cGAS-STING signaling in diabetic retinopathy

糖尿病视网膜病变中的 cGAS-STING 信号传导

• 批准号: 10610331
• 负责人: Jian-Xing Ma
• 金额: $ 38.75万
• 依托单位: WAKE FOREST UNIVERSITY HEALTH SCIENCES
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-05-01 至 2027-04-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10610331
• 关键词: Ablation; Address; Adhesions; Agonist; Animal Model; Antiinflammatory Effect; Attenuated; Blood Vessels; Blood capillaries; Capillary Endothelial Cell; Cells; Clinical Research; Cyclic GMP; Data; Diabetes Mellitus; Diabetic Retinopathy; Diabetic mouse; Down-Regulation; Exposure to; Extravasation; Fenofibrate; Gene Activation; Genus Hippocampus; Human; Impairment; In Vitro; Inflammation; Inflammatory; Knockout Mice; Knowledge; Leukocytes; Leukostasis; Measures; Mediating; Mitochondria; Mitochondrial DNA; Modeling; Mus; Oral; PPAR alpha; Pathogenesis; Pathogenicity; Pathology; Pathway interactions; Permeability; Phagocytosis; Pharmaceutical Preparations; Phosphorylation; Play; Regulation; Reporting; Retina; Retinal Diseases; Role; Signal Transduction; Stimulator of Interferon Genes; Therapeutic Effect; Transfection; Transgenic Mice; Transgenic Organisms; Type 2 diabetic; Up-Regulation; clinically relevant; diabetic; diabetic patient; immune activation; immunoregulation; inhibitor; migration; mitochondrial genome; monocyte; new therapeutic target; non-diabetic; novel; overexpression; prospective; response; stressor; targeted treatment

PROJECT SUMMARY/ABSTRACT Retinal leukostasis and vascular leakage play important pathogenic roles in diabetic retinopathy (DR). Accumulating evidence suggests that DR is not an isolated retinal disease. Although circulating monocytes are the major leukocyte subset responsible for leukostasis, the underlying regulation for monocyte activation in DR has not been well investigated, which represents a knowledge gap. Two independent and prospective clinical studies reported that fenofibrate, an agonist of peroxisome proliferator-activated receptor alpha (PPARα), has robust therapeutic effects on DR. Our preliminary studies showed that PPARα levels are down-regulated in circulating monocytes of diabetic patients and diabetic animal models. PPARα ablation alone induces monocyte activation, including increased adhesion, migration, and phagocytosis, while fenofibrate attenuates monocyte activation in diabetic mice. The cyclic GMP-AMP synthase (cGAS)-stimulator of interferon genes (STING) pathway plays a crucial role in inflammation. We showed that cGAS and STING are up-regulated in monocytes in a diabetic model and in PPARα-/- mice, and inhibition of STING attenuates monocyte activation and alleviates retinal leukostasis. Therefore, we hypothesize that PPARα suppresses cGAS-STING signaling to alleviate monocyte activation and retinal leukostasis in DR, and that this effect is mediated in part by the mitoprotective function of PPARα in diabetic monocytes. To address this hypothesis, we will first investigate if PPARα suppresses monocyte activation in diabetes to alleviate retinal inflammation and vascular leakage in DR. Using monocyte-specific PPARα conditional KO (PPARαMCKO) mice and monocyte-specific PPARα transgenic (PPARαMCTg) mice, we will determine if ablation of PPARα will exacerbate, while PPARα over-expression will alleviate diabetes-induced monocyte activation (adhesion, migration, phagocytosis), retinal leukostasis, vascular leakage, and acellular capillary formation. Toward the mechanism for the monocyte-regulating function of PPARα, we will investigate if the anti-inflammatory effect of PPARα is through inhibition of cGAS-STING signaling in monocytes in diabetes. We will compare cGAS-STING activation in monocytes of diabetic PPARαMCKO, PPARαMCTg, and WT mice. Furthermore, we will investigate if PPARα ablation promotes cGAS- STING activation in monocytes by exacerbating mitochondrial damage and cytosolic mtDNA release in DR. We also propose to study if the cGAS-STING pathway activation in monocytes plays a causative role in retinal inflammation and vascular leakage in DR. We will determine if a STING inhibitor or ablation of cGAS or STING will ameliorate monocyte activation, retinal leukostasis and vascular leakage in diabetic mice. The proposed studies will identify a novel interaction between PPARα and the cGAS-STING pathway in the regulation of immunometabolism and retinal inflammation in DR. These studies will also elucidate a new mechanism responsible for the therapeutic effects of fenofibrate on DR.

项目摘要/摘要 视网膜白质淤积和血管渗漏在糖尿病视网膜病变(DR)发病中起重要作用。 越来越多的证据表明，DR并不是一种孤立的视网膜疾病。尽管循环中的单核细胞 负责白细胞稳定的主要白细胞亚群，这是DR患者单核细胞激活的潜在调节因素 没有得到很好的调查，这代表着知识差距。两个独立和前瞻性的临床 研究报道，非诺贝特是过氧化物酶体增殖物激活受体α(PPARα)的激动剂，具有 对Dr.的强劲疗效我们的初步研究表明，PPARα水平在 糖尿病患者和糖尿病动物模型的循环单核细胞。单用PPARα消融诱导单核细胞 激活，包括增加黏附、迁移和吞噬功能，而非诺贝特则减弱单核细胞 糖尿病小鼠的激活。干扰素基因的环GMP-AMP合成酶(CGAS)刺激物 途径在炎症中起着至关重要的作用。我们发现cGAS和STING在单核细胞中表达上调。 在糖尿病模型和PPARα-/-小鼠中，抑制STING可减弱单核细胞的激活并缓解 视网膜白质淤积症。因此，我们假设PPARα抑制cGAS-STING信号以缓解 糖尿病视网膜病变中单核细胞的激活和视网膜白质的稳定，这种作用部分是通过线粒体保护来实现的。 PPARα在糖尿病单核细胞中的作用为了解决这一假设，我们将首先调查PPARα 抑制糖尿病患者的单核细胞激活以减轻DR的视网膜炎症和血管渗漏 单核细胞特异性PPARα条件KO(PPARαMCKO)小鼠及单核细胞特异性PPARα转基因 (PPARαMCTG)小鼠，我们将确定PPARα的消融是否会加剧，而PPARα的过度表达将 减轻糖尿病引起的单核细胞活化(黏附、迁移、吞噬)、视网膜白细胞停滞、血管 渗漏，无细胞毛细血管形成。对单核细胞调节作用机制的探讨 我们将研究PPARα的抗炎作用是否是通过抑制cGAS-α来实现的 糖尿病患者单核细胞中的信号转导。我们将比较糖尿病患者单核细胞中cGAS-STING活性 PPARα小鼠、PPARαMCTG小鼠和WT小鼠。此外，我们将研究PPARα消融是否促进cGAS- WE博士通过加剧线粒体损伤和胞浆mtDNA释放来激活单核细胞中的刺激物 我还建议研究单核细胞中cGAS-STING通路的激活是否在视网膜中起到致病作用 DR中的炎症和血管渗漏我们将确定刺痛抑制剂或cGAS或刺痛的消融 将改善糖尿病小鼠的单核细胞活化、视网膜白血球停滞和血管渗漏。建议数 研究将确定PPARα和cGAS-STING通路之间在调节 DR的免疫代谢和视网膜炎症这些研究还将阐明一种新的机制 负责非诺贝特对DR的治疗效果。