cGAS-STING signaling in diabetic retinopathy

糖尿病视网膜病变中的 cGAS-STING 信号传导

基本信息

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
项目类别：
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

项目摘要

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/摘要视网膜白细胞和血管泄漏在糖尿病性视网膜病（DR）中起重要的致病作用。积累的证据表明DR不是孤立的残留疾病。虽然循环的单核细胞是负责白细胞的主要白细胞子集，这是DR中单核细胞激活的基本调节尚未得到很好的研究，这代表了知识差距。两个独立和前瞻性临床研究报告说，过氧化物体增生剂激活的受体α（PPARα）的激动剂曲否纤维纤维曲面具有强大的治疗对DR的影响。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。仅PPARα消融就会诱导单核细胞激活，包括粘合剂，迁移和吞噬作用，而fenofrate减弱单核细胞糖尿病小鼠的激活。循环GMP-AMP合酶（CGA） - 干扰素基因的刺激器（sting）途径在炎症中起着至关重要的作用。我们表明CGA和STIN在单核细胞中被上调在糖尿病模型和PPARα-/ - 小鼠中，刺激抑制会减弱单核细胞的激活并减轻视网膜白细胞。因此，我们假设PPARα抑制CGAS丁字信号以减轻 DR中的单核细胞激活和残留的白细胞症，该作用部分由Miteratectortotototototototototototototototototototototototototototototototototototototototothothotototain PPARα在糖尿病单核细胞中的功能。为了解决这一假设，我们将首先研究PPARα是否抑制糖尿病中的单核细胞激活，以减轻DR的定期注射和血管泄漏。使用单核细胞特异性PPARα条件KO（PPARαMCKO）小鼠和单核细胞特异性PPARα转基因（PPARαMCTG）小鼠，我们将确定PPARα的消融是否会加剧，而PPARα过表达将减轻糖尿病诱导的单核细胞激活（粘附，迁移，吞噬作用），视网膜白细胞增活，血管泄漏和细胞毛细血管形成。迈向单核细胞调节功能的机制 PPARα，我们将研究PPARα的抗炎作用是否通过抑制CGA 糖尿病单核细胞中的信号传导。我们将比较糖尿病单核细胞中的CGAS丁字激活 PPARαMCKO，PPARαMCTG和WT小鼠。此外，我们将研究PPARα消融是否促进CGA- 通过加剧线粒体损伤和DR中的胞质mtDNA释放，在单核细胞中激活。我们还建议研究单核细胞中的CGAS-sting途径激活在视网膜中起因作用 DR的炎症和血管泄漏。我们将确定CGAS或CGAS的刺痛抑制剂或Sting是糖尿病小鼠的单核细胞激活，视网膜白细胞和血管泄漏。提议研究将在调节中确定PPARα与CGAS刺途径之间的新型相互作用 DR的免疫代谢和视网膜炎症。这些研究还将阐明一种新机制负责非诺贝特对DR的治疗作用。