权益分类	功能权益	普通用户	{{item.name}}会员
{{category.name}}	{{benefitItem.name}}

Role of innate immunity and the microbiome in colitis-associated dysplasia

先天免疫和微生物组在结肠炎相关发育不良中的作用

基本信息

批准号：
10659444
负责人：
Maria Teresa Abreu
金额：
$ 38.94万
依托单位：
UNIVERSITY OF MIAMI SCHOOL OF MEDICINE
依托单位国家：
美国
项目类别：
财政年份：
2014
资助国家：
美国
起止时间：
2014-09-01 至 2027-04-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10659444
关键词：
Animal Model Bacteria Bacterial Translocation Biopsy Cells Characteristics Chronic Colectomy Colitis Colon Colon Carcinoma Colonic inflammation Cytometry DNA Damage Data Defect Dependence Development Dysplasia Epithelial Cells Epithelium Feces Fright Functional disorder Funding Generations Genetic Transcription Germ-Free Human Hydrogen Peroxide Image Immune signaling Immune system Inflammation Inflammatory Intestines Lesion Link Liver Mediating Metagenomics Methods Modeling Mucous Membrane Mus Myeloid-derived suppressor cells NADPH Oxidase Natural Immunity Oxidases Oxidative Stress Oxygen Pathogenesis Pathway interactions Patients Permeability Predisposition Production Proteobacteria Research Personnel Risk Role Sampling Signal Induction Signal Transduction Specimen T-Lymphocyte TLR4 gene Techniques Testing Translating Tumor Promotion Ulcerative Colitis Work biobank chemokine colitis associated cancer colitis-associated neoplasia colon dysplasia cytokine deep sequencing dysbiosis gut bacteria intestinal epithelium metabolome metabolomics microbial microbiome monolayer mouse model premalignant prevent recruit single-cell RNA sequencing translational approach tumor tumor microbiome tumorigenesis tumorigenic villin

项目摘要

PROJECT ABSTRACT The two greatest fears expressed by patients with ulcerative colitis (UC) are developing colon cancer and losing their colon. Although colitis-associated cancer is less common, dysplasia is more common and often results in colectomy. Our proposal leverages the work of the previous funding period and advances in the field to take a translational approach to unraveling dysplasia in colitis. The focus of our studies has been the link between innate immune signaling and intestinal bacteria leading to colitis-associated neoplasia. Our results have led us to focus on the role of dual oxidase 2 (DUOX2) in dysplasia. DUOX2 is a NADPH oxidase that catalyzes the conversion of oxygen into hydrogen peroxide (H2O2) upon interaction with the maturation factor DUOXA2. It is consistently upregulated in biopsies from IBD patients and DUOX2/DUOXA2 expression is further increased in patients who have had dysplasia. Our group has shown that both inflammatory and microbial signals induce the expression and activity (H2O2 production) of DUOX2 in colonic epithelial cells. We have proven that chronic activation of DUOX2 leads to the formation of tumors, which is almost totally abrogated by inactivating DUOX2 in the epithelium. In the current proposal, we hypothesize that IBD-associated dysbiosis activates Duox2 and local production of H2O2 leading to epithelial barrier dysfunction, recruitment of tumor-promoting myeloid derived suppressor cells (MDSCs), and generation of a tumorigenic microbiome in a feed forward loop. This is pursued in the following specific aims: 1) Determine the dependence of inflammatory colonic dysplasia on epithelial Duox2 signaling. Here we will investigate epithelial barrier dysfunction and DNA damage pathways caused by epithelial Duox2 activation using colonoid models (human and murine). Using humanized germ-free mice, we will determine if the UC-dysplasia microbiome is sufficient to cause DUOX2-mediated permeability defects and DNA damage. 2) Dissect the role of tumor-promoting MDSCs on dysplasia development in the setting of DUOX2-mediated oxidative stress. Our preliminary data demonstrate that TLR4-driven tumors have enhanced recruitment of tumor supporting MDSCs. Here we will identify DUOX2-dependent epithelial factors (chemokines/cytokines) and the transcriptional (single cell-RNA seq) and functional (T cell suppressive) characteristics of MDSCs in our murine models of tumorigenesis and UC patients with dysplasia. 3) Identify targetable microbial pathways linked to Duox2 activation and dysplasia. Transfer of the microbiome from tumor-susceptible villin-TLR4 mice is sufficient to transfer CAC susceptibility. New metagenomic and metabolomic data show clear differences between UC dysplasia and UC without dysplasia. We will use our mouse models and UC dysplasia samples to perform deep sequencing and metabolomic characterization of the tumor-promoting microbiome. Metabolites will be tested for their ability to induce or inhibit H2O2/DUOX2 in colonoids. The work proposed herein will provide the mechanistic justification for subsequent human studies to target Duox2 and specific microbial pathways to halt progression from UC inflammation to dysplasia.

项目摘要溃疡性结肠炎 (UC) 患者最担心的两个问题是罹患结肠癌和失去生命他们的冒号。尽管结肠炎相关癌症不太常见，但发育异常更常见，并且经常导致结肠切除术。我们的提案利用了上一个资助期的工作和该领域的进展来采取解决结肠炎发育不良的转化方法。我们研究的重点是两者之间的联系先天免疫信号和肠道细菌导致结肠炎相关肿瘤。我们的成果引领我们重点关注双氧化酶 2 (DUOX2) 在发育不良中的作用。 DUOX2 是一种 NADPH 氧化酶，可催化与成熟因子 DUOXA2 相互作用后，氧气转化为过氧化氢 (H2O2)。这是 IBD 患者的活检组织中 DUOX2/DUOXA2 表达持续上调，并且 DUOX2/DUOXA2 表达进一步增加患有不典型增生的患者。我们的小组已经证明炎症和微生物信号都会诱导 DUOX2 在结肠上皮细胞中的表达和活性（H2O2 产生）。我们已经证明，慢性 DUOX2 的激活导致肿瘤的形成，而通过灭活 DUOX2 几乎可以完全消除肿瘤在上皮细胞中。在当前的提案中，我们假设 IBD 相关的生态失调会激活 Duox2 和局部产生 H2O2 导致上皮屏障功能障碍，募集促进肿瘤的骨髓来源抑制细胞（MDSC），以及在前馈循环中生成致瘤微生物组。这是追求的具体目标如下： 1) 确定炎症性结肠发育不良对上皮细胞的依赖性 Duox2 信号传导。在这里，我们将研究上皮屏障功能障碍和 DNA 损伤途径使用类结肠模型（人和小鼠）进行上皮 Duox2 激活。使用人源化无菌小鼠，我们将确定 UC 发育不良微生物群是否足以引起 DUOX2 介导的通透性缺陷，以及 DNA损伤。 2) 剖析促肿瘤 MDSC 在不典型增生中的作用 DUOX2 介导的氧化应激。我们的初步数据表明 TLR4 驱动的肿瘤已增强募集肿瘤支持性 MDSC。在这里我们将鉴定DUOX2依赖性上皮因子（趋化因子/细胞因子）和转录（单细胞 RNA seq）和功能（T 细胞抑制）我们的小鼠肿瘤发生模型和不典型增生的 UC 患者中 MDSC 的特征。 3）识别与 Duox2 激活和发育不良相关的可靶向微生物途径。微生物组的转移来自肿瘤敏感的villin-TLR4小鼠足以转移CAC易感性。新的宏基因组和代谢组学数据显示 UC 不典型增生和不典型增生的 UC 之间存在明显差异。我们将使用我们的小鼠模型和 UC 发育不良样本，以进行深度测序和代谢组学表征促进肿瘤的微生物组。将测试代谢物诱导或抑制 H2O2/DUOX2 的能力结肠样。本文提出的工作将为后续的人体研究提供机制依据靶向 Duox2 和特定微生物途径，阻止 UC 炎症向发育不良的进展。

项目成果

期刊论文数量（37）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Intestinal Epithelial Inactivity of Dual Oxidase 2 Results in Microbiome-Mediated Metabolic Syndrome.

DOI：
10.1016/j.jcmgh.2023.06.009
发表时间：
2023
期刊：
CELLULAR AND MOLECULAR GASTROENTEROLOGY AND HEPATOLOGY
影响因子：
7.2
作者：
Hazime, Hajar;Ducasa, G. Michelle;Santander, Ana M.;Brito, Nivis;Gonzalez, Eddy E.;Ban, Yuguang;Kaunitz, Jonathan;Akiba, Yasutada;Fernandez, Irina;Burgueno, Juan F.;Abreu, Maria T.
通讯作者：
Abreu, Maria T.

Practical techniques for detection of Toll-like receptor-4 in the human intestine.

检测人肠道中 Toll 样受体 4 的实用技术。