Mechanism and Functional Significance of Polarity Reversal in Mechanosensory Organs

机械感觉器官极性反转的机制和功能意义

基本信息

批准号：
10057376
负责人：
Kathleen E Cullen
金额：
$ 69.83万
依托单位：
JACKSON LABORATORY
依托单位国家：
美国
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-12-01 至 2024-11-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10057376
关键词：
Ablation Acceleration Address Adopted Adult Affect Age Anatomy Animal Model Anterior Auditory Automobile Driving Behavior Birth Calcium Cell Differentiation process Cell Maturation Cell Polarity Cell physiology Cells Cessation of life Complex Data Development Disease Dizziness Electrophysiology (science)Ensure Epithelial Epithelial Cells Equilibrium Evoked Potentials Eye Movements Fishes Frequencies Functional disorder G-Protein-Coupled Receptors G-substrate GTP-Binding Proteins Genetic Genetic Epistasis Goals Gravity Perception Hair Hair Cells Head Head Movements Hearing Heterotrimeric GTP-Binding Proteins Homologous Gene Image Impairment Intercellular Junctions Ion Channel Labyrinth Lateral Measures Mechanics Mediating Modality Molecular Motion Mus Mutant Strains Mice Organ Orphan Pathway interactions Pattern Pertussis Toxin Phenocopy Physiology Population Positioning Attribute Process Proteins Research Role Saccule and Utricle Saccule structure Sense Organs Sensory Shapes Signal Transduction Sister Stimulus System Testing Time Utricle structure Vertebrates Vision Visual Water Movements Work Zebrafish afferent nerve base behavior test emx2 protein gamma-Aminobutyric Acid gaze innovation insight interest kinetosome lateral line macula mechanotransduction molecular marker mutant nerve supply neuromast planar cell polarity prevent programs public health relevance receptor receptor function regional difference response signal processing therapy design transcription factor vestibulo-ocular reflex virtual water flow

Ablation Acceleration Address Adopted Adult Affect Age Anatomy Animal Model Anterior Auditory Automobile Driving Behavior Birth Calcium Cell Differentiation process Cell Maturation Cell Polarity Cell physiology Cells Cessation of life Complex Data Development Disease Dizziness Electrophysiology (science)Ensure Epithelial Epithelial Cells Equilibrium Evoked Potentials Eye Movements Fishes Frequencies Functional disorder G-Protein-Coupled Receptors G-substrate GTP-Binding Proteins Genetic Genetic Epistasis Goals Gravity Perception Hair Hair Cells Head Head Movements Hearing Heterotrimeric GTP-Binding Proteins Homologous Gene Image Impairment Intercellular Junctions Ion Channel Labyrinth Lateral Measures Mechanics Mediating Modality Molecular Motion Mus Mutant Strains Mice Organ Orphan Pathway interactions Pattern Pertussis Toxin Phenocopy Physiology Population Positioning Attribute Process Proteins Research Role Saccule and Utricle Saccule structure Sense Organs Sensory Shapes Signal Transduction Sister Stimulus System Testing Time Utricle structure Vertebrates Vision Visual Water Movements Work Zebrafish afferent nerve base behavior test emx2 protein gamma-Aminobutyric Acid gaze innovation insight interest kinetosome lateral line macula mechanotransduction molecular marker mutant nerve supply neuromast planar cell polarity prevent programs public health relevance receptor receptor function regional difference response signal processing therapy design transcription factor vestibulo-ocular reflex virtual water flow

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项目摘要

PROJECT SUMMARY/ABSTRACT Vestibular disorders affect as many as 35% of adults past age 40. Studies of the vestibular inner ear have yielded important insights into how we process and compensate for head motion including the existence of parallel channels of information in the afferent nerve. In macular organs, for example, two populations of hair cells adopt opposite planar orientations of their hair bundles and thus opposite responses to head movements. This highly conserved bidirectional organization was first described in neuromasts, the lateral line organs sensing water movements in fish, but the genetic program implementing this reversal during development is only starting to be deciphered. Consequently, ablation studies to reveal the importance of reversal for vestibular function have not been possible until recently. Here we propose to address this question by investigating the consequences of inactivating an orphan G protein coupled receptor (GPCRx), implicated by our preliminary data in orientation reversal in mouse hair cell epithelia. Based on our preliminary data, we suggest that mouse GPCRx functions downstream of the transcription factor EMX2 and upstream of the heterotrimeric G protein Gi to reverse a ground state of polarity established by planar cell polarity proteins. We will test this hypothesis and also use the GPCRx mutant as an animal model to pinpoint how polarity reversal shapes macular organ responses and downstream effects on vestibular behaviors. To reach these goals, we will: 1) Use genetics to determine how GPCRx instructs reversal at the molecular level, solving its epistatic relationship to EMX2, Gi and planar cell polarity proteins in mice, and use zebrafish to test whether GPCRx-Gi is a conserved effector pathway for reversal. 2) Use molecular markers, electrophysiology and calcium imaging to resolve hair cell maturation and function in absence of polarity reversal. 3) Determine how polarity reversal affects afferents' organization and function, with afferent recordings, as well as overall vestibular function using behavioral tests. Our coherent body of preliminary evidence ensures the feasibility and the high interest of the project, and our focus on a virtually unstudied receptor protein guarantees innovation. The multi-PI team is ideally suited to address complementary questions in both the mouse and zebrafish acoustico-lateralis systems. We anticipate that this collaborative effort will be decisive towards solving the mechanism of hair cell orientation reversal, its conservation across vertebrates and its significance for mammalian vestibular physiology. Thorough understanding of polarity reversal will help interpret and design treatments for vestibular dysfunctions.

项目摘要/摘要前庭障碍影响多达35％的成年人40岁。前庭内耳的研究对我们如何处理和补偿头部运动有重要见解，包括存在传入神经中的并行信息渠道。例如，在黄斑器官中，两个头发种群细胞采用相反的平面方向的头发束，因此对头部运动的反应相反。这个高度保守的双向组织首先在Neuromasts中描述感知鱼类的水运动，但是在开发过程中实施这种逆转的基因计划是仅开始决定。因此，消融研究以揭示逆转的重要性直到最近才可能进行前庭功能。在这里，我们建议通过研究灭活孤儿G蛋白偶联受体（GPCRX）的后果，与我们在小鼠毛细胞上皮中取向逆转的初步数据。根据我们的初步数据，我们建议小鼠GPCRX函数在转录因子EMX2的下游和上游异三聚体G蛋白GI逆转平面细胞极性蛋白建立的极性基态。我们将检验该假设，还将使用GPCRX突变体作为动物模型来指出极性逆转塑造黄斑器官的反应和对前庭行为的下游影响。到达这些目标，我们将：1）使用遗传学来确定GPCRX如何在分子层面上逆转，以解决其小鼠中与EMX2，GI和平面细胞极性蛋白的上皮关系，并使用斑马鱼测试是否是否 GPCRX-GI是逆转的保守效应途径。 2）使用分子标记，电生理学和在没有极性逆转的情况下，钙成像以解决毛细胞的成熟和功能。 3）确定如何极性逆转影响着传入的记录以及总体上的传入的组织和功能使用行为测试的前庭函数。我们的初步证据的一致机构可确保可行性以及该项目的浓厚兴趣，以及我们对几乎未研究的受体蛋白的关注创新。 Multi-Pi团队非常适合解决鼠标和斑马鱼声学系统。我们预计这项协作努力将被决定解决毛细胞取向逆转的机理，其跨脊椎动物的保护及其意义用于哺乳动物的前庭生理学。对极性逆转的彻底理解将有助于解释和设计前庭功能障碍的治疗方法。