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Wnt pathway mutations alter hair cell regeneration in the zebrafish fish lateral line

Wnt 通路突变改变斑马鱼侧线毛细胞再生

基本信息

批准号：
10663381
负责人：
Hillary Faye McGraw
金额：
$ 19.56万
依托单位：
UNIVERSITY OF MISSOURI KANSAS CITY
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-07-11 至 2026-06-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10663381
关键词：
Adult Affect Age Biological Models Cell Differentiation process Cell Proliferation Cell Survival Cells Cellular Morphology Cellular biology Cochlea Data Defect Development Disease Equilibrium Esthesia Exposure to FOXG1B gene Family Fishes Force of Gravity Generations Genes Genetic Genetic Transcription Goals Hair Cells Hearing Human Injury Labyrinth Ligand Binding Mammals Mediating Modeling Molecular Mutation Natural regeneration Neomycin Neonatal Noise Outcome Pathway interactions Pharmaceutical Preparations Population Proliferating Proteins Quality of life Research Role Sensory Sensory Hair Supporting Cell System Testing Touch sensation Transcriptional Activation Vertebrates WNT Signaling Pathway Water Work Zebrafish cell injury equilibration disorder experience experimental study gene function genetic manipulation hair cell regeneration hair regeneration hearing impairment hearing loss treatment inhibitor lateral line model organism mutant neonatal mice noise exposure ototoxicity permanent hearing loss pharmacologic public health relevance receptor regenerative response stem cells targeted treatment transcription factor zebrafish development

项目摘要

Abstract Debilitating hear loss affects over 6% of the world’s population and can result in a profound decrease in the quality of life for those afflicted. Hearing is mediated by mechanosensory hair cells located in the cochlea of the inner ear. Another population of hair cells in the inner ear makes up the vestibular system to relay the sensation of balance and gravity. Hair cell damage results in sensory defects. The causes of hair cell damage include age, noise exposure, ototoxic drugs, disease, and injury. In adult mammals, once hair cells are lost, they do not regenerate, resulting in permanent hearing loss and balance disorders. In addition to mediating the sensations of hearing and balance, mechanosensory hair cells are also required for close touch sensation in the lateral line systems of aquatic vertebrates. Lateral line hair cells are morphologically and genetically very similar to inner ear hair cells. In contrast to the inner ear hair cell of mammals, the hair cells of the lateral line system are robustly regenerative. The zebrafish (Danio rerio), has emerged as a valuable model to study the mechanisms of mechanosensory hair cell regeneration. Research using pharmacological manipulation of the canonical Wnt pathway suggests that it is critical for regulating the cellular proliferation and differentiation required for hair cell regeneration. To genetically confirm a role for Wnt signaling during regeneration, we will use three zebrafish lines carrying mutations at different points in the Wnt pathway. In Aim 1, we will characterize hair cell regeneration in the krm1nl10 mutant, which results in overactivation of Wnt signaling. In Aim 2, we will characterize regeneration in the lef1nl2 mutant line, which results in an inhibition of Wnt activity. In Aim 3, we will examine regeneration in a third line, foxg1aa266, which contains a mutation in the Wnt transcriptional target gene foxg1a. Together, we will use these lines to determine how cellular proliferation, differentiation, and survival are regulated by the Wnt pathway during regeneration of mechanosensory hair cells. The long-term goal of this work is to provide a mechanism for regenerate hair cells in the human inner ear.

摘要

项目成果

期刊论文数量（1）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Kremen1 regulates the regenerative capacity of support cells and mechanosensory hair cells in the zebrafish lateral line.

DOI：
10.1016/j.isci.2023.108678
发表时间：
2024-01-19
期刊：
ISCIENCE
影响因子：
5.8
作者：
Megerson, Ellen;Kuehn, Michael;Leifer, Ben;Bell, Jon M.;Snyder, Julia L.;McGraw, Hillary F.
通讯作者：
McGraw, Hillary F.