Mechanistic study and therapeutic development for subretinal fibrosis

视网膜下纤维化的机制研究和治疗开发

• 批准号: 10749681
• 负责人: Shusheng Wang
• 金额: $ 38.82万
• 依托单位: TULANE UNIVERSITY OF LOUISIANA
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-09-01 至 2027-12-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10749681
• 关键词: Age related macular degeneration; Cell Lineage; Cells; Choroidal Neovascularization; Cicatrix; Clinical Treatment; Connective Tissue; Data; Endothelial Cells; Endothelium; Epithelium; Extracellular Matrix; Fibrosis; Gene Expression Profile; Goals; Growth Factor; Hemorrhage; Human; Injury; Knock-in; Lasers; Legal Blindness; MADH3 gene; Macrophage; Mesenchymal; MicroRNAs; Modeling; Molecular; Mus; Myofibroblast; Pathogenesis; Pathway interactions; Patients; Pharmaceutical Preparations; Proliferative Vitreoretinopathy; Repression; Retina; Retinal Detachment; Retinal Diseases; Role; Small Nuclear RNA; Spatial Distribution; Structure; Testing; Therapeutic; Transforming Growth Factor beta; Virus; cell type; legally blind; neovascularization; overexpression; periostin; response; small molecule; therapeutic development; therapeutic evaluation; therapeutic target; wound healing

PROJECT SUMMARY Subretinal fibrosis underlies the end-stage pathogenesis of several retinal diseases including age- related macular degeneration (AMD) and proliferative vitreoretinopathy (PVR). Fibrosis results from neovascularization or injuries and is part of the wound healing response characterized by the formation of excessive accumulation of extracellular matrix (ECM) connective tissue. Subretinal fibrosis can generate contractile force, cause scar formation, massive subretinal hemorrhage, and retinal detachment, therefore disrupting retinal structures and eventually leading to legal blindness. The cellular and molecular mechanism of subretinal fibrosis is still unclear, and the clinical treatment for this condition is very limited. Myofibroblast is a predominant cell type that are critically involved in fibrosis. The cellular contribution to myofibroblasts is diverse and heterogenous, with multiple cell types involved. For example, RPE cells contribute to fibrosis through epithelial-mesenchymal transition (EMT), endothelial cells contribute to fibrosis through endothelial-mesenchymal transition (endMT), and macrophages contribute to fibrosis through macrophage-mesenchymal transition (MMT). To fully understand the mechanism of subretinal fibrosis, the role of myofibroblast and the contribution of different cell-types to subretinal fibrosis need to be resolved. MicroRNAs (miRNAs or miRs) are endogenous small molecules which can regulate diverse pathways in different cell types. Several miRNAs, including miR-29, miR-24, and miR-21 have been associated with fibrosis. Our preliminary data showed that miR-24 overexpression inhibits EMT, endMT and fibrosis by regulating TGF-β/SMAD3 and LIMK2/MRTF pathways, suggesting miR-24 could serve as an ideal therapeutic target for subretinal fibrosis by targeting two major pathways in different cell types. The broad goal of this proposal is to elucidate the cellular contribution, identity and function of myofibroblasts in subretinal fibrosis and test the therapeutic potential of miR-24 in subretinal fibrosis. We hypothesize that: (1) myofibroblasts from multiple cell lineages could contribute to subretinal fibrosis; and (2) miR-24, can repress EMT, endoMT and MMT by regulating TGF-β/SMAD3 and LIMK2/MRTF pathways, therefore representing an excellent “one drug/multiple targets” model for treating subretinal fibrosis in AMD and PVR. Two Aims will be pursued: Aim I is to define the function, identity, and origin of myofibroblasts in subretinal fibrosis; and Aim II is to determine the therapeutic potential of miR-24 in subretinal fibrosis. Successful completion of the proposed project will pave the way to study the mechanism and therapeutics of subretinal fibrosis in human AMD and PVR patients.

项目概要 视网膜下纤维化是多种视网膜疾病（包括年龄相关疾病）的终末期发病机制的基础。 相关黄斑变性（AMD）和增殖性玻璃体视网膜病变（PVR）的结果。 来自新生血管形成或损伤，是伤口愈合反应的一部分，其特征是 细胞外基质（ECM）结缔组织过度积累的形成。 视网膜下纤维化可产生收缩力，导致疤痕形成、大量视网膜下纤维化 出血和视网膜脱离，从而破坏视网膜结构，最终导致 视网膜下纤维化的细胞和分子机制仍不清楚，并且 这种情况的临床治疗非常有限。肌成纤维细胞是一种主要的细胞类型。 对肌成纤维细胞的细胞贡献是多种多样的。 异质性，涉及多种细胞类型，例如，RPE 细胞会导致纤维化。 通过上皮间质转化（EMT），内皮细胞通过以下方式促进纤维化： 内皮-间质转化（endMT），巨噬细胞通过 巨噬细胞间质转化（MMT） 充分了解视网膜下的机制。 纤维化、肌成纤维细胞的作用以及不同细胞类型对视网膜下纤维化的贡献 MicroRNA（miRNA 或 miR）是内源性小分子，可以解决这些问题。 调节不同细胞类型中的多种途径，包括 miR-29、miR-24 和 miR-24。 我们的初步数据表明 miR-21 与纤维化相关。 过表达通过调节 TGF-β/SMAD3 和 LIMK2/MRTF 抑制 EMT、endMT 和纤维化 途径，表明 miR-24 可以作为视网膜下纤维化的理想治疗靶点 该提案的主要目标是阐明不同细胞类型中的两个主要途径。 肌成纤维细胞在视网膜下纤维化中的细胞贡献、身份和功能并测试 miR-24 在视网膜下纤维化中的治疗潜力我们认为：（1）肌成纤维细胞。 来自多种细胞谱系的 miR-24 可能导致视网膜下纤维化；(2) miR-24 可以抑制 EMT、endoMT 和 MMT 通过调节 TGF-β/SMAD3 和 LIMK2/MRTF 通路，因此 代表了治疗 AMD 视网膜下纤维化的优秀“单药/多靶点”模型 将追求两个目标：目标 I 是定义 PVR 的功能、身份和起源。 视网膜下纤维化中的肌成纤维细胞；目标 II 是确定治疗潜力 miR-24 在视网膜下纤维化中的作用的成功完成将为该项目奠定基础。 研究人类 AMD 和 PVR 视网膜下纤维化的机制和治疗方法 患者。