Immunopathogenic mechanisms of dry eye disease
Immunopathogenic mechanisms of dry eye disease
批准号:
10197402
负责人:
Reza Dana
金额:
$12.49万
依托单位国家:
美国
项目类别:
财政年份:
2010
资助国家:
美国
项目状态:
已结题
起止时间:
2010-09-30 至 2024-11-30
关键词:
AdultAgeAge related macular degenerationAgingAmericanAntigen-Presenting CellsBlindnessCaringCellsChronicCorneal UlcerDataDesiccationDevelopmentDiagnosisDirect CostsDiseaseDoseElementsEpithelialEpitheliumExposure toEyeEye diseasesFinancial HardshipFunctional disorderGFI1 geneGenerationsHealthcare SystemsHigh PrevalenceHomeostasisHomingImmuneImmunityImmunologic MemoryImpairmentIn VitroInflammationInflammatoryInterferon Type IIInterleukin-17Interleukin-2Interleukin-7Knockout MiceKnowledgeLaboratoriesMaintenanceMediatingMemoryMolecularMusOphthalmologyPathogenicityPatientsPhenotypePrevalencePrincipal InvestigatorProcessRegulationRegulatory T-LymphocyteResearchRiskSeriesSeveritiesSeverity of illnessSourceStressSubstance PVisitVisualWorkagedbasecorneal scarcytokineeffective therapyexperimental studyeye drynessfunctional restorationimprovedin vivoinsightinterleukin-23novelocular surfaceproductivity losspromoterresponserestorationtherapeutic targettraffickingtranscription factortranslational impact
中文摘要
干眼病(DED)是一种慢性免疫介导的眼表疾病,其特征是
上皮屏障的破坏和持续的眼表炎症,在严重的情况下会导致
因角膜溃疡和疤痕而失明。DED可以说是最常见的眼科疾病
患者就诊于眼科护理专业人员的情况,据估计,超过1600万美国成年人
被诊断出患有DED(比老年性黄斑变性高几倍)。值得注意的是,
DED的患病率随着年龄的增长而增加。DED给美国医疗体系带来的财政负担是巨大的,
据估计,每年由生产力损失造成的直接成本和支出超过35亿美元。
包括首席调查员在内的几个实验室的工作揭示了关键的见解
关于DED的免疫发病机制。现在有强有力的证据表明,T辅助17(Th17)细胞
是免疫介导的眼表损伤的关键促进剂。私家侦探的实验室显示
记忆Th17(MTh17)细胞维持疾病的慢性化,导致眼表上皮病
在暴露于干燥的压力下后会持续数月。此外,公安局实验室的数据显示,
调节性T细胞(Tregs)在抑制DED的Th17反应方面存在缺陷。此外,私家侦探的实验室
已经确定了控制抗原提呈细胞(APC)激活和贩运的关键机制
DED,以及效应器TH17的引爆、扩张和寻的。尽管在解体方面取得了实质性进展
在潜在的免疫致病机制中,重要的问题仍然没有答案。
我们假设:(1)慢性DED的特征是脑功能长期受损。
正常维持免疫静止的调节性T细胞(Treg),以及(2)老年人更多
由于Th17的内存池较大,易患DED,其功能不受老年人的充分调节
特雷格斯。该项目的主要目标是:(I)准确定义
确定DED患者长期Treg功能障碍的特征和机制;(Ii)确定
MTh17细胞的细胞前体以及影响mTh17细胞生成的细胞因子机制
免疫记忆;以及(Iii)确定在衰老过程中放大mTh17免疫的因素。要实现这些目标
目标,定义了三个具体目标,以回答以下问题:目标1:什么是
DED患者耐受性Treg功能障碍的发病机制?目标2:哪些效应器Th17子集
倾向于进入内存池(从而允许DED慢性化),以及哪些因素调节这一点
流程呢?最后目标3:增强Th17介导的细胞和分子机制是什么
衰老中的死亡?预计这项研究将产生重大的翻译影响,因为
DED的流行,我们对其免疫发病机制的了解仍然有限,以及相对的
缺乏有效的治疗方法。
英文摘要
Dry eye disease (DED) is a chronic immune-mediated disorder of the ocular surface, characterized by
disruption of the epithelial barrier and sustained ocular surface inflammation, which in severe cases results
in blindness from corneal ulceration and scarring. DED is arguably the most common ophthalmologic
condition for which patients visit eye care professionals, with more than 16 million US adults estimated to
have been diagnosed with DED (several folds higher than age-related macular degeneration). Notably, the
prevalence of DED increases with age. The financial burden of DED to the US healthcare system is vast,
with direct costs and expenses from productivity losses estimated to exceed $3.5 billion annually.
The work of several laboratories, including the Principal Investigator's, has revealed key insights
concerning the immunopathogenesis of DED. There is now strong evidence that T helper-17 (Th17) cells
are critical promoters of immune-mediated damage to the ocular surface. The PI's laboratory has shown
that memory Th17 (mTh17) cells maintain disease chronicity, resulting in ocular surface epitheliopathy that
persists for many months after exposure to desiccating stress. Moreover, data from the PI's lab show that
regulatory T cells (Tregs) are defective in suppressing the Th17 response in DED. In addition, the PI's lab
has identified critical mechanisms controlling antigen-presenting cell (APC) activation and trafficking in
DED, as well as effector Th17 priming, expansion and homing. Despite substantial progress in unraveling
underlying immunopathogenic mechanisms, important questions remain unanswered.
We hypothesize that (1) chronic DED is characterized by long-term impairment in the function of
regulatory T cells (Tregs) that normally maintain immune quiescence, and that (2) the aged are more
susceptible to DED due to a larger pool of memory Th17, whose function is inadequately regulated by aged
Tregs. The principal objectives of this project are to (i) precisely define the phenotypic changes that
characterize, and the mechanisms that promote long-term Treg dysfunction in DED; (ii) determine the
cellular precursors of mTh17 cells, as well as the cytokine mechanisms that influence the generation of
immunologic memory; and (iii) define the factors that amplify mTh17 immunity in aging. To achieve these
objectives, three specific aims have been defined to answer the following questions: Aim 1: What are the
causative mechanisms of enduring Treg dysfunction in DED? Aim 2: Which effector Th17 subsets are
predisposed to enter the memory pool (thus permitting DED chronicity), and what factors regulate this
process? And finally Aim 3: What are the cellular and molecular mechanisms that augment Th17-mediated
DED in aging? It is anticipated that this research will have significant translational impact given the high
prevalence of DED, the still limited knowledge we have regarding its immunopathogenesis, and the relative
scarcity of effective treatments.
期刊论文(0)
专著(0)
科研奖励(0)
会议论文
The Impact of Donor Diabetes on Corneal Immune Cells and Graft Survival
-
批准号:10707166
-
项目类别:
-
资助金额:$49.25万
-
财政年份:2022
-
负责人:Reza Dana
-
依托单位:
Therapeutic Function of alpha-Melanocyte Stimulating Hormone (α-MSH) in Acute Injury and Chronic Degeneration of Corneal Endothelium
-
批准号:10394920
-
项目类别:
-
资助金额:$23.89万
-
财政年份:2021
-
负责人:Reza Dana
-
依托单位:
Therapeutic Function of alpha-Melanocyte Stimulating Hormone (α-MSH) in Acute Injury and Chronic Degeneration of Corneal Endothelium
-
批准号:10191281
-
项目类别:
-
资助金额:$29.55万
-
财政年份:2021
-
负责人:Reza Dana
-
依托单位:
Efficacy of the Neuropeptide Alpha-Melanocyte Stimulating Hormone (α-MSH) in Promoting Survival of Corneal Endothelial Cells in Eye Banking and Transplantation
-
批准号:9762115
-
项目类别:
-
资助金额:$29.55万
-
财政年份:2018
-
负责人:Reza Dana
-
依托单位:
Immunopathogenic mechanisms of dry eye disease
-
批准号:8539627
-
项目类别:
-
资助金额:$39.81万
-
财政年份:2010
-
负责人:Reza Dana
-
依托单位:
Immunopathogenic mechanisms of dry eye disease
-
批准号:7949195
-
项目类别:
-
资助金额:$43.84万
-
财政年份:2010
-
负责人:Reza Dana
-
依托单位:
Immunopathogenic mechanisms of dry eye disease
-
批准号:8328689
-
项目类别:
-
资助金额:$41.9万
-
财政年份:2010
-
负责人:Reza Dana
-
依托单位:
Immunopathogenic mechanisms of dry eye disease
-
批准号:9129776
-
项目类别:
-
资助金额:$49.25万
-
财政年份:2010
-
负责人:Reza Dana
-
依托单位:
Immunopathogenic mechanisms of dry eye disease
-
批准号:10524044
-
项目类别:
-
资助金额:$49.25万
-
财政年份:2010
-
负责人:Reza Dana
-
依托单位:
Immunopathogenic mechanisms of dry eye disease
-
批准号:9884617
-
项目类别:
-
资助金额:$49.25万
-
财政年份:2010
-
负责人:Reza Dana
-
依托单位:
Immunopathogenic mechanisms of dry eye disease
-
批准号:8139780
-
项目类别:
-
资助金额:$41.9万
-
财政年份:2010
-
负责人:Reza Dana
-
依托单位:
Immunopathogenic mechanisms of dry eye disease
-
批准号:10063525
-
项目类别:
-
资助金额:$47.77万
-
财政年份:2010
-
负责人:Reza Dana
-
依托单位:
Immunopathogenic mechanisms of dry eye disease
-
批准号:8928621
-
项目类别:
-
资助金额:$48.27万
-
财政年份:2010
-
负责人:Reza Dana
-
依托单位:
Immunopathogenic mechanisms of dry eye disease
-
批准号:9321030
-
项目类别:
-
资助金额:$49.25万
-
财政年份:2010
-
负责人:Reza Dana
-
依托单位:
Immunopathogenic mechanisms of dry eye disease
-
批准号:10312003
-
项目类别:
-
资助金额:$47.77万
-
财政年份:2010
-
负责人:Reza Dana
-
依托单位:
Immunopathogenic mechanisms of dry eye disease
-
批准号:8692069
-
项目类别:
-
资助金额:$49.25万
-
财政年份:2010
-
负责人:Reza Dana
-
依托单位:
New Strategies for Modulation of Corneal and Ocular Surface Inflammation
-
批准号:7685378
-
项目类别:
-
资助金额:$11.88万
-
财政年份:2008
-
负责人:Reza Dana
-
依托单位:
New Strategies for Modulation of Corneal and Ocular Surface Inflammation
-
批准号:8330890
-
项目类别:
-
资助金额:$11.88万
-
财政年份:2008
-
负责人:Reza Dana
-
依托单位:
New Strategies for Modulation of Corneal and Ocular Surface Inflammation
-
批准号:8133828
-
项目类别:
-
资助金额:$11.88万
-
财政年份:2008
-
负责人:Reza Dana
-
依托单位:
New Strategies for Modulation of Corneal and Ocular Surface Inflammation
-
批准号:7513469
-
项目类别:
-
资助金额:$11.88万
-
财政年份:2008
-
负责人:Reza Dana
-
依托单位:
国内基金
海外基金
登录
查看更多内容
补阳还五汤通过AGE-RAGE通路调控脓毒症免疫失衡的机制与转化研究
-
批准号:JCZRLH202601523
-
项目类别:省市级项目
-
资助金额:--
-
批准年份:2026
-
负责人:
-
依托单位:
靶向递送一氧化碳调控AGE-RAGE级联反应促进糖尿病创面愈合研究
-
批准号:JCZRQN202500010
-
项目类别:省市级项目
-
资助金额:--
-
批准年份:2025
-
负责人:
-
依托单位:
对香豆酸抑制AGE-RAGE-Ang-1通路改善海马血管生成障碍发挥抗阿尔兹海默病作用
-
批准号:2025JJ70209
-
项目类别:省市级项目
-
资助金额:--
-
批准年份:2025
-
负责人:雷芬芳
-
依托单位:
AGE-RAGE通路调控慢性胰腺炎纤维化进程的作用及分子机制
-
批准号:--
-
项目类别:面上项目
-
资助金额:--
-
批准年份:2024
-
负责人:万荣
-
依托单位:
甜茶抑制AGE-RAGE通路增强突触可塑性改善小鼠抑郁样行为
-
批准号:2023JJ50274
-
项目类别:省市级项目
-
资助金额:--
-
批准年份:2023
-
负责人:贺志明
-
依托单位:
蒙药额尔敦-乌日勒基础方调控AGE-RAGE信号通路改善术后认知功能障碍研究
-
批准号:--
-
项目类别:地区科学基金项目
-
资助金额:33万元
-
批准年份:2022
-
负责人:都义日
-
依托单位:
补肾健脾祛瘀方调控AGE/RAGE信号通路在再生障碍性贫血骨髓间充质干细胞功能受损的作用与机制研究
-
批准号:--
-
项目类别:面上项目
-
资助金额:52万元
-
批准年份:2022
-
负责人:叶宝东
-
依托单位:
LncRNA GAS5在2型糖尿病动脉粥样硬化中对AGE-RAGE 信号通路上相关基因的调控作用及机制研究
-
批准号:
-
项目类别:省市级项目
-
资助金额:10.0万元
-
批准年份:2022
-
负责人:于海兵
-
依托单位:
围绕GLP1-Arginine-AGE/RAGE轴构建探针组学方法探索大柴胡汤异病同治的效应机制
-
批准号:81973577
-
项目类别:面上项目
-
资助金额:55.0万元
-
批准年份:2019
-
负责人:辛贵忠
-
依托单位:
AGE/RAGE通路microRNA编码基因多态性与2型糖尿病并发冠心病的关联研究
-
批准号:81602908
-
项目类别:青年科学基金项目
-
资助金额:18.0万元
-
批准年份:2016
-
负责人:刘括
-
依托单位: