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Dynamic interaction among proteins in hair cells

毛细胞中蛋白质之间的动态相互作用

基本信息

批准号：
9527906
负责人：
Jing Zheng
金额：
$ 49万
依托单位：
NORTHWESTERN UNIVERSITY AT CHICAGO
依托单位国家：
美国
项目类别：
财政年份：
2012
资助国家：
美国
起止时间：
2012-03-01 至 2019-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9527906
关键词：
Acoustics Adhesives Affect Age Alleles Anatomy Auditory Auditory Physiology Behavior Binding Binding Proteins Biochemistry Biological Biophysics CDH23 gene CRISPR/Cas technology Calmodulin Cell Shape Cells Cellular Morphology Cellular Structures Cellular biology Centrosome Cochlea Code Complex Cytoplasmic Protein Data Development Dimensions Electrophysiology (science)Epithelial Cells Excision Foundations Future GFI1 gene Gene Mutation Genes Genomics Goals Hair Cells Hearing Human Immunohistochemistry Impairment In Vitro Individual Inherited Knock-in Mouse Knock-out Knockout Mice Knowledge Labyrinth LacZ Genes Link Maintenance Maps Mass Spectrum Analysis Mediating Methods Microtubule-Associated Proteins Microtubules Minus End of the Microtubule Molecular Molecular Biology Morphogenesis Mus Mutation Names Neuraxis Neurons Organ Organ of Corti Outer Hair Cells Pathology Pathway interactions Patients Pattern Peripheral Pharmacological Treatment Physiological Physiology Pigmentation physiologic function Pillar Cell Play Protein Isoforms Proteins Proteomics Reflex action Regulation Reporter Reporter Genes Role Sensory Disorders Signal Transduction Spectrin Steel Structure Supporting Cell System Testing Therapeutic Transport Vesicles Usher Syndrome Vesicle Transport Pathway WD Repeat Waardenburg syndrome cell type deafness design experimental study external ear auricle gene therapy hearing impairment in vitro Assay in vivo mouse model mutant mutant mouse model negative affect novel operation polarized cell prevent sound spiral ganglion

项目摘要

PROJECT SUMMARY The cochlea converts sound waves into electrical signals to convey information to the central nervous system. Highly specialized cells including hair cells, supporting cells and spiral ganglion neurons mediate this operation. Because complex and sophisticated microtubule (MT) networks are needed for the individualized cell shapes and structures required for peripheral signal coding, uncovering the protein networks that modulate MT organization will enrich our understanding of both normal and impaired cochlear physiology. The goal of this proposal is to investigate three largely unexplored proteins, whose functions may be important for the regulation of MTs in the inner ear: CAMSAP3, CDH23-C, and WDR47. CAMSAP3 is a MT minus-end binding protein, while CDH23-C, a cytoplasmic isoform of CDH23, and WDR47, a protein of unknown function, both interact with CAMSAP3. Deletion or mutation of these genes is linked to hearing impairment in humans and in mouse models. Thus, they may potentially be responsible for causing hereditary hearing loss. In AIM I, we investigate the role of CAMSAP3 using conditional knockout mouse models that lack CAMSAP3 in individual cell types in the cochlea including hair cells, supporting cells, and spiral ganglion neurons. We will examine these mice using various anatomical and physiological methods to determine the function of CAMSAP3 in hearing. In AIM II, we investigate the functional consequences of impaired interaction between CDH23-C and CAMSAP3. We will generate a CDH23-C mutant mouse model that mimics the human Usher Syndrome 1D mutation that negatively affects this interaction, and evaluate the importance of the role of CDH23-C in MT regulation via its interaction with CAMSAP3. The experiments are designed to reveal a novel molecular mechanism that involves MT modulation in the cochlea and that is implicated in Usher Syndrome 1D. In Aim III, we investigate the function of WDR47 in hearing through both in vivo and in vitro approaches. We will determine the detailed expression patterns of WDR47 in the cochlea and investigate WDR47's contribution to hearing using WDR47 knockout mice. We will also dissect the molecular basis of interactions between WDR47 and CAMSAP3, and uncover WDR47-associated proteins through both biochemistry and proteomics. Taken together, the proposed studies aim to provide critical information regarding the protein networks that regulate MT organization in the cochlea by focusing on three proteins. Our comprehensive approach utilizes a variety of methods including molecular and cell biology, biophysics, electrophysiology, in vivo physiology and mass spectrometry, thereby allowing us to achieve our goals. The data obtained from the proposed experiments will provide new knowledge about the molecular mechanisms underlying the pathology of hearing loss, and enrich our understanding of the protein networks important for hearing and deafness. This information will guide our current and future efforts in directing treatments and/or in preventing hearing loss.

项目总结