The mechanism of inner ear pressure homeostasis by the endolymphatic sac

内淋巴囊维持内耳压力稳态的机制

• 批准号: 9309422
• 负责人: SEAN G MEGASON
• 金额: $ 40.48万
• 依托单位: HARVARD MEDICAL SCHOOL
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-02-09 至 2022-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9309422
• 关键词: Adolescent; Adult; Affect; Anatomy; Animal Model; Apical; Attention; Autophagocytosis; Brain; Cell membrane; Cells; Cessation of life; Confocal Microscopy; Data; Defect; Development; Diffusion; Disease; Distal; Drug Targeting; Dura Mater; Dyes; Ear; Economic Inflation; Electron Microscopy; Endolymph; Endolymphatic Hydrops; Endolymphatic duct; Epithelial; Epithelial Cells; Epithelium; Equilibrium; Etiology; Excision; Failure; Foundations; Genetic; Goals; Hearing; Histology; Homeostasis; Hour; Human; Image; Immunofluorescence Immunologic; Immunologic Surveillance; Injection of therapeutic agent; Intercellular Junctions; Knowledge; Labyrinth; Lead; Liquid substance; Measures; Meniere' s Disease; Modeling; Molecular; Morphology; Mus; Pathway interactions; Pendred Syndrome; Pharmaceutical Preparations; Pharmacology; Phenotype; Physiologic pulse; Physiology; Play; Population; Prevention; Process; Quail; Reagent; Regulation; Research; Resolution; Rest; Role; Saccule structure; Sensory; Series; Side; Signal Transduction; Structure; Swelling; Syndrome; Temporal bone structure; Testing; Therapeutic Intervention; Thinness; Travel; Vertebrates; Vestibular Aqueduct; Work; Zebrafish; base; blind; cell type; cranium; endolymphatic sac; experimental study; hearing impairment; human disease; inner ear diseases; mutant; novel; pressure; reconstruction; small molecule; sound; translational impact

Abstract Hearing and balance loss is prevalent in every population and poses significant challenges to those affected. For many types of hearing and balance loss including Meniere's Disease, Enlarged Vestibular Aqueduct Syndrome, and Pendred Syndrome, the mechanism underlying the disease is currently unknown but is suggested to result from the loss of endolypmh volume and pressure control in the inner ear. Our long-term goal is to understand how the exquisite morphology of the inner ear is created during development and maintained in adults. Here we focus on the role of inner ear fluid pressure regulation by the endolymphatic sac in this process. The endolymphatic sac is a deeply conserved yet mysterious and poorly studied part of the inner ear. It has previously been suggested that the endolymphatic sac absorbs excess endolymph but through an unknown mechanism. Our preliminary data using state of the art timelapse imaging on larval zebrafish reveals that the endolymphatic sac pulses: the lumenal volume slowly increases over 1-3 hours and then rapidly decreases over several minutes. Endolymph pressure is necessary and sufficient for the expansion of the endolymphatic sac, and breaches in the epithelial barrier are necessary and sufficient for its collapse. These breaches occur at a novel cell-cell junction we term “basal lamellar junctions” that seem to act as pressure relief valves. These preliminary data support our central hypothesis that regulated breaches in the epithelial barrier of the endolymphatic sac at specialized pressure relief valves are essential for proper fluid homeostasis in the inner ear; failure of these pressure relief valves causes endolypmh pressure to build up leading to inner ear swelling, death of sensory cells, and unregulated tearing of the otic epithelium called endolymphatic hydrops. We plan to test our central hypothesis using three specific aims: 1) identify the molecular and cellular mechanisms of valve formation; 2) determine the role of the valve in homeostasis of endolymph pressure and composition; and 3) determine the structure and function of the valve across species and developmental stages. Our experimental approach will use functional studies on zebrafish and quail and descriptive studies on mouse and human. Our studies will employ state of the art 3D, timelapse, confocal microscopy and serial section electron microscopy along with genetic, pharmacological, and physical perturbations. At the completion of this project, we will have a deeper understanding of the normal physiology of the endolymphatic sac and how disruptions to this physiology may lead to disease. Better knowledge of pressure homeostasis as well as the small molecule reagents we develop will provide a foundation for development of potential therapeutic interventions for these diseases. We are optimistic that this work will establish a new causal mechanism for inner ear pressure diseases such as Meniere's.

抽象的 听力和平衡丧失在每个人群中都很普遍，给受影响的人带来了巨大的挑战。 适用于多种类型的听力和平衡丧失，包括梅尼埃病、前庭导水管扩大 综合症和彭德雷综合症，该疾病的潜在机制目前尚不清楚，但 认为是由于内耳内膜容量和压力控制的长期丧失造成的。 目标是了解内耳的精致形态在发育过程中是如何形成的 在这里，我们重点关注内淋巴囊调节内耳流体压力的作用。 在此过程中，内淋巴囊是一个非常保守但神秘且研究很少的部分。 以前有人认为内淋巴囊吸收多余的内淋巴，但通过 我们使用最先进的斑马鱼幼体延时成像获得的初步数据。 揭示了内淋巴囊的脉动：管腔体积在 1-3 小时内缓慢增加，然后 内淋巴压力对于扩张来说是必要且充分的 内淋巴囊和上皮屏障的破裂对于其崩溃是必要且充分的。 这些缺口发生在一种新的细胞-细胞连接处，我们称之为“基底层状连接”，它似乎充当 这些初步数据支持我们的中心假设，即监管违规行为。 专门的泄压阀处的内淋巴囊上皮屏障对于适当的液体至关重要 内耳的稳态；这些压力释放阀的故障导致内膜压力增大 导致内耳肿胀、感觉细胞死亡以及耳上皮不受控制的撕裂（称为 我们计划使用三个具体目标来检验我们的中心假设：1）确定 瓣膜形成的分子和细胞机制；2）确定瓣膜在体内平衡中的作用； 内淋巴压力和成分；3) 确定不同物种的瓣膜结构和功能 我们的实验方法将使用斑马鱼和鹌鹑的功能研究 我们的研究将采用最先进的 3D、延时摄影、共焦技术进行描述性研究。 显微镜和连续切片电子显微镜以及遗传、药理学和物理 完成这个项目后，我们将对正常的生理机能有更深入的了解。 内淋巴囊的结构以及这种生理学的破坏如何可能导致疾病。 压力稳态以及我们将开发的小分子试剂将为 我们对这项工作的发展持乐观态度。 为梅尼埃病等内耳压力疾病建立新的因果机制。