Genetic and Molecular Analysis of Hair Cell Regeneration in Zebrafish

描述（由申请人提供）：本提案的总体目标是确定调节毛细胞再生的遗传和分子途径。正向遗传筛选提供了一种无偏见的方法来鉴定正常再生所需的基因。斑马鱼是唯一适合于筛选，以确定突变体与异常毛细胞再生毛细胞在侧线是在身体的外部和易于可视化和操作。在此筛选过程中发现的基因异常再生将被映射和表征，这些基因的功能将提供有关斑马鱼侧线再生调控的细胞和分子生物学的见解。了解这些专门的机械感觉细胞的再生可以提供适用于人类健康的见解，特别是与年龄相关的听力损失和平衡障碍。毛细胞的替换在鱼类和其他非哺乳类脊椎动物中很常见，但在人类中不发生。了解斑马鱼毛细胞再生的遗传和分子组成可能有助于治疗甚至预防人类毛细胞损失。该提案描述了在初步筛选中鉴定的再生突变体Moby-1的表征，并提出了三个研究目标：表征3个额外的突变体，进一步分析Moby-1以确定再生减少是否是增殖减少或早熟终止的结果，最后，定位突变以鉴定受影响的基因。该提案中的实验将提供新的突变菌株，这是整个斑马鱼社区的资源，确定潜在的新基因，并揭示其在毛细胞再生中的功能，并有助于开发人类听力和平衡障碍的治疗方法

DESCRIPTION (provided by applicant): The overall goal of this proposal is to define the genetic and molecular pathways regulating hair cell regeneration. Forward genetic screens provide an unbiased approach to identifying genes required for normal regeneration. The zebrafish is uniquely suited for a screen to identify mutants with abnormal hair cell regeneration hair cells in the lateral line are on the outside of the body and readily accessible for visualization and manipulation. Genes identified during this screen for abnormal regeneration will be mapped and characterized and the function of these genes will provide insights as to the cellular and molecular biology regulating regeneration in the zebrafish lateral line. Understanding regeneration of these specialized mechanosensory cells may provide insights applicable to human heath, particularly age related hearing loss and balance disorders. Replacement of hair cells is common in fish and other non-mammalian vertebrates but does not occur in humans. Understanding the genetic and molecular components underlying hair cell regeneration in zebrafish may contribute to treating or even preventing hair cell loss in humans. This proposal describes the characterization of moby-1, a regeneration mutant identified in preliminary screening and presents three research aims: characterization of 3 additional mutants, further analysis of mby-1 to determine whether decreased regeneration is the result of decreased proliferation or precocious termination and finally, mapping mutations to identify the affected gene. The experiments in this proposal will provide new mutant strains, a resource for the entire zebrafish community, identify potentially novel genes, and uncover their function in hair cell regeneration, and contribute to the development of treatments for human hearing and balance disorders