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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

基本信息

批准号：
10090586
负责人：
SEAN G MEGASON
金额：
$ 39.74万
依托单位：
HARVARD MEDICAL SCHOOL
依托单位国家：
美国
项目类别：
财政年份：
2017
资助国家：
美国
起止时间：
2017-02-09 至 2023-01-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10090586
关键词：
3-Dimensional 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 Electron Microscopy Endolymph Endolymphatic Hydrops Endolymphatic duct Epithelial Epithelial Cells Equilibrium Etiology Excision Exposure to Failure Fluid Balance Foundations Genetic Goals Hearing Histology Homeostasis Hour Human Image Immunofluorescence Immunologic Immunologic Surveillance Injections Intercellular Junctions Knowledge Labyrinth Lead Liquid substance Measures Meniere&apos 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

项目摘要

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.

摘要听力和平衡丧失在每个人群中都很普遍，对受影响的人构成了重大挑战。对于许多类型的听力和平衡丧失，包括梅尼埃病，前庭水管扩大综合征和Pendred综合征，该疾病的潜在机制目前尚不清楚，这可能是由于内耳内压和内压控制的丧失所致。我们的长期目的是了解内耳的精致形态是如何在发育过程中形成的，维持在成年人。在这里，我们重点介绍的作用，内耳流体压力调节的内淋巴囊在这个过程中。内淋巴囊是一个非常保守的，但神秘的和很少研究的一部分，内耳以前曾提出，内淋巴囊吸收过量的内淋巴，但通过一个未知的机制。我们的初步数据使用最先进的时间推移成像对幼斑马鱼显示内淋巴囊搏动：管腔体积在1-3小时内缓慢增加，然后在几分钟内迅速下降。内淋巴压是扩张的必要和充分条件。内淋巴囊和上皮屏障的破坏是其崩溃的必要条件和充分条件。这些破坏发生在一种新的细胞-细胞连接处，我们称之为“基底板层连接”，减压阀这些初步数据支持了我们的中心假设，即监管违规行为，内淋巴囊的上皮屏障在专门的压力释放阀是必要的适当的流体内耳的内环境平衡;这些减压阀的失效导致耳内压力增加导致内耳肿胀、感觉细胞死亡和耳上皮不受控制的撕裂，内淋巴积水我们计划使用三个具体目标来测试我们的中心假设：1）识别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，内淋巴压和组成;以及3）确定跨物种瓣膜的结构和功能和发展阶段。我们的实验方法将使用斑马鱼和鹌鹑的功能研究，对小鼠和人的描述性研究。我们的研究将采用最先进的3D，时间推移，共聚焦显微镜和连续切片电子显微镜沿着与遗传，药理学，和物理扰动在这个项目完成后，我们将有一个更深入的了解正常的生理以及这种生理机能的破坏如何导致疾病。更好地了解压力稳态以及我们开发的小分子试剂将为开发针对这些疾病的潜在治疗干预措施。我们乐观地认为，这项工作将为内耳压力疾病如梅尼埃病建立一个新的致病机制。