Brain-gut-retina axis in diabetic retinopathy

糖尿病视网膜病变中的脑-肠-视网膜轴

• 批准号: 10595142
• 负责人: CHARLES J FRAZIER
• 金额: $ 55.06万
• 依托单位: UNIVERSITY OF ALABAMA AT BIRMINGHAM
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-03-01 至 2027-01-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10595142
• 关键词: Ablation; Acceleration; Adaptive Immune System; Adrenergic Receptor; Anatomy; Animals; Area; Bacterial Infections; Blood capillaries; Brain; CD8-Positive T-Lymphocytes; Cell physiology; Cell secretion; Cells; Characteristics; Circadian Rhythms; Circulation; Communication; Cre lox recombination system; Cytomegalovirus; Data; Dependovirus; Development; Diabetes Mellitus; Diabetic Retinopathy; Diabetic mouse; Diphtheria Toxin; Disease; Electrophysiology (science); Enteral; Environmental Risk Factor; Excision; Flow Cytometry; Functional disorder; Genetic; Health; Homeostasis; Host Defense; Hyperactivity; Hypothalamic dysfunction; Hypothalamic structure; IL17 gene; Immune; Impairment; Inflammation; Inflammatory; Injections; Injury; Innate Immune System; Insulin-Dependent Diabetes Mellitus; Intestines; Mediating; Modeling; Mus; Mycoses; Nerve; Neurons; Neurotransmitters; Octreotide; Output; Pathogenesis; Pathogenicity; Pathologic; Phenotype; Plasma; Population; Property; Publishing; Regulatory T-Lymphocyte; Reporter; Retina; Role; Serum; Signal Transduction; Site; Somatostatin; Streptozocin; Synapses; System; T-Lymphocyte; T-Lymphocyte Subsets; Testing; Tissues; Viral; cell motility; comparison control; cytokine; cytotoxic; designer receptors exclusively activated by designer drugs; diabetic; dysbiosis; gain of function; gut microbiome; immune function; immunoregulation; intestinal barrier; loss of function; microbiota; microorganism antigen; migration; monocyte; non-diabetic; novel strategies; optogenetics; paraventricular nucleus; peripheral blood; pharmacologic; preservation; prevent; programs; recruit; response; single-cell RNA sequencing; small hairpin RNA; somatostatin analog; tissue injury; tool; trafficking; transcriptome sequencing; Ablation; Acceleration; Adaptive Immune System; Adrenergic Receptor; Anatomy; Animals; Area; Bacterial Infections; Blood capillaries; Brain; CD8-Positive T-Lymphocytes; Cell physiology; Cell secretion; Cells; Characteristics; Circadian Rhythms; Circulation; Communication; Cre lox recombination system; Cytomegalovirus; Data; Dependovirus; Development; Diabetes Mellitus; Diabetic Retinopathy; Diabetic mouse; Diphtheria Toxin; Disease; Electrophysiology (science); Enteral; Environmental Risk Factor; Excision; Flow Cytometry; Functional disorder; Genetic; Health; Homeostasis; Host Defense; Hyperactivity; Hypothalamic dysfunction; Hypothalamic structure; IL17 gene; Immune; Impairment; Inflammation; Inflammatory; Injections; Injury; Innate Immune System; Insulin-Dependent Diabetes Mellitus; Intestines; Mediating; Modeling; Mus; Mycoses; Nerve; Neurons; Neurotransmitters; Octreotide; Output; Pathogenesis; Pathogenicity; Pathologic; Phenotype; Plasma; Population; Property; Publishing; Regulatory T-Lymphocyte; Reporter; Retina; Role; Serum; Signal Transduction; Site; Somatostatin; Streptozocin; Synapses; System; T-Lymphocyte; T-Lymphocyte Subsets; Testing; Tissues; Viral; cell motility; comparison control; cytokine; cytotoxic; designer receptors exclusively activated by designer drugs; diabetic; dysbiosis; gain of function; gut microbiome; immune function; immunoregulation; intestinal barrier; loss of function; microbiota; microorganism antigen; migration; monocyte; non-diabetic; novel strategies; optogenetics; paraventricular nucleus; peripheral blood; pharmacologic; preservation; prevent; programs; recruit; response; single-cell RNA sequencing; small hairpin RNA; somatostatin analog; tissue injury; tool; trafficking; transcriptome sequencing

Summary Abstract This application puts for the notion of a brain-gut- retinal axis that becomes dysfunctional in diabetic retinopathy (DR). The innate immune system has been strongly implicated in the pathogenesis of DR, but less is known about the role of the adaptive immune system. At the interface of these two systems is a critical population of cells, Th17 cells, that typically reside in the gut during health. Th17 cells have homeostatic properties, mediating host defense against bacterial and fungal infections; however, it remains unclear how intestinal Th17 cells integrate diverse signals into a set of cellular programs that allow them to maintain tissue homeostasis yet also become pathogenic, serving as primary drivers of tissue inflammation. We have identified a critical role of somatostatinergic neurons in the paraventricular nucleus of the hypothalamus (PVN) in regulation of immune function through “loss of function” studies and “gain of function studies. SST expression is dramatically reduced in the PVN of diabetic animals. Hypothalamic dysfunction, as seen in diabetes, has the capacity to induce injury directly through hyperactivation of sympathetic nerves. Based on preliminary and published data, we put for the hypothesis that: Diabetes-induced loss of inhibitory SST neurons in the PVN drives increased autonomic input to the intestine shifting Th17 cells from a homeostatic to a pathologic state. Pathologic Th17 cells leave the intestine and traffic to areas of tissue injury such as the retina in DR. In the retina the pathologic Th17 cells secrete proinflammatory cytokines that recruitment innate immune cells into the retina exacerbating DR. To examine this hypothesis, we propose the following aims: Aim 1: To test if impaired function of hypothalamic SST neurons in diabetes contributes to hyperactivity of autonomic efferents to the gut and increases activation of enteric neurons. Aim 2: To selectively ablate SST PVN neurons (in the absence of diabetes) and evaluate if this results in increased autonomic input to the gut and a shift from “homeostatic” Th17 cells to a “pathogenic” Th17 cells that migrate to the retina and recruit circulating immune cells. Aim 3: To determine if maintaining hypothalamic SST levels at nondiabetic levels in diabetic mice will preserve the function of homeostatic Th17 cells in the gut and prevent their recruitment to the retina delaying the development of DR. Impact: SST analogues may provide an important complementary strategy for DR management by preventing increased sympathetic drive to the gut and Th17 cell dysfunction.

摘要摘要 该应用程序构成了脑肠道视网膜轴的概念，该轴在糖尿病患者中变得功能失调 视网膜病（DR）。先天免疫系统与DR的发病机理有很大的关系 但是对自适应免疫系统的作用知之甚少。在这两个系统的界面上是 关键的细胞Th17细胞的关键群体通常位于健康期间的肠道中。 Th17细胞具有 稳态特性，介导宿主防御细菌和真菌感染；但是，它 尚不清楚肠道Th17细胞如何将潜水信号整合到一组蜂窝程序中 允许他们维持组织稳态但也变得致病，作为主要驱动因素 组织炎症。我们已经确定了生长抑素能神经元在阶段性室内的关键作用 下丘脑（PVN）的核通过“失去功能”研究调节免疫功能 和“功能研究的获取。在糖尿病动物的PVN中，SST表达大大降低。 如在糖尿病中所见，下丘脑功能障碍具有直接通过 交感神经的过度激活。根据初步和已发布的数据，我们为 假设：糖尿病诱导的PVN抑制性SST神经元丧失驱动器增加了自主神经。 输入到肠道，将Th17细胞从稳态转移到病理状态。病理Th17细胞 将肠道和交通留给组织损伤的区域，例如DR的视网膜。在视网膜中 病理Th17细胞秘密促炎细胞因子募集先天性免疫细胞进入 视网膜加剧博士。为了审查这一假设，我们提出以下目的：目标1：测试是否是否 下丘脑SST神经元在糖尿病中的功能受损会导致自主性多动症 目标2：选择性烧毁SST PVN 神经元（在没有糖尿病的情况下），并评估这是否导致肠道自主神经输入增加 从“稳态” Th17细胞转移到迁移到视网膜的“致病” Th17细胞 募集循环的免疫细胞。目标3：确定是否保持下丘脑SST水平 糖尿病小鼠的非糖尿病水平将保留肠道内稳态Th17细胞的功能 防止他们招募视网膜，以延迟DR的发展。影响：SST类似物可能 通过防止同情心增加，为DR管理提供了重要的完整策略 开车到肠道和Th17细胞功能障碍。