SPROUTY GENE FUNCTION IN MOUSE INNER EAR DEVELOPMENT

描述（由申请人提供）：内耳是检测声压以及线性和角加速度的器官，对于听觉和平衡感至关重要。内耳的感觉区包含机械感觉毛细胞和它们相关的非感觉支持细胞。内耳的三维结构以及组成感觉区的细胞的模式和形态对于内耳的精确功能至关重要，并且它们在发育期间的破坏可能导致先天性平衡和听力缺陷。此外，在成年期，哺乳动物中不能再生的毛细胞的损伤可导致迟发性听力损失。内耳三维结构形成的分子机制以及毛细胞及其相关支持细胞形成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-细胞信号传导事件是必不可少的，并且它们的缺失或失调与先天性疾病和癌症相关。我们提出的Sprouty（Spry）基因家族，RTK信号的调制器，在小鼠内耳发育的家庭的研究。我们最近表明，Spry 2是一个小鼠耳聋的基因座，我们建议扩大我们的理解，在内耳发育的Spry基因的作用。我们已经发现，Spry 1-/-; Spry 2-/-突变体在内耳上皮的三维结构中具有扰动，并且我们提出实验来确定这种形态发生缺陷的原因。我们还发现，Spry 2突变小鼠在胚胎发育过程中会发育出额外的毛发和支持细胞，并且在此过程中，SPRY 2通常可以拮抗成纤维细胞生长因子受体1（FGFR 1）信号传导。我们提出的实验，以找到这些额外的细胞出现在Spry 2突变体的细胞机制，并解决的FGFR 1/SPRY 2信号通路的作用，在毛细胞数量的测定。这些研究应该阐明确定内耳上皮结构和控制毛细胞数量的机制，这可能有助于我们理解前庭异常，并提出产生新的毛细胞治疗年龄相关性听力损失的策略。相关性：内耳是对我们的听觉和平衡感至关重要的器官。我们建议研究一类称为Sprouty基因的基因在内耳形成中的作用，以帮助我们理解平衡障碍，并提出治疗与年龄相关的听力损失的新策略。

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.