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: 10339181
• 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/10339181
• 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; 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.

项目总结/摘要 视网膜白细胞淤滞和血管渗漏在糖尿病视网膜病变（DR）中起重要的致病作用。 越来越多的证据表明，DR不是一种孤立的视网膜疾病。虽然循环单核细胞 负责白细胞停滞的主要白细胞亚群，DR中单核细胞活化的潜在调节 还没有得到很好的调查，这代表了一个知识差距。两个独立的前瞻性临床研究 研究报道，非诺贝特，一种过氧化物酶体增殖物激活受体α（PPARα）的激动剂， 我们的初步研究表明，在DR患者中， 糖尿病患者和糖尿病动物模型的循环单核细胞。单独的PPARα消融诱导单核细胞 激活，包括增加粘附、迁移和吞噬作用，而非诺贝特减弱单核细胞 在糖尿病小鼠中激活。环GMP-AMP合酶（cGAS）-干扰素基因（STING）刺激因子 在炎症中起着至关重要的作用。我们发现cGAS和STING在单核细胞中上调， 在糖尿病模型和PPARα-/-小鼠中，STING的抑制减弱了单核细胞的活化和增殖， 视网膜白细胞停滞因此，我们假设，PPARα抑制cGAS-STING信号转导，以减轻 单核细胞活化和视网膜白细胞停滞，这种作用部分是由线粒体保护因子介导的。 糖尿病单核细胞中过氧化物酶体增殖物激活受体α的功能。为了解决这一假设，我们将首先研究是否PPARα 抑制糖尿病单核细胞活化，减轻DR视网膜炎症和血管渗漏。 单核细胞特异性PPARα条件性KO（PPARαMCKO）小鼠和单核细胞特异性PPARα转基因小鼠 (PPARαMCTg）小鼠，我们将确定是否消融的PPARα将加剧，而PPARα过度表达， 减轻糖尿病诱导的单核细胞活化（粘附、迁移、吞噬作用）、视网膜白细胞停滞、血管 渗漏和无细胞毛细血管形成。对单核细胞调节功能的机制进行了探讨。 我们将研究PPARα的抗炎作用是否通过抑制cGAS-STING来实现 糖尿病中单核细胞的信号传导。我们将比较糖尿病患者单核细胞中cGAS-STING的活化， PPARαMCKO、PPARαMCTg和WT小鼠。此外，我们将研究是否PPARα消融促进cGAS- STING通过加重DR患者的线粒体损伤和胞浆mtDNA释放而激活单核细胞。 我还建议研究单核细胞中的cGAS-STING通路激活是否在视网膜病变中起致病作用。 我们将确定是否使用STING抑制剂或cGAS或STING的消融， 将改善糖尿病小鼠的单核细胞活化、视网膜白细胞停滞和血管渗漏。拟议 研究将确定一种新的相互作用之间的PPARα和cGAS-STING途径的调节， 这些研究也将阐明DR的新机制 负责非诺贝特对DR的治疗作用。