The role of HMGB1 in gut antimicrobial defense and the pathophysiology of inflammatory bowel disease

HMGB1 在肠道抗菌防御和炎症性肠病病理生理学中的作用

基本信息

批准号：
10198911
负责人：
Jeannette Sophia Messer
金额：
$ 16.62万
依托单位：
CLEVELAND CLINIC LERNER COM-CWRU
依托单位国家：
美国
项目类别：
财政年份：
2017
资助国家：
美国
起止时间：
2017-07-01 至 2023-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10198911
关键词：
Abdominal Pain Acetylmuramyl-Alanyl-Isoglutamine Achievement Address Adherence Affect American Apoptosis Autophagocytosis Bacteria Bacterial Adhesion Behavior Binding Bioinformatics Biology Career Choice Cell Culture Techniques Cell Death Cell Survival Cell Wall Cellular Stress Response Characteristics Chicago Chronic diarrhea Client Clinical Colitis Colon Data Development Disease Epithelial Epithelial Cells Escherichia coli Feces Functional disorder Gastrointestinal Physiology Genes Genetic Polymorphism Germ-Free Gnotobiotic Goals Goblet Cells HMGB1 Protein Human Immune response In Vitro Inflammation Inflammatory Inflammatory Bowel Diseases Inflammatory Response International Intestinal Diseases Intestinal Mucosa Intestines Investigation K-Series Research Career Programs Knowledge Lead Lesion Mammalian Cell Mediating Medicine Mentors Metagenomics Microbe Microbiology Mucins Mucosal Immune Responses Mucous Membrane Mucous body substance Mus Mutation Natural Immunity Pathway interactions Patients Physiological Play Population Proteins Research Research Personnel Role Sampling Scientist Severity of illness Shapes Stress Surface Symbiosis Techniques Testing Tissues Training Translational Research Universities Virulence Wild Type Mouse Work antimicrobial base cell motility dysbiosis effective therapy experience experimental study gut bacteria gut colonization gut microbiota host-microbe interactions immune activation innovation instructor interest intestinal barrier intestinal epithelium knowledge base loss of function microbial mouse model multidisciplinary novel therapeutics prevent protein function response

项目摘要

PROJECT SUMMARY/ABSTRACT This is a K08 Mentored Clinical Scientist Research Career Development Award application for Dr. Jeannette S. Messer, a Pathway to Independence Instructor in The University of Chicago Department of Medicine. Her long-term goal is to become an internationally recognized expert and researcher in the field of host-microbe interactions in human inflammatory diseases. In order to achieve this goal, she will require training to address four defined gaps in her knowledge: translational research [Gap #1], gnotobiotic mouse models [Gap #2], microbiology [Gap #3], and bioinformatic techniques to study microbial populations [Gap #4]. Dr. Messer has assembled a multidisciplinary team of expert mentors and scientists with significant experience in human inflammatory bowel disease, gnotobiotic mouse utilization and management, microbiology, and bioinformatic approaches to analysis of microbial populations of the gut to close these gaps in knowledge and remove the identified barriers to her transition to independence and achievement of her long term goal. Inflammatory bowel diseases (IBD) are diseases of chronic diarrhea and abdominal pain that affect an estimated 1.6 million Americans. Bacteria are thought to play an important role in IBD pathophysiology through activation of mucosal immune responses. However, the mechanisms through which bacteria trigger or perpetuate mucosal immune responses are still poorly understood. Therefore, there is an urgent unmet need to determine how bacteria contribute to immune activation and mucosal damage during IBD in order to develop effective therapies that take the microbial component of the disease into account. High mobility group box 1 (HMGB1) is produced in intestinal epithelial cells (IEC) in response microbes. HMGB1 is decreased in IEC from active IBD lesions and conditional deletion of HMGB1 from IEC exacerbates colitis in murine models. The colitis seen in mice lacking IEC HMGB1 is characterized by increased IEC death and in vitro studies have shown that IEC lacking HMGB1 are more susceptible to apoptosis when challenged with the bacterial cell wall component muramyl dipeptide. HMGB1 is also found in stool and concentrations of this protein in the stool are increased during active IBD. Dr. Messer has now found that mice conditionally deficient in IEC HMGB1 also have evidence of dysbiosis and the intestinal barrier between bacteria and host tissues is compromised. These factors suggest that HMGB1 may have a role in antimicrobial defense in the intestine. Therefore, experiments in this study will test the hypothesis that HMGB1 plays an essential role in maintaining gut microbial commensalism and loss of HMGB1-mediated gut antimicrobial defense, in conditions such as IBD, leads to microbe-induced inflammation and mucosal damage. In Aim 1 Dr. Messer will determine mechanisms of HMGB1-mediated gut antimicrobial defense with the goal of understanding how HMGB1 regulates bacterial colonization and virulence. Aim 2 will determine mechanisms whereby derangement of HMGB1-mediated gut antimicrobial defense contributes to mucosal damage and IBD. The goal of this aim is to determine the impact of HMGB1 on host responses to gut bacteria. In each of these aims she will utilize innovative and cutting-edge techniques including germ-free mice, primary intestinal epithelial cell cultures, and bacterial metagenomics. She will also utilize human samples to investigate HMGB1 expression and changes to the types or behavior of bacteria colonizing the intestinal mucosa during IBD. Execution of these aims will provide didactic and hands-on training that will address the identified deficiencies in Dr. Messer's knowledge base and allow her to advance in her career path toward becoming an independent investigator. Furthermore, understanding HMGB1-regulated host-microbe interactions will directly address an urgent, unmet need in the field of IBD pathophysiology and open up new avenues of investigation as well as suggest novel therapies for these diseases.

项目概要/摘要这是 K08 指导临床科学家研究职业发展奖申请。 Jeannette S. Messer，芝加哥大学独立之路讲师药品。她的长期目标是成为该领域国际公认的专家和研究员人类炎症性疾病中宿主-微生物的相互作用。为了实现这个目标，她需要培训以解决她知识中的四个明确差距：转化研究[差距#1]、无菌小鼠模型[差距#2]、微生物学[差距#3]和研究微生物种群的生物信息学技术[差距#4]。梅塞尔博士组建了一支由经验丰富的专家导师和科学家组成的多学科团队在人类炎症性肠病、无菌小鼠的利用和管理、微生物学和生物信息学方法对肠道微生物种群进行分析，以缩小知识和技术方面的差距消除她向独立过渡和实现长期目标所发现的障碍。炎症性肠病 (IBD) 是影响肠道菌群的慢性腹泻和腹痛疾病。估计有 160 万美国人。细菌被认为在 IBD 病理生理学中发挥重要作用通过激活粘膜免疫反应。然而，细菌触发或持续的粘膜免疫反应仍然知之甚少。因此，有一个迫切的未满足的需求确定细菌如何在 IBD 期间促进免疫激活和粘膜损伤，从而发展考虑到疾病的微生物成分的有效疗法。高迁移率族盒 1 (HMGB1) 在反应微生物的肠上皮细胞 (IEC) 中产生。 IEC 中 HMGB1 因活动性 IBD 病变而减少，并且 IEC 中 HMGB1 有条件删除会加剧小鼠模型中的结肠炎。缺乏 IEC HMGB1 的小鼠结肠炎的特点是 IEC 死亡增加体外研究表明，缺乏HMGB1的IEC在受到挑战时更容易发生细胞凋亡与细菌细胞壁成分胞壁酰二肽。 HMGB1 也存在于粪便中，其浓度在活动性 IBD 期间，粪便中的这种蛋白质会增加。梅塞尔博士现在发现小鼠有条件地 IEC HMGB1 缺陷也有生态失调和细菌与宿主之间肠道屏障的证据组织受到损害。这些因素表明 HMGB1 可能在抗菌防御中发挥作用。肠。因此，本研究中的实验将检验 HMGB1 在在一定条件下维持肠道微生物共生并丧失 HMGB1 介导的肠道抗菌防御例如IBD，会导致微生物引起的炎症和粘膜损伤。在目标 1 中，Messer 博士将通过以下方法确定 HMGB1 介导的肠道抗菌防御机制：目的是了解 HMGB1 如何调节细菌定植和毒力。目标 2 将决定 HMGB1 介导的肠道抗菌防御紊乱有助于粘膜损伤和炎症性肠病。该目的的目的是确定 HMGB1 对宿主对肠道细菌反应的影响。在每一个目标中，她都将利用创新和尖端技术，包括无菌小鼠、初级技术肠上皮细胞培养和细菌宏基因组学。她还将利用人体样本研究 HMGB1 表达以及肠道定植细菌类型或行为的变化 IBD 期间的粘膜。这些目标的执行将提供教学和实践培训，以解决发现了梅塞尔博士知识库的缺陷，并让她在职业道路上取得进步成为一名独立调查员。此外，了解 HMGB1 调节的宿主微生物相互作用将直接解决 IBD 病理生理学领域紧迫的、未满足的需求，并开辟新的领域研究途径并提出针对这些疾病的新疗法。