Macrophage miR146B and Ocular Neovascularization

巨噬细胞 miR146B 与眼部新生血管形成

• 批准号: 10004649
• 负责人: RAJENDRA S APTE
• 金额: $ 40.63万
• 依托单位: WASHINGTON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-09-30 至 2022-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10004649
• 关键词: Address; Affect; Age; Age related macular degeneration; Age-Years; Aging; Applications Grants; Bioinformatics; Biological Assay; Blindness; Cells; Cholesterol Homeostasis; Choroidal Neovascularization; Code; Complement; Complex; Computer software; Data; Disease; Elderly; Event; Exudative age-related macular degeneration; Eye; Functional disorder; Gene Expression; Gene Expression Profile; Gene Expression Regulation; Gene Targeting; Genes; Genetic Transcription; Goals; Immune system; Immunoprecipitation; In Vitro; Industrialization; Inflammation; Knock-out; Knockout Mice; Laboratories; Lead; Longevity; Luciferases; Mediating; Messenger RNA; Metabolic; Metabolism; MicroRNAs; Mitochondria; Molecular; Molecular Target; Mus; Neurons; Nucleotides; Pathogenesis; Pathogenicity; Pathologic; Pathologic Neovascularization; Pathway interactions; Pattern; Phenotype; Photoreceptors; Pilot Projects; Play; Proteomics; Regulation; Reporter; Role; Site; Specificity; Structure of retinal pigment epithelium; Technology; Testing; Therapeutic Intervention; Time; Transcriptional Regulation; Translational Repression; Untranslated RNA; Validation; Vascular Proliferation; age related; aged; base; conditional knockout; deep sequencing; gain of function; gene function; genome-wide; geographic atrophy; in vivo; inhibitor/antagonist; loss of function; mRNA Transcript Degradation; macrophage; novel; ocular neovascularization; overexpression; prevent; targeted treatment; therapeutic target; transcriptome; transcriptome sequencing; virtual

Age-related macular degeneration (AMD) is the leading cause of blindness in people over 50 years of age in the industrialized world. Vision loss in advanced AMD is either due to pathologic angiogenesis called choroidal neovascularization (CNV) or from loss of the retinal pigmented epithelium and overlying photoreceptor neurons in geographic atrophy. CNV tends to be catastrophic and accounts for about 80-90% of severe vision loss in AMD. Macrophage-mediated inflammation plays a critical role in the pathogenesis of CNV in AMD. The aging macrophage manifests its dysfunction in AMD by altered activation and polarization. The regulatory mechanisms that govern gene expression changes within macrophages are poorly characterized. MicroRNAs regulate gene expression at a global level but with cellular specificity and do so by mRNA degradation and translational repression. We propose to examine which miRNAs are altered in the aging macrophage, identify the specific gene targets that they regulate and assess the effects of modifying both the miRNA and genes in macrophages on their fate, function and ability to regulate CNV. This could be especially insightful as it might confirm age as a continuous variable that can be quantitatively regulated at an intrinsic level. We hope to identify novel miRNA, genes and molecular pathways that could be therapeutically targeted in AMD to prevent vision loss in this devastating disease.

老年性黄斑变性(AMD)是老年人致盲的主要原因 在工业化世界里，50岁。进展期AMD的视力丧失要么是由于 病理性血管生成称为脉络膜新生血管(CNV)或由于脉络膜新生血管丢失 地理性萎缩的视网膜色素上皮和覆盖的光感受器神经元。 CNV往往是灾难性的，约占严重视力丧失的80%-90% AMD。巨噬细胞介导的炎症在CNV的发病机制中起关键作用 在AMD。衰老的巨噬细胞在AMD中通过改变激活来表现其功能障碍 和两极分化。控制基因表达变化的调控机制 巨噬细胞内部的特征很差。MicroRNAs调控基因的表达 全球水平，但具有细胞特异性，并通过mRNA降解和翻译来实现 压抑。 我们建议检查在老化的巨噬细胞中哪些miRNAs发生了变化，识别 特定的基因靶点，它们调节和评估修改两者的效果 巨噬细胞中的miRNA和基因对其命运、功能和调节CNV的能力的影响。这 可能特别有洞察力，因为它可能会确认年龄是一个连续变量，可以 在内在水平上进行数量调控。我们希望发现新的miRNA、基因和 可作为AMD治疗靶点以预防视力丧失的分子途径 在这种毁灭性的疾病中。