权益分类	功能权益	普通用户	{{item.name}}会员
{{category.name}}	{{benefitItem.name}}

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 DR 不是一种孤立的视网膜疾病。尽管循环单核细胞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充分研究，这代表了知识差距。两个独立且前瞻性的临床研究报告称，非诺贝特是过氧化物酶体增殖物激活受体 α (PPARα) 的激动剂，具有对 DR 具有强大的治疗效果。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。单独去除 PPARα 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的激活。环 GMP-AMP 合酶 (cGAS) 干扰素基因刺激剂 (STING) 通路在炎症反应中发挥着至关重要的作用。我们发现单核细胞中 cGAS 和 STING 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视网膜白细胞瘀滞。因此，我们假设 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，并且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。为了解决这个假设，我们将首先研究 PPARα 是否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。使用单核细胞特异性 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 的消融是否会加剧，而 PPARα 的过度表达是否会加剧减轻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。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 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的 cGAS-STING 激活 PPARαMCKO、PPARαMCTg 和 WT 小鼠。此外，我们将研究 PPARα 消融是否会促进 cGAS- DR 中单核细胞中的 STING 激活通过加剧线粒体损伤和胞质 mtDNA 释放来实现。我们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 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。拟议的研究将确定 PPARα 和 cGAS-STING 通路在调节中的新型相互作用 DR 中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。