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

• 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
• 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' 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

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 昼夜节律是人类生物学和生理学的重要组成部分。越来越多的 研究表明，我们的生物时钟的破坏对健康有害，夜间旋转和旋转 有大大增加了发展多种疾病病理的风险，包括癌症， 糖尿病，肥胖和慢性炎症性肠病。那是对机制的理解 哪些昼夜节律与疾病的发展有关，将对不断增长的 人口百分比受到各种形式的昼夜节律破坏。 昼夜节律和胃肠道炎症受损直接与几个领先 消化道疾病，包括炎症性肠病（IBD）。虽然在昼夜节律中学习不好 上下文，完成激活以及完成过敏毒素C3A和C5A已与 免疫功能障碍与许多疾病的发展密切相关，包括哮喘，癌症， 糖尿病和炎症性肠病。我们的初步数据表明完成过敏毒素， 在宿主防御和免疫反应中起着关键作用的幽默宠物，可能会提供链接 昼夜节律的破坏和疾病的脆弱性，包括胃肠道疾病。这些数据 表明完成过敏毒素（在胡椒体的水平及其特定水平 受体）在体内直接控制昼夜节律，并提供肠道淋巴的昼夜节律调节 在体内交换。该应用的总体假设是感染的调节 完成系统的免疫力（主要通过完成激活过敏毒素肽）为 24小时的昼夜节律的破坏会导致免疫失调，从而极大地影响 反应和正常淋巴功能。昼夜节律补体介导的功能障碍 炎症和免疫力反过来导致疾病的增加，包括但不限 开发消化疾病，例如IBD。为了支持这一假设，新的初步 显示数据表明C5A在肠道淋巴机中调节细胞含量和T细胞极化 以昼夜节律的方式组织。另外，完成过敏毒素的表达 受体C3AR和C5AR1在昼夜依赖性外围的模型中缺乏Peyer的斑块 心律不齐。这些数据强烈表明C3A/C3AR和C5A/C5AR1轴是一种新颖而重要的 发生宿主淋巴免疫响应的昼夜节律循环的机制，它是先前的 昼夜节律的疾病病理学之间的未知但重要的联系，包括发展 炎症性肠病。使用昼夜节律模型，遗传和环境操纵 补体系统，最先进的成像和分子/生物分析工具，我们将描绘 完成过敏毒素以昼夜节律调节肠道淋巴染的机制。