Function of LIM-domain Transcriptional Regulators in Inner Ear Development
LIM 结构域转录调节因子在内耳发育中的功能
基本信息
- 批准号:8098054
- 负责人:
- 金额:$ 31.36万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2008
- 资助国家:美国
- 起止时间:2008-03-01 至 2013-04-30
- 项目状态:已结题
- 来源:
- 关键词:AbbreviationsAdultAffectApoptosisCell Differentiation processCellsCochleaColorCompetenceDataDevelopmentDiseaseDistalEctopic ExpressionEmbryoEpithelialEpitheliumGangliaGenesHair CellsHealthHelix-Turn-Helix MotifsInner Hair CellsKnock-in MouseKnockout MiceKnowledgeLIM DomainLabyrinthLacZ GenesLeadMaintenanceMedialModelingMolecularMouse StrainsMusNatural regenerationNeuronsOrganOrgan of CortiOuter Hair CellsPatternPrimordiumProcessProteinsRegulationRelative (related person)Reporter GenesRhombotin 2RoleSensoryStagingSupporting CellTestingTissuesTranscriptional RegulationUnited StatesUtricular maculaVestibulebasecompetence factordeafnessganglion cellhair cell regenerationhearing impairmenthomeodomaininsightneuron developmentneuronal survivalnovel strategiesnull mutationpreventprogramsprotein functionstemtranscription factor
项目摘要
DESCRIPTION (provided by applicant): A major cause of deafness disorders stem from the degeneration of hair cells within the inner ear although in many cases the mechanisms underlying these disorders is not understood. By defining the mechanisms controlling normal hair cell development, we will gain a better understanding of how these processes are disrupted in pathological situations and how the hair cells can be regenerated. The central hypothesis of this proposal is that the expression of the LIM-homeodomain transcription factor Isl1 provides the ventral cochlear epithelium with a competence to form the sensory organ and that the negative regulation of Isl1 function by the LIM-domain-only transcriptional regulators LMO3 and LMO4 restricts the competence to the presumptive OC (OC) region. In our preliminary studies, we have shown that during the sensory development in the cochlea at E12.5 to E16.5, Isl1 is expressed in a broad domain in the ventral cochlear epithelium, including the presumptive OC. Interestingly, the expression of LMO3 is detected in the lesser epithelial ridge (LER), whereas LMO4 expression is confined to the greater epithelial ridge (GER) and to the distal LER (dLER). The combined LMO3 and LMO4 expression domain overlaps with that of Isl1 except in the presumptive OC region where Isl1 is expressed alone. Consistent with our hypothesis, we have shown that loss of LMO4 results in the formation of supernumerary hair cells in the dLER, confirming a role for LMO4 as a negative regulator of sensory organ development. Thus, based on the established roles of LMO proteins in inhibiting LIM-HD proteins' function in transcriptional regulation, the combined action of Isl1, LMO3 and LMO4 could determine the formation of the OC region. In order to test this hypothesis and investigate the roles of LIM-domain factors in the inner ear development, we propose the following three specific aims: 1). To determine the requirement for LMO4 in the sensory and neuronal development in the cochlea and vestibule by targeted disruption of LMO4; 2). To determine whether the ectopic expression of LMO4 in the presumptive prosensory region represses the sensory development by the conditional activation of LMO4 expression in the Isl1-expressing cells; and 3). To determine the role of Isl1 in the sensory and neuronal development of the inner ear by the conditional deletion of Isl1. PUBLIC HEALTH RELEVANCE Loss of the inner ear hair cells in the organ of Corti is the leading cause of hearing loss that affects 278 million people worldwide, including 28 million in the United States. However, since the loss of hair cells is an irreversible process and mammalian inner ear lacks the capability to regenerate hair cells, effective remedies to replace hair cells remain elusive. The studies proposed in this application will provide new insights into the molecular mechanisms underlying the sensory organ formation in the inner ear and could lead to novel approaches in the treatment and eventual cure of deafness by de novo hair cell regeneration. The central hypothesis of this proposal is that the expression of the LIM-homeodomain transcription factor provides the ventral cochlear epithelium with the competence to form the sensory organ and that the LIM-domain-only transcriptional regulators suppress the role of LIM-homeodomain factor in the ventral cochlea except the presumptive organ of Corti region. Thus, the combined function of LIM-homeodomain and LIM-domain-only factors regulates the competence in the ventral cochlear epithelium and determines the region of the presumptive organ of Corti.
描述(由申请人提供):耳聋疾病的主要原因源于内耳内毛细胞的退化,尽管在许多情况下这些疾病的机制尚不清楚。通过定义控制正常毛细胞发育的机制,我们将更好地了解这些过程在病理情况下如何被破坏以及毛细胞如何再生。该提议的中心假设是,LIM 同源结构域转录因子 Isl1 的表达为腹侧耳蜗上皮提供了形成感觉器官的能力,并且仅 LIM 结构域转录调节因子 LMO3 和 Isl1 的负调节功能。 LMO4 将能力限制在假定的 OC (OC) 区域。在我们的初步研究中,我们表明,在 E12.5 至 E16.5 的耳蜗感觉发育过程中,Isl1 在腹侧耳蜗上皮的广泛区域中表达,包括假定的 OC。有趣的是,LMO3 的表达在小上皮嵴 (LER) 中检测到,而 LMO4 的表达仅限于大上皮嵴 (GER) 和远端 LER (dLER)。 LMO3 和 LMO4 的组合表达域与 Isl1 的表达域重叠,但假定的 OC 区域除外,其中 Isl1 单独表达。与我们的假设一致,我们已经证明 LMO4 的缺失会导致 dLER 中多余毛细胞的形成,证实了 LMO4 作为感觉器官发育的负调节因子的作用。因此,基于LMO蛋白在抑制LIM-HD蛋白转录调节功能中的既定作用,Isl1、LMO3和LMO4的联合作用可以决定OC区域的形成。为了检验这一假设并研究 LIM 域因素在内耳发育中的作用,我们提出以下三个具体目标:1)。通过有针对性地破坏 LMO4 来确定耳蜗和前庭感觉和神经元发育对 LMO4 的需求; 2)。确定假定的原感觉区中 LMO4 的异位表达是否通过条件激活表达 Isl1 的细胞中 LMO4 表达来抑制感觉发育;和3)。通过条件性删除 Isl1 来确定 Isl1 在内耳感觉和神经元发育中的作用。公共卫生相关性 柯蒂氏器内耳毛细胞的丧失是听力损失的主要原因,影响着全世界 2.78 亿人,其中包括美国的 2800 万人。然而,由于毛细胞的丧失是一个不可逆转的过程,并且哺乳动物内耳缺乏再生毛细胞的能力,因此替代毛细胞的有效疗法仍然难以捉摸。本申请中提出的研究将为内耳感觉器官形成的分子机制提供新的见解,并可能导致通过从头毛细胞再生治疗和最终治愈耳聋的新方法。该提议的中心假设是,LIM-同源域转录因子的表达为腹侧耳蜗上皮提供了形成感觉器官的能力,并且仅包含 LIM-域的转录调节因子抑制了 LIM-同源域因子在感觉器官中的作用。除柯蒂区推定器官外的腹侧耳蜗。因此,LIM 同源结构域和仅 LIM 结构域因子的组合功能调节腹侧耳蜗上皮的能力并确定推测的 Corti 器官的区域。
项目成果
期刊论文数量(0)
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Lin Gan其他文献
Lin Gan的其他文献
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{{ truncateString('Lin Gan', 18)}}的其他基金
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Ace2 in the healthy and inflamed taste system
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9082149 - 财政年份:2016
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- 批准号:
8719121 - 财政年份:2013
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The role of BARHL2 in the mosaic pattering and dendritic tiling of retinal amacri
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$ 31.36万 - 项目类别:
Function of LIM-domain Transcriptional Regulators in Inner Ear Development
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8260402 - 财政年份:2008
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$ 31.36万 - 项目类别:
Function of LIM-domain Transcriptional Regulators in Inner Ear Development
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7826716 - 财政年份:2008
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$ 31.36万 - 项目类别:
Function of LIM-domain Transcriptional Regulators in Inner Ear Development
LIM 结构域转录调节因子在内耳发育中的功能
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7464837 - 财政年份:2008
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$ 31.36万 - 项目类别:
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