ACE2 on gut barrier dysfunction and BRB disruption

ACE2 对肠道屏障功能障碍和 BRB 破坏的影响

基本信息

批准号：
10379018
负责人：
Michael Edwin Boulton
金额：
$ 36.94万
依托单位：
UNIVERSITY OF ALABAMA AT BIRMINGHAM
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：
2022-01-01 至 2026-11-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10379018
关键词：
ACE2 Angiopoietin-2 Angiotensin II Angiotensins Binding Blood Blood Circulation Blood Glucose Blood capillaries Blood-Retinal Barrier Bone Marrow Bypass Cells Clinical Clinical Trials Communication Data Defect Deterioration Development Diabetes Mellitus Diabetic Retinopathy Diabetic mouse Dipeptides Endocrine Endothelial Cells Enterocytes Epithelial Cells Equilibrium Extravasation Eye Functional disorder G-Protein-Coupled Receptors Genetic Glucagon Glucose Goals Health Homeostasis Hormones Human Hyperglycemia Immune Insulin Insulin-Dependent Diabetes Mellitus Interruption Intestinal permeability Intestines Lead Leaky Gut Leukostasis Ligands Literature Mediating Metabolic Microvascular Dysfunction Mus Myeloid Cells Non-Insulin-Dependent Diabetes Mellitus Nutraceutical Pancreas Pathogenesis Pathology Pattern recognition receptor Peptides Permeability Phenotype Physiological Probiotics Production Proteins Receptor Activation Renin-Angiotensin System Retina Role Serum Testing Tissues Toll-like receptors Tryptophan Work absorption arm base blood glucose regulation db/db mouse diabetic dimer gastrointestinal epithelium glucose monitor glucose transport gut dysbiosis gut microbiome immune activation interest intestinal epithelium loss of function microbial novel overexpression prevent receptor restoration systemic inflammatory response uptake

项目摘要

The overarching goal of this project is to determine the role of angiotensin converting enzyme 2 (ACE2) in the diabetic gut, how it impacts hyperglycemia and glycemic variability, and thus contributes to the pathogenesis of diabetic retinopathy (DR). The protective arm of the renin angiotensin system (RAS) consists of ACE2, which converts angiotensin II (Ang-II) to angiotensin 1-7 (Ang-1-7). Ang-1-7 opposes the effects of Ang-II by virtue of its actions on the MAS receptor. While the systemic (endocrine) RAS works with local (tissue) RAS such as that in the eye and gut to achieve homeostasis in health, in diabetes loss of key components of the protective RAS can lead to widespread pathology. The literature and our preliminary data support that diabetes results in loss of expression of ACE2 in the gut, bone marrow, and retina. Glycemic variability is implicated in DR pathogenesis. Intestinal ACE2 can regulate glucose homeostasis by modulating tryptophan absorption and incretin release and by generating Ang 1- 7 from luminal Ang II. Ang 1-7 by binding to Mas receptor can block glucose transport in the gut similar to what has been described in the pancreas. Based on this, we hypothesis: In T2D, loss of enterocyte ACE2 decreases: i) tryptophan uptake and incretin secretion leading to hyperglycemia; ii) MAS receptor activation increasing gut glucose absorption; and iii) gut barrier integrity resulting in leakage of gut microbial peptides into the circulation. All three mechanisms increase retinal permeability and activating immune cells promoting DR pathology. Aim 1 will test if dysregulation of ACE2 in the gut epithelium results in i) interruption of tryptophan transport by B0AT1 decreasing incretin secretion and ii) reduced MAS receptor activation leading to increased glucose absorption in the gut. Aim 2 will test if in db/db mice, loss of intestinal ACE2 will result in increasing circulating levels of gut microbial peptides that will activate TLRs on retinal endothelial cells and lead to increased retinal leukostasis and blood retinal barrier dysfunction. Aim 3 will examine if nutraceuticals or probiotics can restore the balance of the intestinal RAS (ACE2/Ang-1-7/MAS) in db/db mice to prevent development of DR. Impact: We propose a novel mechanism for deterioration of glucose homeostasis and increased glucose variability in diabetes- the loss of function of the ACE2:B0AT1 oligomer form of ACE2 (unique to the intestinal epithelium) and reduced levels of intestinal Ang 1-7 resulting in less intestinal MAS receptor activation. The dysregulated intestinal RAS can lead to serious retinal pathology promoting DR.

该项目的总体目标是确定血管紧张素转换酶 2 的作用 (ACE2) 在糖尿病肠道中的作用，它如何影响高血糖和血糖变异性，从而有助于糖尿病视网膜病变（DR）的发病机制。肾素血管紧张素系统 (RAS) 的保护臂由 ACE2 组成，它将血管紧张素 II (Ang-II) 转化为血管紧张素 1-7 (Ang-1-7)。 Ang-1-7 反对 Ang-II 通过其对 MAS 受体的作用而产生影响。而全身（内分泌）RAS 与局部（组织）RAS（例如眼睛和肠道中的 RAS）合作，以实现健康的体内平衡，糖尿病保护性 RAS 关键成分的缺失可能导致广泛的病理变化。文献我们的初步数据支持糖尿病导致肠道、骨骼中 ACE2 表达缺失骨髓和视网膜。血糖变异性与 DR 发病机制有关。肠道ACE2可以调节通过调节色氨酸吸收和肠促胰岛素释放以及产生 Ang 1- 来维持葡萄糖稳态 7来自管腔Ang II。 Ang 1-7 通过与 Mas 受体结合可以阻断肠道中的葡萄糖转运，类似于胰腺中所描述的内容。基于此，我们假设：在 T2D 中，肠上皮细胞丢失 ACE2 减少： i) 色氨酸摄取和肠促胰岛素分泌导致高血糖； ii）新加坡金融管理局受体激活增加肠道葡萄糖吸收； iii) 肠道屏障完整性导致肠道微生物肽渗漏到循环系统中。所有三种机制都会增加视网膜渗透性和激活免疫细胞促进 DR 病理学。目标 1 将测试是否失调肠上皮中的 ACE2 导致 i) B0AT1 中断色氨酸转运，减少肠促胰岛素分泌；ii) MAS 受体激活减少，导致肠道葡萄糖吸收增加。目标 2 将测试 db/db 小鼠肠道 ACE2 的缺失是否会导致肠道循环水平增加微生物肽会激活视网膜内皮细胞上的 TLR，导致视网膜白细胞停滞和血视网膜屏障功能障碍。目标 3 将检查营养保健品或益生菌是否可以恢复 db/db 小鼠肠道 RAS (ACE2/Ang-1-7/MAS) 的平衡，以预防博士。影响：我们提出了一种导致葡萄糖稳态恶化和增加的新机制。糖尿病中的血糖变异性 - ACE2 的 ACE2:B0AT1 寡聚体形式的功能丧失（ACE2 所独有的）肠上皮）和肠道 Ang 1-7 水平降低，导致肠道 MAS 受体减少激活。肠道 RAS 失调可导致严重的视网膜病变，从而促进 DR。