In toto imaging and genomics to decode ear hair cell formation and regeneration

全面成像和基因组学解码耳毛细胞的形成和再生

基本信息

批准号：
8413441
负责人：
SEAN G MEGASON
金额：
$ 38.78万
依托单位：
HARVARD MEDICAL SCHOOL
依托单位国家：
美国
项目类别：
财政年份：
2010
资助国家：
美国
起止时间：
2010-02-15 至 2015-01-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8413441
关键词：
Acoustics Animals Antibodies Atlases Belief Binding Sites Bioinformatics Biological Models Biological Process Biology Cell Lineage Cell physiology Cells Chimeric Proteins Custom Data Data Analyses Development Dimensions Ear Embryo Embryonic Development Enhancers Equilibrium Fibroblast Growth Factor Fishes Four-dimensional Funding Generations Genes Genetic Genetic Transcription Genome Genomics Hair Hair Cells Health Hearing Histones Human Image Labyrinth Larva Lasers Left Logic Maps Medical Methods Microscopy Modification Molecular Molecular Models Natural regeneration Neurons Photons Process Relative (related person)Research Resolution Resources Role Sensory Stem cells Supporting Cell Systems Biology Technology Therapeutic Time Tissues Transcriptional Regulation Variant Vertebrates Work Zebrafish base cell type chromatin immunoprecipitation digital digital models functional genomics hair cell regeneration hearing impairment histone modification insight killings molecular modeling movie next generation sequencing precursor cell programs promoter public health relevance response small molecule software development transcription factor virtual

项目摘要

DESCRIPTION (provided by applicant): Loss of hearing and balance is a widespread and debilitating medical condition in humans, and is predominantly caused by a loss of hair cells, the primary sensory cell of the inner ear. Hair cells do not naturally regenerate in humans, in contrast to other animals such as zebrafish where hair cells readily regenerate. To understand hair cell formation during development and hair cell regeneration in response to damage we will undertake an integrative systems biology based approach. Our approach integrates in toto imaging which provides systematic high resolution analysis across the space and time of hair cell generation with omic approaches that allow systematic analysis of transcriptional activity across the genome. Specifically, we will use in toto imaging, a technology we developed, to generate a 4-dimensional, cell-based Digital Ear that comprehensively quantifies the cellular processes that form and regenerate hair cells in zebrafish. We will use cell-type-specific ChIP-seq of histone modifications to determine the enhancers, promoters, and insulators active across the entire genome at all the key steps of hair cell generation. Bioinformatic approaches will be used to map transcription factor binding sites within defined enhancers to the genes they control to construct a comprehensive cis-regulatory network within the virtual cells of our Digital Ear. This research will provide unprecedented insight into how the genome encodes the stepwise specification of hair cells, with potentially important implications for hair cell regeneration in humans. Relevance to Health Deficiencies in hearing and balance are widespread and debilitating. They are principally caused by loss of the sensory cells (hair cells) of the inner ear hair which cannot regenerate in humans but can in other animals. We seek to understand the genetic and cellular control of inner ear hair cell regeneration.

描述（由申请人提供）：听力和平衡丧失是人类普遍存在且使人衰弱的疾病，主要是由毛细胞（内耳的主要感觉细胞）丧失引起的。人类的毛细胞不会自然再生，而斑马鱼等其他动物的毛细胞很容易再生。为了了解发育过程中毛细胞的形成以及毛细胞响应损伤的再生，我们将采用基于综合系统生物学的方法。我们的方法集成到toto成像中，通过组学方法提供毛细胞生成的空间和时间的系统高分辨率分析，允许系统分析整个基因组的转录活性。具体来说，我们将使用我们开发的 toto 成像技术来生成 4 维、基于细胞的数字耳，全面量化斑马鱼毛细胞形成和再生的细胞过程。我们将使用组蛋白修饰的细胞类型特异性 ChIP-seq 来确定在毛细胞生成的所有关键步骤中整个基因组中活跃的增强子、启动子和绝缘子。生物信息学方法将用于将定义的增强子内的转录因子结合位点映射到它们控制的基因，以在我们的数字耳的虚拟细胞内构建全面的顺式调控网络。这项研究将为基因组如何编码毛细胞的逐步规范提供前所未有的见解，对人类毛细胞再生具有潜在的重要意义。与健康的相关性听力和平衡能力缺陷很普遍，而且使人衰弱。它们主要是由内耳毛发的感觉细胞（毛细胞）损失引起的，这种细胞在人类中无法再生，但在其他动物中可以再生。我们寻求了解内耳毛细胞再生的遗传和细胞控制。