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

基本信息

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
项目类别：
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&apos 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

项目摘要

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.

针对血管内皮生长因子（VEGF）的治疗药物取得了显着的成果在患有新生血管形式的年龄相关性黄斑变性（nAMD）的患者中取得了成功。一个新兴的然而，临床问题是许多 nAMD 患者在接受治疗后出现视网膜下纤维化 (SRF) 抗VEGF治疗。 SRF会对视网膜造成不可逆的结构性损伤，是一种重大视力- 威胁性并发症，没有有效的治疗方法。 nAMD 中 SRF 的发病机制主要是未知。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定义。 SRF 可以在具有自发性或实验诱导的脉络膜新生血管（CNV）。在我们已发表的初步研究中，我们发现极低密度脂蛋白受体 (Vldlr) 基因定向缺失的小鼠在以下情况下会出现 SRF：他们的 CNV 病变消退了。使用单细胞 RNA 测序，我们鉴定了内皮前体细胞（EPC）作为显示纤维化标记的主要细胞簇。在 JR5558 中也观察到类似的发现小鼠和激光诱导的 CNV。 EPC 具有干细胞样特性，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逐渐丢失它们的细胞结构并转分化为成纤维细胞样细胞。我们假设 TGF-β 介导 EPC 的代谢重编程是一个关键信号事件，有助于形成和进展 CNV 之后的 SRF。对于本申请中提出的项目，我们将确定 EPC 在小鼠中的作用 CNV 模型和患有湿性 AMD 的人类供体眼组织。我们还将检查新陈代谢响应 TGF-β 的 EPC 重编程。此外，我们将探讨 Muller 细胞来源的 IL- 33 促进巨噬细胞产生 TGF-β，抑制 IL-33 信号传导是否会抑制 SRF。这些研究的结果将揭示 SRF 的新分子和细胞机制，并定义新的潜在治疗干预的目标。