Retinal Muller Glial Cells in the initiation of diabetic retinopathy
视网膜米勒胶质细胞在糖尿病视网膜病变的发生中的作用
基本信息
- 批准号:10709522
- 负责人:
- 金额:$ 37.73万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2022
- 资助国家:美国
- 起止时间:2022-09-30 至 2026-05-31
- 项目状态:未结题
- 来源:
- 关键词:AblationApoptosisBlindnessBlood VesselsCRISPR/Cas technologyCandidate Disease GeneCellsClustered Regularly Interspaced Short Palindromic RepeatsComplications of Diabetes MellitusDefectDependovirusDevelopmentDiabetes MellitusDiabetic RetinopathyDiseaseDisease ProgressionFailureGenesGenetic TranscriptionGerm CellsGliosisHomeostasisHomologous GeneHumanImmune systemInflammationInflammatoryInflammatory ResponseKnowledgeLesionMessenger RNAModelingMolecularNerve DegenerationNeurogliaNeuronsOxidative StressPlayProliferatingProteinsRNA-Binding ProteinsRattusRetinaRetinal DiseasesRoleSymptomsSystemTestingUp-RegulationWorkZinc Fingersaging populationcell typecellular targetingcombinatorialdiabetes controldiabetic rateffective therapyfirst responderimprovedin vivoin vivo Modelinflammatory modulationneovascularizationneurovascularnovelnovel therapeutic interventionnovel therapeuticsoverexpressionoxidationpreventprotective effectprotective pathwayresponseretinal neuronsingle-cell RNA sequencingtherapeutic candidatetherapeutically effectivetooltranscriptomics
项目摘要
PROJECT SUMMARY/ABSTRACT
The molecular mechanisms responsible for the initiation of diabetic retinopathy (DR), and the primary cellular
targets of diabetes in the retina have not been fully elucidated. This represents a significant barrier to the
development of effective therapies to prevent or slow down the initiation of the disease. When challenged by
diabetes, retinal neurons, glia, and the vasculature all display abnormalities. Even though it is currently not
clear which cell types are the primary targets of diabetes, Müller glial cells (MG), as one of the first responders
of diabetes in the retina, are essential for the development of diabetic retinopathy. However, the molecular
mechanisms controlling the diabetes-induced Müller glial responses remain understudied.
We applied single cell transcriptomic analysis (single cell RNA-seq) to systematically profile diabetes-
induced multicellular responses in the retina of diabetic rat models (preliminary studies). Among the 53 types of
retinal cell detected by single cell RNA-seq, MG were one of the first responders to diabetes at the
transcriptional level. Notably, MG initially upregulated genes that play protective roles in other systems,
including anti-apoptosis, anti-proliferation, anti-oxidation, and anti-inflammation genes, but failed to maintain
expression levels of these protective genes as the disease progressed. This failure could contribute to the
development of DR. We hypothesize that MG exert protective roles by upregulating protective genes in the
early stage of DR, and that enhancing this intrinsic protective mechanism will protect the retina from diabetes-
induced damage.
The proposed studies will test this hypothesis in two aims. In Aim 1, we will focus on studying one of the
candidate protective genes, Zinc finger protein 36 homolog (Zfp36), which was initially upregulated by diabetes
in MG and then downregulated as DR progressed, using diabetic rat models. In Aim 2, we will determine
whether multiplexing activation of protective pathways in MG with a novel CRISPR-based technique can
further protect the retina from diabetes-induced damage.
In summary, the proposed study aims to uncover the roles of MG in initiating DR, focusing on dissecting
their protective effects. This work will lead to better understanding of DR and new therapeutic candidates.
项目总结/摘要
糖尿病视网膜病变(DR)发生的分子机制,以及原发性视网膜病变的细胞机制,
糖尿病在视网膜中的靶点尚未完全阐明。这是一个重大障碍,
开发有效的治疗方法来预防或减缓疾病的发生。当受到挑战时,
糖尿病、视网膜神经元、神经胶质和脉管系统都显示异常。尽管目前还没有
明确哪些细胞类型是糖尿病的主要目标,Müller胶质细胞(MG),作为第一反应者之一
糖尿病视网膜病变的发生与发展有着密切的关系。然而,分子
控制糖尿病诱导的Müller神经胶质反应的机制仍然研究不足。
我们应用单细胞转录组学分析(单细胞RNA-seq)系统地分析糖尿病-
在糖尿病大鼠模型的视网膜中诱导多细胞反应(初步研究)。在53种类型的
通过单细胞RNA-seq检测到的视网膜细胞,MG是糖尿病的第一反应者之一,
转录水平。值得注意的是,MG最初上调在其他系统中发挥保护作用的基因,
包括抗凋亡、抗增殖、抗氧化和抗炎基因,但未能维持
随着疾病的进展,这些保护基因的表达水平。这一失败可能会导致
我们假设MG通过上调DR中的保护基因发挥保护作用。
早期阶段的DR,增强这种内在的保护机制将保护视网膜免受糖尿病-
诱发的损害。
拟议的研究将在两个目标中检验这一假设。在目标1中,我们将重点研究
候选保护基因,锌指蛋白36同源物(Zfp 36),最初由糖尿病上调
使用糖尿病大鼠模型,在MG中表达,然后随着DR的进展而下调。在目标2中,我们将确定
用一种新的基于CRISPR的技术在MG中多重激活保护性通路是否可以
进一步保护视网膜免受糖尿病引起的损害。
总之,拟议的研究旨在揭示MG在启动DR中的作用,重点是解剖
它们的保护作用。这项工作将导致更好地了解DR和新的治疗候选人。
项目成果
期刊论文数量(0)
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科研奖励数量(0)
会议论文数量(0)
专利数量(0)
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{{ truncateString('Sui Wang', 18)}}的其他基金
Mechanisms regulating the plasticity of postmitotic cells in mammalian retina
调节哺乳动物视网膜有丝分裂后细胞可塑性的机制
- 批准号:
10184992 - 财政年份:2021
- 资助金额:
$ 37.73万 - 项目类别:
Mechanisms regulating the plasticity of postmitotic cells in mammalian retina
调节哺乳动物视网膜有丝分裂后细胞可塑性的机制
- 批准号:
10610823 - 财政年份:2021
- 资助金额:
$ 37.73万 - 项目类别:
Mechanisms regulating the plasticity of postmitotic cells in mammalian retina
调节哺乳动物视网膜有丝分裂后细胞可塑性的机制
- 批准号:
10390436 - 财政年份:2021
- 资助金额:
$ 37.73万 - 项目类别:
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