Complement and Circadian Interactions in Inflammation and Immunity

炎症和免疫中的补体和昼夜节律相互作用

基本信息

批准号：
10595544
负责人：
Kristin Eckel Mahan
金额：
$ 39万
依托单位：
UNIVERSITY OF TEXAS HLTH SCI CTR HOUSTON
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-04-15 至 2026-03-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10595544
关键词：
Affect Anaphylatoxins Animals Applications Grants Arrhythmia Asthma Behavioral Biological Clocks C3AR1 gene Cells Chronic Chronic Disease Circadian Dysregulation Circadian Rhythms Colitis Complement Complement 3a Complement 5a Complement Activation Complement Receptor Data Development Diabetes Mellitus Digestive System Disorders Disease Functional disorder Gastrointestinal Diseases Gastrointestinal tract structure Genetic Genetic Complementation Test Goals Gut associated lymphoid tissue Health Histologic Host Defense Hour Human Human Biology Image Immune Immune System Diseases Immune response Immunity Immunoassay Impairment Inflammation Inflammatory Inflammatory Bowel Diseases Innate Immune Response Intestinal Content Intestines Jet Lag Syndrome Knockout Mice Knowledge Light Link Lymph Lymphatic Lymphatic System Lymphatic function Lymphoid Tissue Malignant Neoplasms Mediating Modeling Molecular Mus Obesity Output Pacemakers Pathogenesis Pathology Patients Peptides Periodicity Peripheral Peyer&apos s Patches Phase Physiology Population Property Receptor Signaling Regulation Risk Role Rotation Signal Transduction Source System T-Lymphocyte Testing Th1 Cells Therapeutic Time Tissues circadian circadian pacemaker complement system cytokine design experimental study gastrointestinal in vivo knockout animal mouse model mutant new therapeutic target novel polarized cell receptor response suprachiasmatic nucleus tool transcriptome sequencing

项目摘要

ABSTRACT Circadian (24-hour) rhythms are an essential part of human biology and physiology. A growing number of studies have shown that disruption of our biological clock is detrimental to health, with night and rotating shift workers at substantially increased risk of developing numerous disease pathologies, including cancer, diabetes, obesity, and chronic inflammatory bowel disease. Thus, an understanding of the mechanisms by which circadian disruption are linked to disease development would be of great benefit to a growing percentage of the population subjected to circadian disruption of various forms. Impaired circadian rhythms and gastrointestinal inflammation are directly associated with several leading digestive tract disorders, including inflammatory bowel disease (IBD). While not well studied in a circadian context, complement activation and the complement anaphylatoxins, C3a and C5a, have been implicated in immune dysfunction are tightly linked to the development of numerous diseases, including asthma, cancer, diabetes, and inflammatory bowel disease. Our preliminary data indicate that the complement anaphylatoxins, which are phlogistic peptides with critical roles in host defense and the immune response, may provide the link between circadian disruption and vulnerability to diseases, including gastrointestinal disease. These data indicate that the complement anaphylatoxins (at the level of the peptides themselves as well as their specific receptors) are under direct circadian control in vivo and provide circadian modulation of intestinal lymph exchange in vivo. The overall hypothesis of this application is that the regulation of inflammation and immunity by the complement system (largely via the complement activation anaphylatoxin peptides) is greatly affected by disruption of the 24-hour circadian clock leading to dysregulation of the immune response and normal lymphatic function. Th circadian dependent complement mediated dysfunction of inflammation and immunity in turn leads to increased disease pathologies, including but not limited to the development of digestive disorders such as IBD. In support of this hypothesis, novel preliminary data are presented showing that C5a modulates the cellular content and T-cell polarization in gut lymphoid tissue in a circadian dependent manner. In addition, the expression of the complement anaphylatoxin receptors, C3aR and C5aR1, is deficient in Peyer’s patches in a model of circadian-dependent peripheral arrhythmicity. These data strongly suggest that the C3a/C3aR and C5a/C5aR1 axis is a novel and important mechanism by which circadian gating of the host lymphatic immune response occurs, and that it is a previously unknown yet important link between circadian disruption and disease pathologies, including the development of inflammatory bowel disease. Using circadian mutant models, genetic and environmental manipulation of the complement system, state of the art imaging, and molecular/bio-analytical tools we will delineate the mechanisms by which the complement anaphylatoxins modulate intestinal lymphatics in a circadian manner.

抽象的昼夜节律（24 小时）是人类生物学和生理学的重要组成部分。研究表明，生物钟被破坏会对健康造成影响，尤其是夜班和轮班工人患多种疾病的风险大大增加，包括癌症，因此，了解糖尿病、肥胖症和慢性炎症性肠病的机制。哪些昼夜节律紊乱与疾病的发展有关，这将对日益增长的人们大有裨益遭受各种形式昼夜节律紊乱的人口百分比。昼夜节律受损和胃肠道炎症与多种主要疾病直接相关消化道疾病，包括炎症性肠病（IBD），但尚未在昼夜节律中进行充分研究。补体激活和补体过敏毒素 C3a 和 C5a 与免疫功能障碍与许多疾病的发展密切相关，包括哮喘、癌症、我们的初步数据表明补体过敏毒素，它们是在宿主防御和免疫反应中发挥关键作用的炎性肽，可能提供了联系这些数据揭示了昼夜节律紊乱与疾病（包括胃肠道疾病）的脆弱性之间的关系。表明补体过敏毒素（在肽本身的水平以及它们的特异性受体）在体内受到直接昼夜节律控制，并提供肠道淋巴的昼夜节律调节该应用的总体假设是炎症和炎症的调节。补体系统的免疫（主要通过补体激活过敏毒素肽）受到 24 小时生物钟破坏的严重影响，导致免疫系统失调反应和正常的淋巴功能。Th 昼夜节律依赖性补体介导的功能障碍。炎症和免疫的减弱反过来导致疾病病理增加，包括但不限于为了支持这一假设，新的初步研究表明，消化道疾病（如 IBD）的发展。数据显示 C5a 调节肠道淋巴中的细胞含量和 T 细胞极化此外，补体过敏毒素的表达也呈昼夜节律依赖性。在昼夜节律依赖性外周神经模型中，派尔氏集结中存在 C3aR 和 C5aR1 受体缺陷这些数据强烈表明 C3a/C3aR 和 C5a/C5aR1 轴是一种新颖且重要的轴。宿主淋巴免疫反应发生昼夜节律门控的机制，并且它是先前的昼夜节律紊乱与疾病病理学之间未知但重要的联系，包括发育使用昼夜节律突变模型、遗传和环境操纵来研究炎症性肠病。补体系统、最先进的成像和分子/生物分析工具，我们将描述补体过敏毒素以昼夜节律方式调节肠道淋巴管的机制。