SPROUTY GENE FUNCTION IN MOUSE INNER EAR DEVELOPMENT

Sprouty 基因在小鼠内耳发育中的功能

• 批准号: 7194238
• 负责人: Katherine Shim
• 金额: $ 2.12万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-04-01 至 2007-07-01
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7194238
• 关键词: Acceleration; Address; Adult; Architecture; Auditory; Brain; Cell Count; Cells; Cellular Morphology; Class; Cochlea; Complex; Congenital Disorders; Crista ampullaris; Defect; Development; Developmental Process; Disease; Disruption; Ectoderm; Embryo; Embryonic Development; Epithelium; Equilibrium; Event; Family; Fibroblast Growth Factor; Fibroblast Growth Factor Receptor 1; Gene Family; Genes; Genetic; Goals; Hair; Hair Cells; Hearing; Hearing problem; Homeostasis; Labyrinth; Lead; Life; Malignant Neoplasms; Mammals; Mechanics; Mediating; Molecular; Morphogenesis; Movement; Mus; Mutant Strains Mice; Natural regeneration; Numbers; Organ; Organ of Corti; Otic Placodes; Outer Hair Cells; Pathway interactions; Pattern; Play; Positioning Attribute; Presbycusis; Process; Protein Tyrosine Kinase; Receptor Protein-Tyrosine Kinases; Receptor Signaling; Role; Saccule and Utricle; Semicircular canal structure; Sensory; Side; Signal Pathway; Signal Transduction; Snails; Structure; Supporting Cell; System; day; deafness; gene function; hearing impairment; insight; intercellular communication; member; mutant; neural plate; novel; pressure; receptor; research study; response; sound; three dimensional structure; vibration

DESCRIPTION (provided by applicant): The inner ear is the organ that detects both sound pressure and linear and angular acceleration, and is vital for the senses of hearing and balance. The sensory regions of the inner ear contain the mechanosensory hair cells and their associated nonsensory supporting cells. Both the three-dimensional structure of the inner ear and the pattern and morphology of the cells that comprise the sensory region are crucial for precise function of the inner ear, and their disruption during development can lead to congenital balance and hearing deficits. Furthermore, during adult life, damage of the hair cells, which are not regenerated in mammals, can lead to late-onset hearing loss. The molecular mechanisms by which the three-dimensional structure of the inner ear is formed and by which the hair cells and their associated supporting cells are patterned are unclear, and our long-term goal is to elucidate these molecular mechanisms as a means for uncovering new strategies for the treatment of vestibular and hearing deficits. Receptor tyrosine kinase (RTK) pathways are essential for the cell-cell signaling events required for a number of developmental processes and their absence or misregulation are associated with congenital disease and cancer. We propose the study of the Sprouty (Spry) gene family, a family of modulators of RTK signaling, in mouse inner ear development. We have recently shown that Spry2 is a mouse deafness locus, and we propose to expand our understanding of the role of Spry genes in inner ear development. We have found that Spry1-/-; Spry2-/- mutants have perturbations in the three-dimensional structure of the inner ear epithelium, and we propose experiments to determine the cause of this morphogenetic defect. We have also found that Spry2 mutant mice develop extra hair and supporting cells during embryogenesis, and that SPRY2 may normally antagonize Fibroblast Growth Factor Receptor 1 (FGFR1) signaling in this process. We propose experiments to find the cellular mechanism by which these extra cells appear in the Spry2 mutant and to address the role of the FGFR1/SPRY2 signaling pathway in the determination of hair cell number. These studies should elucidate mechanisms for determining the structure of the inner ear epithelium and for controlling hair cell number which may aid in our understanding of vestibular abnormalities and suggest strategies for generating new hair cells to treat age-related hearing loss. Relevance: The inner ear is the organ that is crucial for both our senses of hearing and balance. We propose the study of a class of genes called Sprouty genes in formation of the inner ear to help in our understanding of balance disorders and to suggest new strategies for the treatment of age-related hearing loss.

描述（由申请人提供）：内耳是检测声音和线性和角度加速度的器官，对于听力和平衡感至关重要。内耳的感觉区域包含机械感觉毛细胞及其相关的非感官支撑细胞。内耳的三维结构以及构成感觉区域的细胞的模式和形态都对内耳的精确功能至关重要，并且它们在发育过程中的破坏都可以导致先天性平衡和听力不足。此外，在成人生活中，毛细胞的损害未在哺乳动物中再生，可能导致迟到的听力损失。形成内耳的三维结构，毛细胞及其相关的支撑细胞的图案不清的分子机制尚不清楚，我们的长期目标是阐明这些分子机制，以揭示用于治疗前庭和听力缺陷的新策略。受体酪氨酸激酶（RTK）途径对于许多发育过程所需的细胞 - 细胞信号传导事件至关重要，并且它们的缺失或不调节与先天性疾病和癌症有关。我们提出了小鼠内耳发育中发育型（SPRY）基因家族（SPRY）基因家族的研究。我们最近表明，Spry2是小鼠耳聋基因座，我们建议扩展我们对Spry基因内耳发育中作用的理解。我们发现Spry1 - / - ; Spry2 - / - 突变体在内耳上皮的三维结构中具有扰动，我们提出了实验以确定这种形态发生缺陷的原因。我们还发现，在胚胎发生过程中，Spry2突变小鼠会形成额外的头发和支撑细胞，并且在此过程中，SPRY2通常会拮抗成纤维细胞生长因子受体1（FGFR1）信号。我们提出的实验是找到这些额外细胞出现在SPRY2突变体中的细胞机制，并解决FGFR1/SPRY2信号通路在确定毛细胞数量中的作用。这些研究应阐明确定内耳上皮结构和控制毛细胞数的机制，这可能有助于我们理解前庭异常，并提出了产生新毛细胞治疗与年龄相关的听力损失的策略。相关性：内耳是对我们听力和平衡感至关重要的器官。我们提出了对内耳形成的一类称为发芽基因的基因的研究，以帮助我们理解平衡疾病，并提出与年龄相关的听力损失治疗的新策略。