The Role of MicroRNAs in Normal and Diseased Corneal Epithelial Homeostasis
MicroRNA 在正常和患病角膜上皮稳态中的作用
基本信息
- 批准号:10737500
- 负责人:
- 金额:$ 55.54万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2015
- 资助国家:美国
- 起止时间:2015-08-01 至 2027-05-31
- 项目状态:未结题
- 来源:
- 关键词:AcuteAdherens JunctionBasal CellBiological ProcessBlindnessCell Differentiation processCell Fate ControlCell MaintenanceCellsClinicalCorneaCorneal DiseasesCorneal InjuryCorneal OpacityDataDefectDiseaseEpidermal Growth Factor ReceptorEpithelial CellsEpitheliumErinaceidaeExposure toFunctional disorderFundingFutureGene set enrichment analysisGenesGoalsHealthHealthcare SystemsHeterogeneityHomeostasisHumanIn Situ HybridizationIndividualInflammation MediatorsInflammatoryInflammatory ResponseInjuryInterleukin-1KeratopathyMaintenanceMediatingMicroRNAsMicroarray AnalysisMitoticMolecularNatural regenerationNumbnessOrgan Culture TechniquesPathogenesisPathologicPathway interactionsPatientsPopulationPopulation HeterogeneityProteomeProteomicsQuality of lifeQuantitative Reverse Transcriptase PCRReceptor SignalingRecurrenceRegulationRegulatory PathwayResearchResolutionRoleSignal TransductionSmall Interfering RNASourceStimulusStressStromal CellsTNF receptor-associated factor 1TNF receptor-associated factor 6TechniquesTechnologyTherapeuticTissuesTransfectionVisionVisual impairmentVisualizationcell fate specificationcell growth regulationcorneal epithelial wound healingcorneal epitheliumcorneal regenerationcytokinediabeticdiabetic patientdifferential expressioneffective therapyempowermentepithelial stem cellepithelial woundepithelium regenerationfunctional gaininhibitorinnovationinterleukin-1 receptor-associated kinaselimbalnotch proteinsingle-cell RNA sequencingsmall molecule inhibitorstem cell biomarkersstem cell homeostasisstem cellstranscriptometranscriptome sequencingtranslational studytreatment strategywound healing
项目摘要
Corneal diseases and injuries leading to visual impairment have significant impact on the quality of life of
patients and constitute a major problem for health care system. Corneal diseases are often manifested through
limbal epithelial stem cell (LESC) dysfunction and loss, leading to corneal opacity, visual impairment, and
blindness. LESC located in the limbal niche are the source of constant corneal epithelial renewal and are
required to maintain corneal epithelial homeostasis by adapting properly to internal and external stimuli.
However, persistent exposure to pathological stress disrupts the adaptive mechanisms of LESC, leading to
serious corneal problems such as altered wound healing, limbal stem cell deficiency (LSCD) and diabetic
keratopathy. Therefore, understanding the precise spatial and temporal regulatory pathways and how each
LESC/limbal epithelial cells (LECs) responds to various stimuli at the single-cell level governing corneal
epithelial regeneration could be key to elucidating the pathogenesis of various corneal diseases and ultimately
developing new and effective treatment strategies. Previously, we have shown the important regulatory role of
miR-146a in corneal epithelial homeostasis and wound healing via its different targeted pathways such as
EGFR, Notch and NF-κB signaling. However, due to the heterogeneity of limbal basal cells and their proximity
to limbal stromal cells, it remains to be determined how miRNAs (miRs) regulate maintenance, differentiation,
and the active stage of limbal progenitor cells in various corneal cell populations in wounded and unwounded
normal and diseased corneas. Recently several studies have shown the heterogeneity and complexity of limbal
niche in relation to regeneration and wound healing and identified new putative LESC markers using newly
emerged empowering scRNA-seq technology. We propose to investigate the regulatory role and contribution of
each miR-146 main targets (EGFR, TRAF6, IRAK1, NUMB and NOTCH-2) in corneal epithelial regeneration in
wounded and unwounded states in normal and diabetic corneas using scRNA-seq, proteomics, loss and gain
of functional studies. We hypothesize that miR-146a contribute to the molecular regulation of cellular
heterogeneity in the limbal niche steady state. We predict that differential miR-146a expression in limbus vs.
central corneal epithelium impacts its regulation of limbal niche cells, LECs and limbal stromal cells, and
mediates corneal regeneration and wound healing in normal and diseased states. Our Specific Aims are:
Specific Aim 1: To identify and characterize downstream targets including EGFR, Notch and inflammatory
mediators of miR-146a in distinct populations of heterogeneous limbal stem cells that contribute to homeostatic
maintenance and regeneration in human normal unwounded and wounded cornea. Specific Aim 2: To reveal
the differential and converged regulatory role of EGFR, inflammatory, and Notch signaling by miR-146a in
corneal epithelial homeostasis and wound healing. Specific Aim 3: To investigate miR146a-based therapeutic
approach by modulating its targets in human diabetic organ-cultured corneas.
导致视力障碍的角膜疾病和损伤对老年人的生活质量有重大影响
并构成医疗保健系统的一个主要问题。角膜疾病通常是通过
角膜缘上皮干细胞(LESC)功能障碍和丢失,导致角膜混浊、视力障碍和
失明。位于角膜龛的LESC是持续更新角膜上皮的来源,
需要通过适当地适应内外刺激来维持角膜上皮细胞的动态平衡。
然而,持续的病理性应激破坏了LESC的适应机制,导致
严重的角膜问题,如伤口愈合改变、角膜缘干细胞缺陷(LSCD)和糖尿病
角膜病。因此,了解精确的空间和时间调控途径以及每个调控途径是如何
LESC/角膜缘上皮细胞(LECs)在控制角膜的单细胞水平上对各种刺激作出反应
上皮再生可能是阐明各种角膜疾病的发病机制的关键,并最终
制定新的有效的治疗策略。在此之前,我们已经展示了
MIR-146a通过其不同的靶向途径参与角膜上皮细胞的动态平衡和伤口愈合
EGFR、Notch和NF-κB信号转导。然而,由于角膜缘基底细胞的异质性及其邻近
对于角膜缘基质细胞,miRNAs(MiRs)如何调控维持,分化,
不同角膜细胞群中角膜缘祖细胞的活跃期
正常和病变的角膜。最近几项研究表明,角膜缘具有异质性和复杂性。
生态位与再生和伤口愈合有关,并使用NEW识别新的假定LESC标记
出现了增强scRNA-seq技术的能力。我们建议调查监管机构的角色和贡献。
每个miR-146在角膜上皮再生中的主要靶点(EGFR、TRAF6、IRAK1、Numb和Noch-2)
用scRNA-seq、蛋白质组学、损失和获得研究正常和糖尿病角膜的损伤和未损伤状态
功能研究的成果。我们推测miR-146a参与了细胞的分子调控。
角膜缘生态位稳定状态下的异质性。我们预测miR-146a在角膜缘和角膜缘中的差异表达。
中央角膜上皮影响其对角膜缘龛细胞、晶状体上皮细胞和角膜缘基质细胞的调节。
在正常和疾病状态下调节角膜再生和伤口愈合。我们的具体目标是:
具体目标1:确定和表征下游靶标,包括EGFR、Notch和炎症
异种角膜缘干细胞不同群体中miR-146a的介体有助于动态平衡
人正常、未损伤和损伤角膜的维持和再生。具体目标2:揭示
MiR-146a对EGFR、炎症和Notch信号的差异性和聚集性调节作用
角膜上皮细胞动态平衡与伤口愈合具体目标3:研究基于miR146a的治疗
在人糖尿病器官培养的角膜中调节其靶点的方法。
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 }}
Mehrnoosh Saghizadeh Ghiam其他文献
Mehrnoosh Saghizadeh Ghiam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('Mehrnoosh Saghizadeh Ghiam', 18)}}的其他基金
Regulation of Limbal Niche in Normal and Diabetic Cornea by Extracellular Vesicles
细胞外囊泡对正常和糖尿病角膜角膜缘生态位的调节
- 批准号:
10381705 - 财政年份:2019
- 资助金额:
$ 55.54万 - 项目类别:
Regulation of Limbal Niche in Normal and Diabetic Cornea by Extracellular Vesicles
细胞外囊泡对正常和糖尿病角膜角膜缘生态位的调节
- 批准号:
10570179 - 财政年份:2019
- 资助金额:
$ 55.54万 - 项目类别:
The Role of MicroRNAs in Normal and Diseased Corneal Epithelial Homeostasis
MicroRNA 在正常和患病角膜上皮稳态中的作用
- 批准号:
9533576 - 财政年份:2015
- 资助金额:
$ 55.54万 - 项目类别:
The Role of MicroRNAs in Normal and Diseased Corneal Epithelial Homeostasis
MicroRNA 在正常和患病角膜上皮稳态中的作用
- 批准号:
9310261 - 财政年份:2015
- 资助金额:
$ 55.54万 - 项目类别:
The Role of MicroRNAs in Normal and Diseased Corneal Epithelial Homeostasis
MicroRNA 在正常和患病角膜上皮稳态中的作用
- 批准号:
9113015 - 财政年份:2015
- 资助金额:
$ 55.54万 - 项目类别:
The Role of MicroRNAs in Normal and Diseased Corneal Epithelial Homeostasis
MicroRNA 在正常和患病角膜上皮稳态中的作用
- 批准号:
9752588 - 财政年份:2015
- 资助金额:
$ 55.54万 - 项目类别:
The Role and Mechanisms of microRNAs in Diabetic Cornea
microRNA在糖尿病角膜中的作用和机制
- 批准号:
8360940 - 财政年份:2012
- 资助金额:
$ 55.54万 - 项目类别:
The Role and Mechanisms of microRNAs in Diabetic Cornea
microRNA在糖尿病角膜中的作用和机制
- 批准号:
8511675 - 财政年份:2012
- 资助金额:
$ 55.54万 - 项目类别:
相似海外基金
Oral pathogen - mediated pro-tumorigenic transformation through disruption of an Adherens Junction - associated RNAi machinery
通过破坏粘附连接相关的 RNAi 机制,口腔病原体介导促肿瘤转化
- 批准号:
10752248 - 财政年份:2024
- 资助金额:
$ 55.54万 - 项目类别:
Adherens junction dynamics and function in epithelial tissue morphogenesis
粘附连接动力学和上皮组织形态发生中的功能
- 批准号:
469118 - 财政年份:2022
- 资助金额:
$ 55.54万 - 项目类别:
Operating Grants
Adherens Junction dysfunction in Hidradenitis Suppurativa
化脓性汗腺炎的粘附连接功能障碍
- 批准号:
10701323 - 财政年份:2022
- 资助金额:
$ 55.54万 - 项目类别:
Adherens junction proteins in neuron-glia interactions
神经元-胶质细胞相互作用中的粘附连接蛋白
- 批准号:
9978138 - 财政年份:2019
- 资助金额:
$ 55.54万 - 项目类别:
Elucidation of the function of Focal adherens junction in morphogenesis
阐明焦点粘附连接在形态发生中的功能
- 批准号:
19K16145 - 财政年份:2019
- 资助金额:
$ 55.54万 - 项目类别:
Grant-in-Aid for Early-Career Scientists
Identifying and characterizing the effect of Aip1 on adherens junction remodeling in Drosophila follicular epithelium
鉴定和表征 Aip1 对果蝇滤泡上皮粘附连接重塑的影响
- 批准号:
528450-2018 - 财政年份:2018
- 资助金额:
$ 55.54万 - 项目类别:
Alexander Graham Bell Canada Graduate Scholarships - Master's
Src-mediated pathways regulating adherens junction assembly.
Src 介导的途径调节粘附连接组装。
- 批准号:
10166863 - 财政年份:2017
- 资助金额:
$ 55.54万 - 项目类别:
Src-mediated pathways regulating adherens junction assembly.
Src 介导的途径调节粘附连接组装。
- 批准号:
9310733 - 财政年份:2017
- 资助金额:
$ 55.54万 - 项目类别:
The function and interaction of focal adhesion and adherens junction in bone mechanosensing and mechanotransduction.
粘着斑和粘附连接在骨力传感和力转导中的功能和相互作用。
- 批准号:
17K17307 - 财政年份:2017
- 资助金额:
$ 55.54万 - 项目类别:
Grant-in-Aid for Young Scientists (B)
a-catenin and its binding partners in adherens junction assembly and function
α-连环蛋白及其在粘附连接组装和功能中的结合伙伴
- 批准号:
357714 - 财政年份:2016
- 资助金额:
$ 55.54万 - 项目类别:
Operating Grants