Analysis of Hair Cell Regeneration in Zebrafish

斑马鱼毛细胞再生分析

• 批准号: 7933796
• 负责人: Tatjana Piotrowski
• 金额: $ 17.23万
• 依托单位: UNIVERSITY OF UTAH
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-09-17 至 2011-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7933796
• 关键词: Adult; Age; Aging; Amphibia; Antibiotic Therapy; Automobile Driving; Behavior; Binding; Bioinformatics; Biological Models; Birds; Candidate Disease Gene; Cell Death; Cell Lineage; Cell Maintenance; Cell Proliferation; Cells; Cochlea; Complex; Coupled; Development; Dissection; Ear; Fishes; Foundations; Gene Expression Profile; Genes; Genetic; Goals; Hair Cells; Homeostasis; Human; Inner Supporting Cell; Laboratories; Labyrinth; Larva; Life Cycle Stages; Location; Mammals; Methods; Microarray Analysis; Modeling; Molecular; Mus; Natural regeneration; Noise; Organ; Pathway interactions; Platyhelminths; Population Dynamics; Process; Promoter Regions; Regulation; Sampling; Sensory; Sensory Hair; Signal Transduction; Staging; Stem cells; Supporting Cell; System; Techniques; Testing; Time; Tissues; Vertebrates; Zebrafish; base; cell type; cohort; cost; deafness; disability; gene function; gene repression; hair cell regeneration; insight; lateral line; neuromast; novel; public health relevance; research study; therapeutic development; tool; transcription factor

DESCRIPTION (provided by applicant): A prominent cause of deafness is loss of hair cells due to age, noise or antibiotic treatments. In contrast to mammalian hair cells, fish, bird and amphibian hair cells are constantly turning over and regenerate following hair cell death. The aim is to take advantage of the lateral line of zebrafish to define and characterize the molecular and cellular interactions occurring during hair cell regeneration with the long-term goal of activating these pathways in mammals. To uncover the mechanisms driving hair cell regeneration, the lateral line of the zebrafish was chosen as an experimental paradigm because of 1) the ability of zebrafish support cells to regenerate hair cells; 2) the functional and morphological similarity between the lateral line hair cells and the hair cells of the inner ear; 3) its accessibility to direct observation and manipulation throughout development; and 4) the ability to rapidly and cost-effectively isolate specific cell types involved in hair cell regeneration, experiments that are difficult to perform in the classical model systems, e.g., mouse and chick. The two laboratories are pursuing the following strategy to identify the earliest genes that are transcribed in support cells subsequent to hair cell death. First, the location and population dynamics of stem cells and surrounding niche cells in normal and regenerating neuromasts will be determined, which is essential for determining the signals required for stem cell maintenance and activation. Secondly, the transcriptome of purified support cells will be defined using microarray analyses. To systematically analyze all candidate genes identified, a novel and powerful bioinformatics approach will be employed to identify genes co-regulated by the same transcription factors. Identifying these important transcription factors will be crucial for our understanding of how regeneration is triggered in lower vertebrates. Combined, these two approaches will discover key hair cell regeneration genes and set the stage for a systematic dissection of this complex problem to inform the development of therapeutics to regenerate hair cells in mammals. PUBLIC HEALTH RELEVANCE: Stem cells are crucial for adult tissue homeostasis and regeneration. The zebrafish lateral line is an excellent model to elucidate the genetic pathways controlling stem cells and sensory hair cell regeneration. Results from our studies will aid in the identification of stem cells in the mammalian ear and in the development of therapeutic strategies to regenerate hair cells in mammals.

描述（由申请人提供）：耳聋的一个显着原因是由于年龄，噪声或抗生素处理而导致毛细胞的丧失。与哺乳动物的毛细胞，鱼，鸟和两栖动物细胞在毛细胞死亡后不断翻转并再生。目的是利用斑马鱼的横向线来定义和表征毛细胞再生过程中发生的分子和细胞相互作用，其长期目标是激活哺乳动物中的这些途径。为了发现驱动毛细胞再生的机制，由于1）斑马鱼支持细胞再生毛细胞的能力，因此选择了斑马鱼的侧线作为实验范式； 2）横向线毛细胞和内耳毛细胞之间的功能和形态相似性； 3）在整个开发过程中直接观察和操纵的可及性； 4）能够快速和成本地分离毛细胞再生的特定细胞类型的能力，在经典模型系统（例如小鼠和小鸡）中难以执行的实验。这两个实验室正在采取以下策略，以识别毛细胞死亡后支持细胞中最早的基因。首先，将确定干细胞的位置和人口动态和周围的细胞在正常和再生神经瘤中的位置和动力学，这对于确定干细胞维持和激活所需的信号至关重要。其次，将使用微阵列分析来定义纯化支持单元的转录组。为了系统地分析所有鉴定的候选基因，将采用一种新颖而强大的生物信息学方法来识别由相同转录因子共同调节的基因。确定这些重要的转录因子对于我们了解如何在下部脊椎动物中触发再生至关重要。这两种方法结合在一起，将发现关键的毛细胞再生基因，并为该复杂问题的系统解剖奠定了基础，以告知疗法的开发以再生哺乳动物的毛细胞。 公共卫生相关性：干细胞对于成人组织稳态和再生至关重要。斑马鱼侧线是阐明控制干细胞和感觉毛细胞再生的遗传途径的绝佳模型。我们的研究结果将有助于鉴定哺乳动物耳朵中的干细胞以及开发哺乳动物中毛细胞的治疗策略。