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：
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
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/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

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.

项目概要/摘要视网膜白细胞停滞和血管渗漏在糖尿病视网膜病变（DR）中发挥重要的致病作用。越来越多的证据表明，尽管循环单核细胞是一种孤立的视网膜疾病，但 DR 并不是一种孤立的视网膜疾病。负责白细胞停滞的主要白细胞亚群，是 DR 中单核细胞激活的基本调节尚未得到很好的研究，这代表了两个独立和前瞻性的临床知识差距。研究报告称，非诺贝特是过氧化物酶体增殖物激活受体 α (PPARα) 的激动剂，具有我们的初步研究表明 PPARα 水平在 DR 中下调。糖尿病患者和糖尿病动物模型的循环单核细胞单独消融可诱导单核细胞。激活，包括增加粘附、迁移和吞噬作用，而非诺贝特则削弱单核细胞糖尿病小鼠中环 GMP-AMP 合酶 (cGAS) 的激活 - 干扰素基因 (STING) 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，抑制 STING 可减弱单核细胞激活并减轻因此，我们认为 PPARα 抑制 cGAS-STING 信号传导以缓解。 DR 中的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性介导的 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 是否存在。抑制糖尿病中的单核细胞活化，减轻 DR 中的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 (PPARαMCTg) 小鼠，我们将确定 PPARα 的消融是否会恶化，而 PPARα 的过度表达是否会恶化糖尿病引起的单核细胞活化（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的单核细胞调节功能的机制。 PPARα，我们将研究PPARα的抗炎作用是否是通过抑制cGAS-STING 我们将比较糖尿病单核细胞中的 cGAS-STING 激活。此外，我们将研究 PPARα 消除是否会促进 cGAS-。在 DR 中，单核细胞中的 STING 激活会加剧线粒体损伤和胞质 mtDNA 释放。还建议研究单核细胞中的 cGAS-STING 通路激活是否在视网膜中起致病作用 DR 中的炎症和血管渗漏，我们将确定是否使用 STING 抑制剂或 cGAS 或 STING 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。研究将确定 PPARα 和 cGAS-STING 通路在调节这些研究还将阐明 DR 中的免疫代谢和视网膜炎症的新机制。负责非诺贝特对 DR 的治疗作用。