Project 2: Mechanistic studies of age-related hearing loss using animal models and human tissue
Project 2: Mechanistic studies of age-related hearing loss using animal models and human tissue
批准号:
10470232
负责人:
Hainan Lang
金额:
$41.28万
依托单位国家:
美国
项目类别:
财政年份:
1997
资助国家:
美国
项目状态:
已结题
起止时间:
1997-07-01 至 2024-08-31
关键词:
Acoustic NerveAction PotentialsAddressAgeAgingAnimal ModelAuditoryAutopsyBiological AssayBiological AvailabilityBlood VesselsCBA/CaJ MouseCarrier ProteinsCellsCellular biologyCharacteristicsClinical ResearchCochleaComparative StudyComplementDemyelinationsElementsFiberFunctional disorderGene Expression ProfileGene Expression ProfilingGenesGeneticHumanImageImmune responseInflammatoryInnate Immune ResponseInnate Immune SystemIon TransportLabyrinthLateralLeadLinkLipidsMeasurementMeasuresMediatingMetabolicMicrogliaModelingMolecularMorphologyMusMutationMyelinNerve DegenerationNerve FibersNeurodegenerative DisordersNeurogliaNeuronsPathologicPathway interactionsPatternPhysiologicalPlayPresbycusisRecovery of FunctionRegulationResolutionRoleSignal TransductionSignaling MoleculeStria VascularisStudy SubjectTemporal bone structureTestingTissue-Specific Gene ExpressionTissuesage relatedage related neurodegenerationagedbasecell typecomplement systemexperimental studyfunctional declinehearing impairmenthuman subjecthuman tissuein vivomRNA Expressionmacrophagemouse modelmultidisciplinarynew therapeutic targetpreventprotein expressionrelating to nervous systemresponsesphingosine 1-phosphatetranscriptome sequencing
中文摘要
项目摘要/摘要--项目2
老年性听力损失(老年性耳聋)是一种常见的神经退行性疾病,可
与耳蜗侧壁(代谢)中几种特殊细胞类型的丢失和/或功能障碍有关
老年性耳聋)和听神经(神经性老年性耳聋)。临床研究中心项目2旨在
确定人类代谢和神经性老年性耳聋的关键细胞和分子机制
老鼠模型和死后的人类颞骨,来自年轻和年长的捐赠者。失调症
小胶质细胞/巨噬细胞和补体级联是先天免疫的两个基本要素
系统,已被证明在几个与年龄相关的神经退行性疾病中起着至关重要的作用。我们的
初步研究表明,耳蜗巨噬细胞可以经历结构和分子方面的变化。
随着年龄的增长而改变,表明功能改变,并且这些改变与
老龄小鼠耳蜗侧壁微血管的病理变化。鞘氨醇-1-磷酸
(S1P)是一种脂质信号分子,调节巨噬细胞的活动。基因表达的初步研究
小鼠耳蜗组织中的模式和年龄相关的巨噬细胞功能障碍表明
在S1P中,随着年龄的增加和耳蜗侧壁巨噬细胞功能障碍的增加,生物利用度增加。此外,
小鼠听神经基因差异表达分析发现,随着基因表达的增加,听神经的主要变化
年龄在先天免疫反应和补体级联通路中的作用。关于其他的最新研究
神经退行性疾病表明,补体调节失调可导致脱髓鞘和神经
退化。基于这些观察,我们的首要假设是年龄相关的调节失调
耳蜗先天免疫系统的异常与衰老侧方特化细胞的退变有关
墙和听神经,导致与代谢和神经一致的听觉功能下降
老年性耳聋。项目2将1)确定S1P介导的巨噬细胞功能障碍与
老年小鼠侧壁的工业微血管变性(目标2.1);和2)阐明两者之间的联系
增龄性补体系统失调伴退行性变与功能衰退之间的关系
听神经纤维,特别是自发频率低的纤维(目标2.2)。侧壁动物模型的建立
项目2中描述的听神经退化也将用于验证遗传和
项目1、3和4中研究的受试者的病理生理学结果。
这些关键免疫反应调节分子的表达模式也将在人类身上进行研究。
通过人类受试者核心(核心B)访问的颞骨。比较能力
来自动物模型、人类颞骨和人类受试者的结果提供了一个无与伦比的机会
解决有关耳蜗巨噬细胞功能障碍和补体的具体作用的问题
与人类老年性耳聋相关的血管和髓鞘神经胶质病理生理学的调节。
英文摘要
PROJECT SUMMARY/ABSTRACT – PROJECT 2
Age-related hearing loss (presbyacusis) is a common neurodegenerative disorder that can be
associated with loss and/or dysfunction of several specialized cell types in the cochlear lateral wall (metabolic
presbyacusis) and the auditory nerve (neural presbyacusis). Project 2 of the Clinical Research Center aims to
identify critical cellular and molecular mechanisms underlying human metabolic and neural presbyacusis using
mouse models and post-mortem human temporal bones from younger and older donors. Dysregulation of
microglia/macrophages and the complement cascade, two fundamental elements of the innate immune
system, have been shown to play vital roles in several age-related neurodegenerative disorders. Our
preliminary studies have revealed that cochlear macrophages may undergo structural and molecular
alterations with increasing age, indicative of functional changes, and that these alterations are associated with
pathological changes in the cochlear lateral wall microvasculature of aged mice. Sphingosine-1-phosphate
(S1P), a lipid signaling molecule, regulates macrophage activity. Preliminary studies of gene expression
patterns and age-related macrophage dysfunction in mouse cochlear tissue suggest a link between a reduction
in S1P bioavailability with increasing age and macrophage dysfunction in the cochlear lateral wall. In addition,
differential gene expression analysis in the mouse auditory nerve has identified major changes with increasing
age in the innate immune response and complement cascade pathways. Recent studies of other
neurodegenerative disorders have shown that complement dysregulation can lead to demyelination and neural
degeneration. Based on these observations, our overarching hypothesis is that age-dependent dysregulation
of the cochlear innate immune system contributes to the degeneration of specialized cells in the aging lateral
wall and auditory nerve, leading to declines in auditory function consistent with metabolic and neural
presbyacusis. Project 2 will 1) determine the relationship between S1P-mediated macrophage dysfunction and
strial microvasculature degeneration in the lateral wall of aged mice (Aim 2.1); and 2) elucidate the links
between age-related dysregulation of the complement system with degeneration and functional declines in
auditory nerve fibers, in particular fibers with low spontaneous rates (Aim 2.2). Animal models of lateral wall
and auditory nerve degeneration characterized in Project 2 will also be used to validate genetic and
pathophysiology results obtained from human subjects studied in Projects 1, 3, and 4. Comparative studies of
the expression patterns of these key immune response regulatory molecules will also be examined in human
temporal bones, which are accessed through the Human Subjects Core (Core B). The ability to compare
results from animal models, human temporal bones, and human subjects provides an unparalleled opportunity
to address questions regarding the specific role of the cochlear macrophage dysfunction and complement
regulation in vascular and myelinating glial pathophysiology associated with human presbyacusis.
期刊论文(0)
专著(0)
科研奖励(0)
会议论文
Peripheral auditory system deficits and autism-like behaviors
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批准号:10187095
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项目类别:
-
资助金额:$19.93万
-
财政年份:2021
-
负责人:Hainan Lang
-
依托单位:
Peripheral auditory system deficits and autism-like behaviors
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批准号:10349592
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项目类别:
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资助金额:$19.93万
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财政年份:2021
-
负责人:Hainan Lang
-
依托单位:
Auditory Nerve Degeneration and Repair
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批准号:8681418
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项目类别:
-
资助金额:$36.88万
-
财政年份:2012
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负责人:Hainan Lang
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依托单位:
Auditory Nerve Degeneration and Repair
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批准号:8507714
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项目类别:
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资助金额:$35.03万
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财政年份:2012
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负责人:Hainan Lang
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依托单位:
Auditory Nerve Degeneration and Repair
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批准号:8370280
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项目类别:
-
资助金额:$36.88万
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财政年份:2012
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负责人:Hainan Lang
-
依托单位:
Auditory Nerve Degeneration and Repair
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批准号:9088445
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项目类别:
-
资助金额:$36.88万
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财政年份:2012
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负责人:Hainan Lang
-
依托单位:
Auditory Nerve Degeneration and Repair
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批准号:9211519
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项目类别:
-
资助金额:$4.76万
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财政年份:2012
-
负责人:Hainan Lang
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依托单位:
Cell survival and cell death in the auditory nerve
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批准号:7178505
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项目类别:
-
资助金额:$7.09万
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财政年份:2006
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负责人:Hainan Lang
-
依托单位:
Cell survival and cell death in the auditory nerve
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批准号:7352782
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项目类别:
-
资助金额:$7.09万
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财政年份:2006
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负责人:Hainan Lang
-
依托单位:
Cell survival and cell death in the auditory nerve
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批准号:7035117
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项目类别:
-
资助金额:$7.3万
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财政年份:2006
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负责人:Hainan Lang
-
依托单位:
Project 2: Mechanistic studies of age-related hearing loss using animal models and human tissue
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批准号:10018499
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项目类别:
-
资助金额:$41.54万
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财政年份:1997
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负责人:Hainan Lang
-
依托单位:
Project 2: Mechanistic studies of age-related hearing loss using animal models and human tissue
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批准号:10675667
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项目类别:
-
资助金额:$40.86万
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财政年份:1997
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负责人:Hainan Lang
-
依托单位:
Project 2: Mechanistic studies of age-related hearing loss using animal models and human tissue
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批准号:10248448
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项目类别:
-
资助金额:$41.43万
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财政年份:1997
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负责人:Hainan Lang
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依托单位:
Human Hematopoietic Stem Cells and the Aging Inner Ear
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批准号:8378527
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项目类别:
-
资助金额:$38.33万
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财政年份:--
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负责人:Hainan Lang
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依托单位:
Human Cochlear Stem Cells and the Aging Inner Ear
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批准号:9012794
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项目类别:
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资助金额:$36.62万
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财政年份:--
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负责人:Hainan Lang
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依托单位:
Human Hematopoietic Stem Cells and the Aging Inner Ear
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批准号:8118950
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项目类别:
-
资助金额:$38.17万
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财政年份:--
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负责人:Hainan Lang
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依托单位:
Human Cochlear Stem Cells and the Aging Inner Ear
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批准号:8786537
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项目类别:
-
资助金额:$28.63万
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财政年份:--
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负责人:Hainan Lang
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依托单位:
Human Hematopoietic Stem Cells and the Aging Inner Ear
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批准号:8299408
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项目类别:
-
资助金额:$37.81万
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财政年份:--
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负责人:Hainan Lang
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依托单位:
Human Cochlear Stem Cells and the Aging Inner Ear
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批准号:8628453
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项目类别:
-
资助金额:$29.05万
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财政年份:--
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负责人:Hainan Lang
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依托单位:
Human Hematopoietic Stem Cells and the Aging Inner Ear
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批准号:7884555
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项目类别:
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资助金额:$37.49万
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财政年份:--
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负责人:Hainan Lang
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依托单位:
海外基金