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:9309422
- 负责人:
- 金额:$ 40.48万
- 依托单位:
- 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 2022-01-31
- 项目状态:已结题
- 来源:
- 关键词:AdolescentAdultAffectAnatomyAnimal ModelApicalAttentionAutophagocytosisBrainCell membraneCellsCessation of lifeConfocal MicroscopyDataDefectDevelopmentDiffusionDiseaseDistalDrug TargetingDura MaterDyesEarEconomic InflationElectron MicroscopyEndolymphEndolymphatic HydropsEndolymphatic ductEpithelialEpithelial CellsEpitheliumEquilibriumEtiologyExcisionFailureFoundationsGeneticGoalsHearingHistologyHomeostasisHourHumanImageImmunofluorescence ImmunologicImmunologic SurveillanceInjection of therapeutic agentIntercellular JunctionsKnowledgeLabyrinthLeadLiquid substanceMeasuresMeniere&aposs DiseaseModelingMolecularMorphologyMusPathway interactionsPendred SyndromePharmaceutical PreparationsPharmacologyPhenotypePhysiologic pulsePhysiologyPlayPopulationPreventionProcessQuailReagentRegulationResearchResolutionRestRoleSaccule structureSensorySeriesSideSignal TransductionStructureSwellingSyndromeTemporal bone structureTestingTherapeutic InterventionThinnessTravelVertebratesVestibular AqueductWorkZebrafishbaseblindcell typecraniumendolymphatic sacexperimental studyhearing impairmenthuman diseaseinner ear diseasesmutantnovelpressurereconstructionsmall moleculesoundtranslational 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
听力和平衡障碍在每个人群中都很普遍,对受影响的人构成了重大挑战。
治疗多种类型的听力和平衡障碍,包括梅尼埃病、前庭导水管扩大
综合症和Pendred综合征,其发病机制目前尚不清楚,但
建议是由于内耳容量和压力控制的丧失所致。我们的长期合作
目的是了解内耳的精细形态是如何在发育和发育过程中创造出来的
在成人中维持。在这里,我们重点讨论内淋巴囊对内耳液体压力的调节作用。
在这个过程中。内淋巴囊是内淋巴囊的一个高度保守而又神秘且研究很少的部分。
内耳。以前有人认为,内淋巴囊吸收过多的内淋巴,但通过
一种未知的机制。斑马鱼幼体最新时间流逝成像的初步数据
显示内淋巴囊搏动:腔体积在1-3小时内缓慢增加,然后
在几分钟内迅速下降。内淋巴压力是扩张的必要条件和充分条件
内淋巴囊和上皮屏障的破裂是其崩溃的必要条件和充分条件。
这些断裂发生在一种新的细胞-细胞连接上,我们称之为“基板连接”,它似乎起到了
减压阀。这些初步数据支持我们的核心假设,即监管的违规行为
内淋巴囊的上皮屏障在特殊的压力释放阀上是保证液体正常的关键。
内耳的动态平衡;这些减压阀失灵会导致内压升高。
导致内耳肿胀,感觉细胞死亡,以及被称为
内淋巴积液。我们计划使用三个具体目标来测试我们的中心假设:1)确定
瓣膜形成的分子和细胞机制;2)确定瓣膜在心脏动态平衡中的作用
内淋巴压力和成分;以及3)决定瓣膜跨物种的结构和功能
和发育阶段。我们的实验方法将使用斑马鱼和鹌鹑的功能研究,以及
关于老鼠和人的描述性研究。我们的研究将采用最先进的3D、时间流逝、共焦
显微镜和连续切片电子显微镜以及遗传学、药理学和物理学
微扰。随着这个项目的完成,我们将对正常生理学有更深入的了解
以及内淋巴囊的破坏如何导致疾病。更好地了解
压力动态平衡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
建立一种新的内耳压力性疾病的致病机制,如梅尼埃病。
项目成果
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SEAN G MEGASON其他文献
SEAN G MEGASON的其他文献
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{{ truncateString('SEAN G MEGASON', 18)}}的其他基金
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:
10090586 - 财政年份:2017
- 资助金额:
$ 40.48万 - 项目类别:
Dynamic regulatory mechanisms of robust pattern formation in the neural tube
神经管中稳健模式形成的动态调节机制
- 批准号:
10417127 - 财政年份:2015
- 资助金额:
$ 40.48万 - 项目类别:
Dynamic regulatory mechanisms of robust pattern formation in the neural tube
神经管中稳健模式形成的动态调节机制
- 批准号:
10162614 - 财政年份:2015
- 资助金额:
$ 40.48万 - 项目类别:
Dynamic regulatory mechanisms of robust pattern formation in the neural tube
神经管中稳健模式形成的动态调节机制
- 批准号:
9199417 - 财政年份:2015
- 资助金额:
$ 40.48万 - 项目类别:
Dynamic regulatory mechanisms of robust pattern formation in the neural tube
神经管中稳健模式形成的动态调节机制
- 批准号:
9817112 - 财政年份:2015
- 资助金额:
$ 40.48万 - 项目类别:
Streamlined cloning of auditory and vestibular mutants by whole genome sequencing
通过全基因组测序简化听觉和前庭突变体的克隆
- 批准号:
8411127 - 财政年份:2012
- 资助金额:
$ 40.48万 - 项目类别:
Streamlined cloning of auditory and vestibular mutants by whole genome sequencing
通过全基因组测序简化听觉和前庭突变体的克隆
- 批准号:
8224539 - 财政年份:2012
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全面成像和基因组学解码耳毛细胞的形成和再生
- 批准号:
8025935 - 财政年份:2010
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全面成像和基因组学解码耳毛细胞的形成和再生
- 批准号:
8212556 - 财政年份:2010
- 资助金额:
$ 40.48万 - 项目类别:
In toto imaging and genomics to decode ear hair cell formation and regeneration
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- 批准号:
8413441 - 财政年份:2010
- 资助金额:
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