Cellular and Molecular Mechanisms of Ear Morphogenesis

耳朵形态发生的细胞和分子机制

基本信息

批准号：
7534350
负责人：
Lisa Goodrich
金额：
$ 39.66万
依托单位：
HARVARD MEDICAL SCHOOL
依托单位国家：
美国
项目类别：
财政年份：
2004
资助国家：
美国
起止时间：
2004-12-23 至 2010-09-22
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7534350
关键词：
Acceleration Agonist Alkaline Phosphatase Alleles Apoptosis Architecture Auditory Auditory system Behavior Binding Biological Assay Biological Testing Bromodeoxyuridine Candidate Disease Gene Cell Adhesion Cell Aggregation Cell Communication Cell Death Cell Proliferation Cells Characteristics Chimeric Proteins Cochlea Complex Computer Systems Development Cytoplasmic Tail Data Defect Development Dimensions Ear Embryo Embryology Epithelium Equilibrium Event Extracellular Domain Failure Family Family member Freezing Gene Expression Generations Genes Genetic Genetic Programming Grant Gravity Perception Hearing Housing Human Hyperactive behavior In Situ Hybridization In Vitro Inherited Integral Membrane Protein Labyrinth Lateral Ligands Light Maps Microinjections Molecular Molecular Target Morphogenesis Mus Mutagenesis Mutant Strains Mice Mutation Nature Organ Otic Vesicle Pattern Phenotype Process Protein Family Proteins Relative (related person)Semicircular canal structure Sensory Series Signal Pathway Signal Transduction Signaling Molecule Staging Staining method Stains Structure TdT-Mediated dUTP Nick End Labeling Assay Testing Therapeutic Intervention Time Tissues Transmembrane Domain Transmission Electron Microscopy Virus cellular targeting congenital deafness equilibration disorder in vivo loss of function malformation mutant novel otoconia overexpression receptor research study sound

项目摘要

DESCRIPTION (provided by applicant): The inner ear houses the sensory organs for hearing and balance. Sound is detected in the cochlea; linear acceleration and gravity are sensed in the otolith organs; and angular acceleration is detected in the three semicircular canals, oriented in three orthogonal dimensions. The entire structure arises during development from a simple ball of epithelium, the otic vesicle. Proper auditory and vestibular function therefore relies on the perfect execution of the genetic programs that transform the otic vesicle into the complex labyrinths of the mature inner ear. At a cellular level, morphogenesis of the inner ear involves regulated cell proliferation, apoptosis, and cell-cell interactions. Identification of the ligands and receptors that control these processes in mice may point to new candidate genes and/or therapeutic interventions for inherited inner ear defects in humans. Many forms of human congenital deafness and balance disorders are caused by malformations of the inner ear, which can range from a complete failure to progress beyond the otic vesicle stage to the loss of specific structures such as the cochlea or one semicircular canal. This study examines the contributions of an intriguing family of novel proteins, the Lrigs, to inner ear development. All three Lrigs are proposed to have extracellular domains largely consisting of protein interaction motifs, a single transmembrane domain, and divergent cytoplasmic tails. Lrig3 is required for formation of the lateral semicircular canal in mice. In order to understand the origin and nature of this defect experiments will be performed using mouse genetics, chick embryology, and molecular assays 1) to determine when and where the three Lrig genes are expressed in the ear, 2) to examine in detail the cellular nature of the Lrig3 mutant phenotype and 3) to define the molecular characteristics of this novel protein family, using both in vitro and in vivo assays. Results from these experiments may shed new light on the complicated series of events that are necessary for normal structure and therefore function of the inner ear.

描述（由申请人提供）：内耳设有感官器官以进行听力和平衡。在耳蜗中检测到声音；在耳石器官中感受到线性加速度和重力；在三个半圆形管中检测到角加速度，以三个正交尺寸为导向。整个结构是由简单的上皮球（眼球囊泡）发育而来的。因此，适当的听觉和前庭功能依赖于将眼球囊泡转化为成熟内耳的复杂迷宫的遗传程序的完美执行。在细胞水平上，内耳的形态发生涉及调节细胞增殖，凋亡和细胞相互作用。在小鼠中控制这些过程的配体和受体的鉴定可能指向人类遗传内耳缺陷的新候选基因和/或治疗性干预措施。许多形式的人类先天性耳聋和平衡性疾病是由内耳畸形引起的，内耳的畸形可能从完全失败到超出眼球囊泡阶段的进展到丧失特定结构（例如耳蜗或一个半圆形管）。这项研究研究了一个有趣的新型蛋白质（LRIGS）对内耳发育的贡献。所有三个LRIG均提出具有主要由蛋白质相互作用基序，单个跨膜结构域和发散的细胞质尾巴组成的细胞外域。 LRIG3是在小鼠中形成横向半圆形管所必需的。为了理解该缺陷实验的起源和性质，将使用小鼠遗传学，雏鸡的胚胎学和分子测定法进行1）确定在耳朵中表达三个LRIG基因的何时何地，2）详细检查了LRIG3突变体表型的细胞性质，并使用该新颖的蛋白质群体，并在使用该新颖的蛋白质家族中定义了该蛋白质的分子特征，并在使用该新颖的蛋白质方面。这些实验的结果可能会对正常结构所必需的一系列复杂事件以及内耳的功能开发新的启示。