulate cytoskeletal dynamics. In Aim 1, we will analyze the physiological function of pejvakin further to determine the extent to which it regulates the function of sensory hair cells and neurons. In Aim 2, we will determine the molecular determinants of gasdermin targeting in hair cells and the relevance of this process to progressive hearing loss. In Aim3, we will characterize the biochemical pathways by which these gasdermins regulate hair cell function and determine the extent to which they modulate the organization of actin and microtubule cytoskeleton networks. The proposed studies will evaluate new in vivo models for progressive hearing loss, provide a deeper understanding of the molecular pathways in which gasdermins act, and provide important clues to the development of novel therapeutic strategies to prevent or treat hearing loss.

描述（由申请人提供）：耳聋是一种极为普遍且残疾的疾病，影响了美国1000名新生儿，其中一半是遗传起源。遗传缺陷对于进行性和年龄相关的听力损失也很重要，这显着损害了大部分人口的大部分生活质量。尽管其临床重要性，但尚不清楚进行性听力损失的分子发病机理。我们和其他人在DFNB59（编码Pejvakin）和Gasdermin基因家族的两个成员DFNA5中将突变与人类的逐渐听力损失联系起来。取决于突变的类型DFNB59患者，患有耳蜗功能障碍或非促进听觉神经病的进行性听力损失。然而，内耳中pejvakin和dfna5的基础病变的确切部位以及内耳的生理功能仍然未知。我们假设这些气敏调节立体核基碱基的细胞骨架相关信号通路，这对于毛细胞的分化和存活至关重要。在我们的初步数据中，我们在 小鼠并表明Pejvakin以细胞自主的方式调节毛细胞功能。我们已经采用了免疫组织化学和毛细胞转染技术，并在头发束的底部鉴定了Pejvakin和dfna5的独特亚细胞分布，与这些蛋白质在立体核根根的组装或功能中一致。此外，我们还有 发现毒气敏的新型结合伙伴是调节细胞骨架动力学的信号通路的关键组成部分。在AIM 1中，我们将进一步分析Pejvakin的生理功能，以确定它调节感觉毛细胞和神经元功能的程度。在AIM 2中，我们将确定毛细胞中加油动物靶向的分子决定因素以及该过程与进行性听力损失的相关性。在AIM3中，我们将表征这些气温剂调节毛细胞功能的生化途径，并确定它们调节肌动蛋白和微管细胞骨架网络的组织程度。拟议的研究将评估新的体内模型，以进行渐进的听力损失，对加油动物作用的分子途径有更深入的了解，并为开发新的治疗策略提供了预防或治疗听力损失的重要线索。