MDSC Polarization and Helicobacter-induced Gastric Metaplasia

MDSC 极化和螺杆菌诱导的胃化生

基本信息

批准号：
10687293
负责人：
JUANITA L. MERCHANT
金额：
$ 40.97万
依托单位：
UNIVERSITY OF ARIZONA
依托单位国家：
美国
项目类别：
财政年份：
2018
资助国家：
美国
起止时间：
2018-09-15 至 2024-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10687293
关键词：
3&apos Untranslated Regions Acute Address African American population Alleles Appearance Atrophic Bacteria Bacterial Infections Binding Binding Sites Cell Death Cells Chronic DNA Dendritic Cells Elements Endothelium Epithelial Epithelial Cells Exhibits Funding Gastric Adenocarcinoma Gastric Metaplasia Genes Genetic Transcription Genome Goals Goblet Cells HMGB1 gene Helicobacter Helicobacter Infections Helicobacter pylori Hispanic Americans Histologic Human Immune Immune response Immunosuppressive Agents Individual Infection Inflammation Inflammatory Response Injections Interferon Type I Interferon-alpha Interferons Interleukin-1 alpha Intestines Ligands Link Mesenchymal Messenger RNA Metaplasia MicroRNAs Minor Mitochondria Mitochondrial DNA Modeling Molecular Mucous body substance Mus Myeloid Cells Myeloid-derived suppressor cells Necrosis Not Hispanic or Latino Oncogenic Organism Organoids Orthologous Gene PTEN gene Pathway interactions Pattern Pattern recognition receptor Peptic Ulcer Play Population Predisposition Preneoplastic Change Production Proteins Reporting Role Shapes Signal Transduction Signal Transduction Pathway Stomach Suppressor-Effector T-Lymphocytes TLR9 gene TNF gene Testing Tissues Ubiquitination Virulence Factors Virus Virus Diseases acute infection cytokine gastric intestinal metaplasia gastric tumorigenesis gene product granulocyte injured knock-down malignant stomach neoplasm mouse model pathogen phosphodiesterase V polarized cell programs promoter recruit relating to nervous system response small molecule smoothened signaling pathway spasmolytic polypeptide transcription factor transcriptome sequencing tumor tumor growth tumor-immune system interactions ubiquitin isopeptidase

项目摘要

Metaplastic changes in the stomach typically develop when the gastric epithelium responds to chronic inflammation induced by such organisms as Helicobacter pylori (H. pylori). We previously showed that a subset of interferon (IFN)-regulated myeloid cells express Schlafen4 (Slfn4), a direct target of the Gli1 transcription factor and exhibit T cell suppressor function indicative of myeloid-derived suppressor cells (MDSCs). These granulocytic myeloid-derived suppressor cell subset (Gr-MDSCs) contribute to the emergence of gastric intestinal metaplasia and spasmolytic-polypeptide-expressing metaplasia (SPEM). We propose that debris from damaged gastric epithelia and immune cells as well as dying bacteria induce a signal transduction pathway generate pathogen recognition ligands collectively known as damage-activated molecular patterns or DAMPs. Type 1 interferons (IFNs) are typically induced by DAMP ligands, e.g., HMGB1, mitochondrial and unmethylated CpG DNA. We have recently found that a SNP within the human TLR9 promoter correlates with atrophy, IM, and GAC. Moreover, the TLR9 SNP creates an NFB binding site resulting in higher TLR9 expression. H. pylori infection sensed by both plasmacytoid dendritic cells (pDC) and gastric epithelial cells (GEC) induces TLR9 expression and ultimately secrete type 1 IFNs (IFNα/β). Thus, in addition to host signaling from injection of the H. pylori virulence factor CagA, H. pylori remnants and cell debris are capable of initiating an immune suppressor response. Since we previously showed that the presence of these Slfn4+- MDSCs correlates with early pre-neoplastic changes, we hypothesize that crosstalk between a subset of immune suppressor cells (SLFN+-MDSCs) and gastric epithelial cells stimulate feedforward signals that ultimately re-program the epithelium towards metaplasia, before the appearance of gastric cancer. Hedgehog signaling (Gli1) and IFNα synergistically induce Slfn4+/SLFN12L+-MDSCs. Three Specific aims are proposed: In Aim 1, we will determine the impact of DAMP ligands (H. pylori DNA) on IFN-producing pDCs versus gastric epithelial cells. In Aim 2, we will demonstrate how Schlafens protect a subset of MDSCs from self- destruction by IFN-induced ROS. In Aim 3, we will demonstrate how PDE inhibition blocks Slfn4/SLFN12L+- MDSCs and modulates the immune microenvironment in an autochthonous model of gastric tumorigenesis. A combination of mouse models and human organoids will be used to understand the role of DAMP ligands in shaping the immune microenvironment after chronic inflammation has occurred. Conditional deletion of Slfn4 and knockdown of the human ortholog SLFN12L will be used to dissect how these Schlafens protect the IFN- responsive MDSCs from cell death. Finally, since modulating the immune microenvironment plays a significant role in tumor growth, we will examine whether small molecules that disrupt or eliminate these Slfn4/SLFN12L impact tumor growth. Completion of these aims will result in a better understanding of the how this important subset of immune modulatory cells are induced, maintained and ultimately targeted by small molecules.

当胃上皮对慢性炎症反应时，胃的化生变化通常会发生。由幽门螺杆菌（H. pylori）等微生物引起的炎症我们之前已经证明了其中的一个子集。干扰素 (IFN) 调节的骨髓细胞表达 Schlafen4 (Slfn4)，这是 Gli1 转录的直接靶标因素并表现出骨髓源性抑制细胞 (MDSC) 的 T 细胞抑制功能指标。粒细胞髓源性抑制细胞亚群 (Gr-MDSC) 有助于胃粘膜的出现我们提出肠化生和解痉多肽表达化生（SPEM）。受损的胃上皮和免疫细胞以及垂死的细菌诱导信号转导途径产生病原体识别配体，统称为损伤激活分子模式或 DAMP 1 型干扰素 (IFN) 通常由 DAMP 配体诱导，例如 HMGB1、线粒体和我们最近发现人类 TLR9 启动子内的一个 SNP 与相关。此外，TLR9 SNP 会产生 NF+B 结合位点，从而产生更高的 TLR9。浆细胞样树突状细胞 (pDC) 和胃上皮细胞均可感知幽门螺杆菌感染的表达。 (GEC) 诱导 TLR9 表达并最终分泌 1 型干扰素 (IFNα/β)。注射幽门螺杆菌毒力因子 CagA、幽门螺杆菌残余物和细胞碎片产生的信号传导能够由于我们之前表明这些 Slfn4+- 的存在，因此启动了免疫抑制反应。 MDSC 与早期肿瘤前变化相关，我们追踪了 MDSC 的一个子集之间的串扰免疫抑制细胞 (SLFN+-MDSC) 和胃上皮细胞刺激前馈信号，最终在刺猬蛋白出现之前将上皮重新编程为化生。信号传导 (Gli1) 和 IFNα 协同诱导 Slfn4+/SLFN12L+-MDSCs 提出了三个具体目标：在目标 1 中，我们将确定 DAMP 配体（幽门螺杆菌 DNA）对产生 IFNα 的 pDC 的影响与在目标 2 中，我们将演示 Schlafens 如何保护 MDSC 子集免受自身损伤。在目标 3 中，我们将演示 PDE 抑制如何阻断 Slfn4/SLFN12L+-。 MDSC 并调节胃肿瘤发生的本地模型中的免疫微环境。小鼠模型和人类类器官的结合将用于了解 DAMP 配体在慢性炎症发生后塑造免疫微环境。人类直系同源物 SLFN12L 的敲低将用于剖析这些 Schlafens 如何保护 IFN- 最后，调节免疫微环境发挥着重要作用。在肿瘤生长中的作用，我们将检查是否有小分子破坏或消除这些 Slfn4/SLFN12L 完成这些目标将有助于更好地理解这一点的重要性。免疫调节细胞的子集被小分子诱导、维持并最终靶向。