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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）患者表达的两个最大的恐惧是发展结肠癌和失去结肠。虽然结肠炎相关的癌症不太常见，但异型增生更常见，通常会导致结肠切除术我们的提案利用上一个供资期的工作和该领域的进展，翻译的方法来解开结肠炎的发育不良。我们研究的重点是先天免疫信号传导和肠道细菌导致结肠炎相关瘤形成。我们的研究结果关注双氧化酶2（DUOX 2）在发育异常中的作用。DUOX 2是一种NADPH氧化酶，催化与成熟因子DUOXA 2相互作用后，氧气转化为过氧化氢（H2 O2）。是在IBD患者的活检组织中，DUOX 2/DUOXA 2表达持续上调，并且DUOX 2/DUOXA 2表达在IBD患者的活检组织中进一步增加。患有发育不良的患者。我们的研究小组已经表明，炎症和微生物信号都可以诱导 DUOX 2在结肠上皮细胞中的表达和活性（H2 O2产生）。我们已经证明慢性 DUOX 2的激活导致肿瘤的形成，通过使DUOX 2失活几乎完全消除肿瘤在上皮中。在目前的提议中，我们假设IBD相关的生态失调激活Duox 2，局部产生H2 O2，导致上皮屏障功能障碍，募集促肿瘤的髓源性抑制细胞（MDSC），以及在前馈环中产生致瘤微生物组。这是追求具体目的如下：1）确定炎性结肠发育不良对上皮细胞的依赖性， Duox 2信号。在这里，我们将研究上皮屏障功能障碍和DNA损伤途径引起的上皮Duox 2活化，使用结肠样模型（人和鼠）。使用人源化无菌小鼠，我们将确定UC发育不良微生物组是否足以引起DUOX 2介导的渗透性缺陷， DNA损伤。2)剖析促肿瘤MDSC在非典型增生发展中的作用， DUOX 2介导的氧化应激。我们的初步数据表明，TLR 4驱动的肿瘤增强了募集支持MDSC的肿瘤。在这里，我们将确定DUOX 2依赖性上皮因子（趋化因子/细胞因子）和转录（单细胞-RNA序列）和功能（T细胞抑制）在我们的肿瘤发生的鼠模型和具有异型增生的UC患者中的MDSC的特征。3)识别与Duox 2激活和发育异常相关的靶向微生物途径。微生物组从肿瘤易感的villin-TLR 4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发育异常和无发育异常的UC之间存在明显差异。我们将用我们小鼠模型和UC异型增生样品进行深度测序和代谢组学表征，肿瘤促进微生物组。将测试二甲双胍诱导或抑制H2 O2/DUOX 2的能力，类结肠本文提出的工作将为随后的人体研究提供机制依据，靶向Duox 2和特定微生物途径，阻止UC炎症进展为发育异常。

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。