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Notch Signaling Pathways in Auditory Supporting Cell Differentiation and Maintenance

听觉支持细胞分化和维持中的Notch信号通路

基本信息

批准号：
9239014
负责人：
ANGELIKA DOETZLHOFER
金额：
$ 34.43万
依托单位：
JOHNS HOPKINS UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2011
资助国家：
美国
起止时间：
2011-03-01 至 2021-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9239014
关键词：
Address Animals Auditory Auditory Physiology Cell Differentiation process Cell Maintenance Cell Maturation Cell Survival Cell physiology Cellular Morphology Cochlea Cues Data Defect Development Epithelium Frequencies Functional disorder Future Gene Targeting Generations Goals Hair Cells Homeostasis Human Lead Ligands Light Mammals Measurement Mediating Molecular Morphology Mus Natural regeneration Neurons Notch Signaling Pathway Outer Hair Cells Physiology Play Production RNA-Binding Proteins Regenerative response Replacement Therapy Repression Role Sensory Sensory Hair Signal Transduction Staging Stimulus Supporting Cell Tissues Transgenic Mice Vertebrates activin A base biophysical properties cell injury deafness gamma secretase gene function hair cell regeneration hearing impairment in vivo regeneration inhibitor/antagonist insight mutant nerve supply new therapeutic target notch protein novel novel therapeutic intervention overexpression postnatal ranpirnase receptor regenerative repaired research study response transcriptome

项目摘要

Project summary Auditory supporting cells (SCs) are essential for the proper development, survival and function of mechano- sensory hair cells (HCs) and their innervating neurons. Defects in the biophysical properties or function of SCs result in auditory dysfunction and hearing loss. Despite their importance the molecular mechanisms that control their development and function are largely unknown. A main objective of our proposed study is to uncover the molecular mechanisms that guide auditory SCs development and function. We recently uncovered that Notch signaling instructs SC development in the murine cochlea. Here in this proposed study we will determine the Notch ligand(s) and receptor(s) that control SC differentiation and survival (aim1) as well characterize potential novel roles for Notch signaling and its targets in SC-guided cochlear innervation and auditory function (aim2). Our proposed studies will advance our understanding of how Notch signaling operates in differentiating SCs as wells as provide new insights into how SCs guide neuronal innervation as well as control cochlear homeostasis. A second major objective of our proposed study is to uncover the molecular mechanisms that control the developmental decline of SCs plasticity in the mammalian cochlea. HC loss in mammals is permanent and is a leading cause for deafness in humans. In non- mammalian vertebrates SCs regenerate lost HCs throughout the lifetime of the animal. In mammals, young immature SCs can be coaxed into regenerating lost HCs by inhibiting Notch signaling or over-stimulation of wnt signaling; however, the ability of murine auditory SC to respond to such regenerative stimuli rapidly declines after the first postnatal week. We recently uncovered that the RNA binding protein LIN28B enhances HC production in the immature cochlea in response to Notch signaling. In aim3 we will investigate how LIN28B/let- 7 axis modifies the regenerative response of the immature SCs, as well as address whether LIN28B re- expression in mature SCs enhances their ability to respond to Notch inhibition and regenerate lost HCs. Findings from the proposed experiments could identify new therapeutic targets and lead to novel therapeutic approaches in the treatment of HC loss and eventual cure of deafness.

项目总结