Targeting the Etiology of Diabetic Retinopathy
针对糖尿病视网膜病变的病因
基本信息
- 批准号:10672874
- 负责人:
- 金额:$ 37.78万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2019
- 资助国家:美国
- 起止时间:2019-09-01 至 2025-07-31
- 项目状态:未结题
- 来源:
- 关键词:AblationAccelerationAddressBlindnessBlood VesselsCarbohydratesClinicalDefectDetectionDevelopmentDiabetes MellitusDiabetic RetinopathyDiabetic mouseDietDisease ProgressionEIF4EBP1 geneElementsEnvironmentEpitopesEtiologyEventExperimental ModelsFatty acid glycerol estersFunctional disorderGene ExpressionGeneticGlucoseGrowth FactorHexosaminesHomeostasisHormonesInflammationInnovative TherapyInsulin-Dependent Diabetes MellitusInterventionLaboratoriesLeadLinkMediatingMessenger RNAMetabolicMetabolic stressModelingMolecularMolecular TargetMuller&aposs cellMusNeurogliaNeuronal DysfunctionNeuronsNutrientOutcomePathogenesisPathologyPathway interactionsPeptide Initiation FactorsPhotoreceptorsPlayPrediabetes syndromeProductionProteinsResearchRetinaRetinal DefectRetinal DiseasesRiboTagRibosomesRoleSourceStreptozocinStressTestingTherapeuticTissuesTranslational ActivationTranslationsVascular Endothelial Growth FactorsVisualbiological adaptation to stresscytokinedesigndiabeticdiabetic patientgenetic manipulationgenetic regulatory proteinglial activationglycosylationimprovedmRNA Translationmouse modelnovelnovel therapeuticspharmacologicpreventprotein expressionrecruitresponseretinal adaptationretinal neuronvascular factorvision developmentvisual dysfunction
项目摘要
Project Summary
Diabetic retinopathy (DR) is clinically defined as a disease of the retinal microvasculature, and most research
on its pathogenesis to date has focused on the vasculature itself. Recent advances in multifocal ERG
demonstrate that neuro-retinal defects precede and even predict the development of DR. Thus, it is important
to investigate the molecular events that contribute to early loss of retinal adaptation to the metabolic
environment in diabetes.!Translation of mRNA is a major regulatory step in gene expression that is important
for controlling the expression of vascular endothelial growth factor (VEGF), as well as other critical growth
factors and cytokines in response to metabolic stress. Our central hypothesis is that a diabetes-induced shift
in the selection of mRNAs for translation within Müller glia results in loss of retinal homeostasis and the
eventual development of DR. Müller cells, the principal glial cell of the retina, are well recognized for the role
they play in the production of homeostatic and trophic factors that support both the vasculature and neuronal
layers of the retina. In diabetic patients, glial activation occurs prior to clinical manifestation of DR and likely
serves as an adaptive response to mitigate tissue damage. However, prolonged changes in Müller glial
protein expression become causative in the development of retinal complications. Specifically, Müller glia are
the principal source of increased retinal VEGF expression in diabetes, as conditional Muller cell specific
disruption of VEGF prevents elevated growth factor expression and reduces retinal vascular pathology. Our
laboratory has shown that diabetes-induced activation of the translational repressor 4E-BP1 promotes retinal
VEGF expression and the development of visual dysfunction in a model of type 1 diabetes. The objective
here is to address a fundamental gap in our understanding of the molecular events that produce early
changes in Müller cell specific protein expression. Using a newly developed RiboTag mouse model, wherein
expression of an epitope-tagged ribosomal subunit is directed to Müller glia, the proposed studies will provide
an unprecedented assessment of translationally active mRNAs in Müller glia within the intact retina. The
proposed studies are designed to characterize defects in the selection of specific mRNAs for translation in two
experimental models of diabetes: streptozotocin administration and high fat/high carbohydrate diet. In addition
to identifying regulatory mechanisms for specific mRNAs that contribute to glial dysfunction, the proposed
studies will also assess the development of retinal defects and visual deficits in the two experimental models
following Müller-specific genetic manipulation of the stress response protein REDD1 or protein O-
GlcNAcylation (i.e. two novel mechanisms for mediating specific changes in mRNA translation). The rationale
is that once the molecular defects in translational control mechanisms in retinal Müller cells are known, the
function/assembly of translation initiation factors can be manipulated pharmacologically, resulting in new
therapeutics that address dysregulated expression of multiple growth factors and cytokines including VEGF.
!
项目概要
糖尿病视网膜病变(DR)在临床上被定义为一种视网膜微血管疾病,大多数研究
迄今为止,关于其发病机制的研究主要集中在脉管系统本身。
证明神经视网膜缺陷先于甚至预测 DR 的发展,因此,这一点很重要。
研究导致视网膜早期丧失代谢适应能力的分子事件
糖尿病的环境。!mRNA 的翻译是基因表达的一个主要调控步骤,非常重要
用于控制血管内皮生长因子 (VEGF) 以及其他关键生长因子的表达
我们的中心假设是糖尿病引起的转变。
选择在 Müller 胶质细胞内进行翻译的 mRNA 会导致视网膜稳态丧失,
DR 细胞(视网膜的主要神经胶质细胞)的最终发育因其作用而得到广泛认可。
它们在支持脉管系统和神经系统的稳态和营养因子的产生中发挥作用
在糖尿病患者的视网膜层中,神经胶质细胞的激活可能发生在 DR 的临床表现之前。
作为减轻组织损伤的适应性反应,然而,穆勒胶质细胞的长期变化。
具体而言,穆勒神经胶质细胞的蛋白质表达成为视网膜并发症发生的原因。
糖尿病视网膜 VEGF 表达增加的主要来源,作为条件性 Muller 细胞特异性
VEGF 的破坏可防止生长因子表达升高并减少视网膜血管病变。
实验室表明,糖尿病诱导的翻译阻遏物 4E-BP1 激活可促进视网膜
1 型糖尿病模型中 VEGF 的表达和视觉功能障碍的发展。
这是为了解决我们对产生早期分子事件的理解中的一个根本差距
使用新开发的 RiboTag 小鼠模型,Müller 细胞特异性蛋白质表达发生变化。
表位标记的核糖体亚基的表达针对穆勒神经胶质细胞,拟议的研究将提供
对完整视网膜内 Müller 胶质细胞中翻译活性 mRNA 的前所未有的评估。
拟议的研究旨在表征在两种情况下选择特定 mRNA 进行翻译时的缺陷
糖尿病实验模型:链脲佐菌素给药和高脂肪/高碳水化合物饮食。
为了确定导致神经胶质细胞功能障碍的特定 mRNA 的调节机制,提出的
研究还将评估两个实验模型中视网膜缺陷和视力缺陷的发展情况
对应激反应蛋白 REDD1 或蛋白 O- 进行 Müller 特异性基因操作后
GlcNAcylation(即介导 mRNA 翻译特定变化的两种新机制)。
是一旦知道视网膜穆勒细胞翻译控制机制的分子缺陷,
翻译起始因子的功能/组装可以通过药理学进行操纵,从而产生新的
解决多种生长因子和细胞因子(包括 VEGF)表达失调的治疗方法。
!
项目成果
期刊论文数量(2)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
REDD1 deletion prevents the development of renal dysfunction in diabetic mice.
REDD1 缺失可防止糖尿病小鼠出现肾功能障碍。
- DOI:
- 发表时间:2022
- 期刊:
- 影响因子:0
- 作者:Sunilkumar,Siddharth;Miller,WilliamP;Toro,Allyson;Yerlikaya,Esma;Dennis,MichaelD
- 通讯作者:Dennis,MichaelD
Retinal Protein O-GlcNAcylation and the Ocular Renin-angiotensin System: Signaling Cross-roads in Diabetic Retinopathy.
- DOI:10.2174/1573399817999210111205933
- 发表时间:2022
- 期刊:
- 影响因子:3.3
- 作者:Dierschke SK;Dennis MD
- 通讯作者:Dennis MD
{{
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 }}
Michael D. Dennis其他文献
Phosphorylation of plant translation initiation factors by CK2
CK2 磷酸化植物翻译起始因子
- DOI:
- 发表时间:
2008 - 期刊:
- 影响因子:0
- 作者:
Michael D. Dennis - 通讯作者:
Michael D. Dennis
Microsoft Word-Dennis et al resubmission.docx
Microsoft Word-Dennis 等人重新提交.docx
- DOI:
- 发表时间:
2012 - 期刊:
- 影响因子:0
- 作者:
Michael D. Dennis;S. Kimball;L. Jefferson - 通讯作者:
L. Jefferson
The Repressors of mTORC1 Signaling, REDD1 and REDD2, Are Induced in Immobilized Rat Skeletal Muscle
mTORC1 信号传导阻遏蛋白 REDD1 和 REDD2 在固定化大鼠骨骼肌中诱导产生
- DOI:
- 发表时间:
2013 - 期刊:
- 影响因子:0
- 作者:
A. Kelleher;S. Kimball;Michael D. Dennis;Rudolf J. Schilder;L. Jefferson - 通讯作者:
L. Jefferson
Michael D. Dennis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('Michael D. Dennis', 18)}}的其他基金
Redox-sensitive activation of REDD1 in diabetic retinopathy
糖尿病视网膜病变中 REDD1 的氧化还原敏感激活
- 批准号:
10490453 - 财政年份:2021
- 资助金额:
$ 37.78万 - 项目类别:
Redox-sensitive activation of REDD1 in diabetic retinopathy
糖尿病视网膜病变中 REDD1 的氧化还原敏感激活
- 批准号:
10275722 - 财政年份:2021
- 资助金额:
$ 37.78万 - 项目类别:
Redox-sensitive activation of REDD1 in diabetic retinopathy
糖尿病视网膜病变中 REDD1 的氧化还原敏感激活
- 批准号:
10655639 - 财政年份:2021
- 资助金额:
$ 37.78万 - 项目类别:
Targeting the Etiology of Diabetic Retinopathy
针对糖尿病视网膜病变的病因
- 批准号:
10224208 - 财政年份:2019
- 资助金额:
$ 37.78万 - 项目类别:
Targeting the Etiology of Diabetic Retinopathy
针对糖尿病视网膜病变的病因
- 批准号:
10270082 - 财政年份:2019
- 资助金额:
$ 37.78万 - 项目类别:
Targeting the Etiology of Diabetic Retinopathy
针对糖尿病视网膜病变的病因
- 批准号:
10480776 - 财政年份:2019
- 资助金额:
$ 37.78万 - 项目类别:
Hyperglycemia-induced translational control of gene expression in the retina
高血糖诱导的视网膜基因表达翻译控制
- 批准号:
9110283 - 财政年份:2015
- 资助金额:
$ 37.78万 - 项目类别:
Hyperglycemia-induced translational control of gene expression in the retina
高血糖诱导的视网膜基因表达翻译控制
- 批准号:
9057160 - 财政年份:2015
- 资助金额:
$ 37.78万 - 项目类别:
Hyperglycemia-induced translational control of gene expression in the retina
高血糖诱导的视网膜基因表达翻译控制
- 批准号:
8704419 - 财政年份:2013
- 资助金额:
$ 37.78万 - 项目类别:
Hyperglycemia-induced translational control of gene expression in the retina
高血糖诱导的视网膜基因表达翻译控制
- 批准号:
8567775 - 财政年份:2013
- 资助金额:
$ 37.78万 - 项目类别:
相似国自然基金
高功率激光驱动低β磁重联中磁岛对电子加速影响的研究
- 批准号:12305275
- 批准年份:2023
- 资助金额:30 万元
- 项目类别:青年科学基金项目
U型离散顺流火蔓延非稳态热输运机理与加速机制研究
- 批准号:52308532
- 批准年份:2023
- 资助金额:30 万元
- 项目类别:青年科学基金项目
NOTCH3/HLF信号轴驱动平滑肌细胞表型转化加速半月板退变的机制研究
- 批准号:82372435
- 批准年份:2023
- 资助金额:49 万元
- 项目类别:面上项目
TWIST1介导的ITGBL1+肿瘤相关成纤维细胞转化加速结肠癌动态演化进程机制及其预防干预研究
- 批准号:82373112
- 批准年份:2023
- 资助金额:49 万元
- 项目类别:面上项目
实施科学视角下食管癌加速康复外科证据转化障碍机制与多元靶向干预策略研究
- 批准号:82303925
- 批准年份:2023
- 资助金额:30 万元
- 项目类别:青年科学基金项目
相似海外基金
Mechanisms of Cardiac Injury Resolution by CX3CR1+ Macrophages
CX3CR1巨噬细胞解决心脏损伤的机制
- 批准号:
10719459 - 财政年份:2023
- 资助金额:
$ 37.78万 - 项目类别:
Investigating cerebrovascular dysfunction and cerebral atrophy in severe traumatic brain injury
严重颅脑损伤中脑血管功能障碍和脑萎缩的调查
- 批准号:
10742569 - 财政年份:2023
- 资助金额:
$ 37.78万 - 项目类别:
Development of a new class of BLVRB-targeted redox therapeutics in breast cancer
开发一类新型 BLVRB 靶向乳腺癌氧化还原疗法
- 批准号:
10759653 - 财政年份:2023
- 资助金额:
$ 37.78万 - 项目类别:
Microvascular Neuroimaging in Age-related Alzheimer's Disease and Tauopathies
年龄相关性阿尔茨海默病和 Tau蛋白病的微血管神经影像学
- 批准号:
10738372 - 财政年份:2023
- 资助金额:
$ 37.78万 - 项目类别:
PGRMC Proteins as Markers of Fertility and Overall Health Status
PGRMC 蛋白作为生育力和整体健康状况的标志
- 批准号:
10729068 - 财政年份:2023
- 资助金额:
$ 37.78万 - 项目类别: