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(申请人提供):耳聋障碍的一个主要原因源于内耳内毛细胞的退化,尽管在许多情况下,这些障碍背后的机制尚不清楚。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是如何被破坏的,以及毛细胞如何再生。这一建议的中心假设是,LIM同源结构域转录因子Isl1的表达为腹侧耳蜗皮细胞提供了形成感觉器官的能力,而仅LIM结构域转录调控因子LMO3和LMO4对Isl1功能的负调控将这种能力限制在假定的OC(OC)区域。在我们的初步研究中,我们已经发现,在E12.5到E16.5的耳蜗感觉发育过程中,Isl1在耳蜗腹上皮中广泛表达,包括可能的OC。有趣的是,LMO3表达在小上皮脊(LER),而LMO4仅表达在大上皮脊(GER)和远端上皮脊(DLER)。LMO3和LMO4的组合表达结构域与IsL1的表达结构域重叠,但在假定的OC区域,IsL1单独表达。与我们的假设一致,我们已经证明了LMO4的丢失导致了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,根据LMO蛋白在转录调控中抑制LIM-HD蛋白功能的既定作用,ISL1、LMO3和LMO4的联合作用可能决定OC区域的形成。为了验证这一假说并研究LIM结构域因素在内耳发育中的作用,我们提出了以下三个具体目标:1)。通过靶向阻断LMO4,确定LMO4在耳蜗区和前庭的感觉和神经元发育中的需要量;确定LMO4在假定前感觉区的异位表达是否通过在表达ISL1的细胞中有条件地激活LMO4表达而抑制感觉发育;目的:通过对Isl1基因的条件性缺失,确定Isl1基因在内耳感觉和神经元发育中的作用。与公共健康相关的Corti器官内耳毛细胞丢失是影响全球2.78亿人听力损失的主要原因,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,而哺乳动物的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,并可能导致通过新生毛细胞再生来治疗和最终治愈耳聋的新方法。这一建议的中心假设是,LIM同源结构域转录因子的表达为腹侧耳蜗皮细胞提供了形成感觉器官的能力,只有LIM结构域转录调控因子抑制了LIM同源结构域因子在除Corti区假定器官之外的腹侧耳蜗中的作用。因此,LIM同源结构域和仅LIM结构域因子的联合作用调节着腹侧耳蜗管上皮的功能,并决定了Corti假定器官的区域。
项目成果
期刊论文数量(0)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
数据更新时间:{{ journalArticles.updateTime }}
{{
item.title }}
{{ item.translation_title }}
- DOI:
{{ item.doi }} - 发表时间:
{{ item.publish_year }} - 期刊:
- 影响因子:{{ item.factor }}
- 作者:
{{ item.authors }} - 通讯作者:
{{ item.author }}
数据更新时间:{{ journalArticles.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ monograph.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ sciAawards.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ conferencePapers.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ patent.updateTime }}
Lin Gan其他文献
Lin Gan的其他文献
{{
item.title }}
{{ item.translation_title }}
- DOI:
{{ item.doi }} - 发表时间:
{{ item.publish_year }} - 期刊:
- 影响因子:{{ item.factor }}
- 作者:
{{ item.authors }} - 通讯作者:
{{ item.author }}
{{ truncateString('Lin Gan', 18)}}的其他基金
Ace2 in the healthy and inflamed taste system
Ace2 在健康和炎症味觉系统中的作用
- 批准号:
10570979 - 财政年份:2022
- 资助金额:
$ 31.36万 - 项目类别:
Ace2 in the healthy and inflamed taste system
Ace2 在健康和炎症味觉系统中的作用
- 批准号:
10463442 - 财政年份:2022
- 资助金额:
$ 31.36万 - 项目类别:
The roles of LIM-Homeodomain Transcription Factors in Retinal Development
LIM-同源域转录因子在视网膜发育中的作用
- 批准号:
10116905 - 财政年份:2020
- 资助金额:
$ 31.36万 - 项目类别:
The Roles of LIM-Homeodomain Transcription Factors in Retinal Development
LIM-同源域转录因子在视网膜发育中的作用
- 批准号:
9229030 - 财政年份:2016
- 资助金额:
$ 31.36万 - 项目类别:
The Roles of LIM-Homeodomain Transcription Factors in Retinal Development
LIM-同源域转录因子在视网膜发育中的作用
- 批准号:
9082149 - 财政年份:2016
- 资助金额:
$ 31.36万 - 项目类别:
The role of BARHL2 in the mosaic pattering and dendritic tiling of retinal amacri
BARHL2 在视网膜 amacri 的马赛克图案和树突状平铺中的作用
- 批准号:
8719121 - 财政年份:2013
- 资助金额:
$ 31.36万 - 项目类别:
The role of BARHL2 in the mosaic pattering and dendritic tiling of retinal amacri
BARHL2 在视网膜 amacri 的马赛克图案和树突状平铺中的作用
- 批准号:
8585275 - 财政年份:2013
- 资助金额:
$ 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
- 批准号:
8260402 - 财政年份:2008
- 资助金额:
$ 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
- 批准号:
7826716 - 财政年份:2008
- 资助金额:
$ 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
- 批准号:
7464837 - 财政年份:2008
- 资助金额:
$ 31.36万 - 项目类别:
相似海外基金
Co-designing a lifestyle, stop-vaping intervention for ex-smoking, adult vapers (CLOVER study)
为戒烟的成年电子烟使用者共同设计生活方式、戒烟干预措施(CLOVER 研究)
- 批准号:
MR/Z503605/1 - 财政年份:2024
- 资助金额:
$ 31.36万 - 项目类别:
Research Grant
RAPID: Affective Mechanisms of Adjustment in Diverse Emerging Adult Student Communities Before, During, and Beyond the COVID-19 Pandemic
RAPID:COVID-19 大流行之前、期间和之后不同新兴成人学生社区的情感调整机制
- 批准号:
2402691 - 财政年份:2024
- 资助金额:
$ 31.36万 - 项目类别:
Standard Grant
Early Life Antecedents Predicting Adult Daily Affective Reactivity to Stress
早期生活经历预测成人对压力的日常情感反应
- 批准号:
2336167 - 财政年份:2024
- 资助金额:
$ 31.36万 - 项目类别:
Standard Grant
Elucidation of Adult Newt Cells Regulating the ZRS enhancer during Limb Regeneration
阐明成体蝾螈细胞在肢体再生过程中调节 ZRS 增强子
- 批准号:
24K12150 - 财政年份:2024
- 资助金额:
$ 31.36万 - 项目类别:
Grant-in-Aid for Scientific Research (C)
Migrant Youth and the Sociolegal Construction of Child and Adult Categories
流动青年与儿童和成人类别的社会法律建构
- 批准号:
2341428 - 财政年份:2024
- 资助金额:
$ 31.36万 - 项目类别:
Standard Grant
Understanding how platelets mediate new neuron formation in the adult brain
了解血小板如何介导成人大脑中新神经元的形成
- 批准号:
DE240100561 - 财政年份:2024
- 资助金额:
$ 31.36万 - 项目类别:
Discovery Early Career Researcher Award
Laboratory testing and development of a new adult ankle splint
新型成人踝关节夹板的实验室测试和开发
- 批准号:
10065645 - 财政年份:2023
- 资助金额:
$ 31.36万 - 项目类别:
Collaborative R&D
Usefulness of a question prompt sheet for onco-fertility in adolescent and young adult patients under 25 years old.
问题提示表对于 25 岁以下青少年和年轻成年患者的肿瘤生育力的有用性。
- 批准号:
23K09542 - 财政年份:2023
- 资助金额:
$ 31.36万 - 项目类别:
Grant-in-Aid for Scientific Research (C)
Identification of new specific molecules associated with right ventricular dysfunction in adult patients with congenital heart disease
鉴定与成年先天性心脏病患者右心室功能障碍相关的新特异性分子
- 批准号:
23K07552 - 财政年份:2023
- 资助金额:
$ 31.36万 - 项目类别:
Grant-in-Aid for Scientific Research (C)
Issue identifications and model developments in transitional care for patients with adult congenital heart disease.
成人先天性心脏病患者过渡护理的问题识别和模型开发。
- 批准号:
23K07559 - 财政年份:2023
- 资助金额:
$ 31.36万 - 项目类别:
Grant-in-Aid for Scientific Research (C)