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

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 该应用提出了脑-肠-视网膜轴在糖尿病患者中变得功能失调的概念 视网膜病变（DR）。先天免疫系统与 DR 的发病机制密切相关， 但人们对适应性免疫系统的作用知之甚少。这两个系统的接口是 Th17 细胞是一个关键的细胞群，在健康期间通常存在于肠道中。 Th17 细胞有 稳态特性，调节宿主对细菌和真菌感染的防御；然而，它 目前尚不清楚肠道 Th17 细胞如何将不同的信号整合到一组细胞程序中 使它们能够维持组织稳态，同时也成为致病性的，成为致病的主要驱动因素 组织炎症。我们已经确定了室旁区生长抑素能神经元的关键作用 下丘脑核（PVN）通过“功能丧失”研究调节免疫功能 和“功能获得研究。糖尿病动物的 PVN 中 SST 表达显着降低。 下丘脑功能障碍，如糖尿病中所见，有能力直接通过以下途径诱发损伤： 交感神经过度活跃。根据初步和已发布的数据，我们预测 假设：糖尿病引起的 PVN 中抑制性 SST 神经元的丧失会导致自主神经功能增强 输入到肠道将 Th17 细胞从稳态转变为病理状态。病理性Th17细胞 离开肠道和交通到组织损伤区域，例如 DR 中的视网膜。在视网膜中 病理性 Th17 细胞分泌促炎细胞因子，将先天免疫细胞招募到 视网膜恶化 DR。为了检验这一假设，我们提出以下目标： 目标 1：检验是否 糖尿病患者下丘脑 SST 神经元功能受损导致自主神经过度活跃 传出肠道并增加肠神经元的激活。目标 2：选择性消融 SST PVN 神经元（在没有糖尿病的情况下）并评估这是否会导致肠道自主输入增加 以及从“稳态”Th17 细胞向迁移至视网膜的“致病性”Th17 细胞的转变 招募循环免疫细胞。目标 3：确定下丘脑 SST 水平是否维持在 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 防止它们招募到视网膜，从而延缓 DR 的发展。影响：SST 类似物可能 通过防止同情心增加，为 DR 管理提供重要的补充策略 驱动肠道和 Th17 细胞功能障碍。