Metabolic reprogramming of endothelial precursor cells in subretinal fibrosis

视网膜下纤维化中内皮前体细胞的代谢重编程

• 批准号: 10752924
• 负责人: JIYANG CAI
• 金额: $ 45.94万
• 依托单位: UNIVERSITY OF OKLAHOMA HLTH SCIENCES CTR
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-09-30 至 2028-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10752924
• 关键词: Actins; Adoptive Transfer; Aftercare; Age; Age related macular degeneration; Amino Acids; Area; Blindness; Blood Vessels; Bone Marrow; Cells; Cellular Structures; Chimeric Proteins; Choroid; Choroidal Neovascularization; Cicatrix; Clinical; Collagen; Complication; Conditioned Culture Media; Development; Disease; Effector Cell; Endothelial Cells; Endothelium; Epithelium; Event; Experimental Models; Exudative age-related macular degeneration; Eye; Fibroblasts; Fibrosis; Gene Expression Profile; Genes; Genetic; Genetic Transcription; Glycolysis; Glycolysis Inhibition; Goals; Growth Factor; Human; Immunofluorescence Immunologic; In Vitro; Interleukins; Knock-out; Knockout Mice; Laser injury; Lasers; Lesion; Macrophage; Measures; Mediating; Mesenchymal; Metabolic; Metabolic Pathway; Metabolism; Microglia; Mitochondria; Modeling; Molecular; Monitor; Mouse Protein; Muller' s cell; Mus; Myeloid Cells; Oxidative Phosphorylation; Patients; Pattern; Production; Proliferating; Property; Publishing; Receptor Gene; Recombinant Interleukins; Recombinants; Retina; Role; Signal Transduction; Smooth Muscle; Source; Spatial Distribution; Stains; Testing; Therapeutic Effect; Therapeutic Intervention; Tissues; Transforming Growth Factor beta; Transforming Growth Factors; Treatment Factor; VLDL receptor; Vascular Endothelial Growth Factors; Vimentin; Vision; Visual Acuity; Wild Type Mouse; angiogenesis; cell type; connective tissue growth factor; cytokine; digital; effective therapy; follow-up; human tissue; in vitro testing; in vivo; inhibitor; intercellular communication; intravitreal injection; laser photocoagulation; metabolomics; mouse model; nano-string; neovascular; neuroinflammation; novel; precursor cell; preference; programs; protein biomarkers; receptor; recruit; repaired; response; retinal damage; single-cell RNA sequencing; small molecule inhibitor; stem-like cell; success; targeted treatment; transcription factor; transdifferentiation; validation studies

Therapeutic agents that target the vascular endothelial growth factor (VEGF) have achieved remarkable success in patients with the neovascular form of age-related macular degeneration (nAMD). An emerging clinical problem, however, is that many of the nAMD patients develop subretinal fibrosis (SRF) after receiving anti-VEGF therapy. SRF can cause irreversible structural damage to the retina and is a major vision- threatening complication with no effective treatment. The disease mechanisms of SRF in nAMD are largely unknown. Transforming growth factor beta (TGF-beta) is a major driver of fibrosis. The source of TGF-beta in SRF, and its main effector cells, have not been well defined. SRF can be modeled in mice with spontaneous or experimentally-induced choroidal neovascularization (CNV). In our published and preliminary studies, we found that mice with targeted deletion in the very low-density lipoprotein receptor (Vldlr) gene developed SRF when their CNV lesions regressed. Using single cell RNA sequencing, we identified endothelial precursor cells (EPCs) as a major cluster of cells that displayed markers of fibrosis. Similar findings were observed in JR5558 mice and in laser-induced CNV. EPCs have stem cell-like properties, and they are recruited to the choroidal and retinal neovessels to facilitate the vascular repair. In the subretinal microenvironment, EPCs gradually lose their cellular structures and transdifferentiate into fibroblast-like cells. We hypothesize that TGF-beta-mediated metabolic reprograming of EPCs is a key signaling event that contributes to the formation and progression of SRF after CNV. For the project proposed in this application, we will determine the roles of EPCs in mouse models of CNV and in human donor eye tissues with wet AMD. We will also examine the metabolic reprogramming of EPCs in response to TGF-beta. Furthermore, we will explore whether Muller cell-derived IL- 33 promotes TGF-beta production from macrophages, and whether inhibiting the IL-33 signaling suppresses SRF. Results from these studies will reveal novel molecular and cellular mechanisms of SRF, and define new targets for potential therapeutic intervention.

靶向血管内皮生长因子（VEGF）的治疗剂已经取得了显著的进展， 在患有年龄相关性黄斑变性（nAMD）的新生血管形式的患者中获得成功。一个新兴 然而，临床问题是，许多nAMD患者在接受治疗后发生视网膜下纤维化（SRF）。 抗VEGF治疗。SRF会对视网膜造成不可逆的结构性损伤，是一种主要的视力障碍- 没有有效治疗的危险并发症。nAMD中SRF的疾病机制主要是 未知转化生长因子β（TGF-β）是纤维化的主要驱动因素。TGF-β的来源 SRF及其主要效应细胞尚未明确。SRF可以在自发或自发的小鼠中建模 实验诱导的脉络膜新生血管形成（CNV）。在我们发表的和初步的研究中，我们发现 极低密度脂蛋白受体（Vldlr）基因靶向缺失的小鼠在 CNV病变消退。利用单细胞RNA测序，我们鉴定了内皮前体细胞， （EPCs）作为显示纤维化标志物的主要细胞簇。在JR 5558中观察到类似结果 小鼠和激光诱导的CNV。EPCs具有干细胞样的特性，它们被招募到脉络膜 和视网膜新生血管以促进血管修复。在视网膜下微环境中，EPCs逐渐丧失 它们的细胞结构和转分化成成纤维细胞样细胞。我们假设TGF-β介导的 EPCs的代谢重编程是一个关键的信号传导事件，有助于EPCs的形成和进展。 CNV后SRF。对于本申请中提出的项目，我们将确定EPCs在小鼠中的作用， CNV模型和患有湿性AMD的人供体眼组织中。我们还将检查代谢 EPCs对TGF-β的反应性重编程。此外，我们还将探讨Muller细胞来源的IL- 33促进巨噬细胞产生TGF-β，抑制IL-33信号传导是否抑制 战略成果框架。这些研究的结果将揭示SRF的新的分子和细胞机制，并定义新的 潜在治疗干预的目标。