THE FUNCTION AND REGULATION OF HISTIDINE DECARBOXYLASE IN GUT INFLAMMATION

组氨酸脱羧酶在肠道炎症中的作用及调控

• 批准号: 8449690
• 负责人: Timothy Cragin Wang
• 金额: $ 33.79万
• 依托单位: COLUMBIA UNIVERSITY HEALTH SCIENCES
• 依托单位国家: 美国
• 财政年份: 1995
• 资助国家: 美国
• 起止时间: 1995-01-30 至 2016-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8449690
• 关键词: Acids; Address; Biogenic Amines; Bone Marrow; Cancer Etiology; Cancer Model; Cell Differentiation process; Cell Lineage; Cell Maturation; Cell surface; Cells; Cholecystokinin; Cholecystokinin B Receptor; Chronic; Coculture Techniques; Colon Carcinoma; Colorectal; Colorectal Cancer; Data; Development; Down-Regulation; Enzymes; Epigenetic Process; Exhibits; Gene Expression; Green Fluorescent Proteins; Growth; Health; Histamine; Histamine Production; Histidine; Histidine Decarboxylase; Human; Hypersensitivity; IKBKB; ITGAM gene; Immune; In Vitro; Inflammation; Inflammatory; Inflammatory Response; Inflammatory disease of the intestine; Interleukin-6; Knockout Mice; Laboratories; Lead; Leukocytes; Ligands; Link; Malignant Neoplasms; Malignant neoplasm of gastrointestinal tract; Mediating; Methylation; Modeling; Mus; Myelogenous; Myeloid Cells; Neoplasms; Phenotype; Physiological Processes; Physiology; Play; Predisposition; Receptor Signaling; Recruitment Activity; Regulation; Reporter; Role; S100A8 gene; Site; Staging; Stimulus; Suppressor-Effector T-Lymphocytes; Testing; Toxin; Transforming Growth Factor beta; Transgenic Organisms; Transplantation; Work; Xenograft Model; Xenograft procedure; cancer cell; cancer prevention; cancer site; cancer therapy; cancer type; carcinogenesis; cell growth; cell type; colon carcinogenesis; cytokine; granulocyte; in vivo; macrophage; monocyte; mouse model; neoplastic cell; neurotransmission; neutrophil; novel; novel marker; prevent; progenitor; promoter; recombinase; treatment strategy; tumor; tumor microenvironment; tumor progression

DESCRIPTION (provided by applicant): The enzyme histidine decarboxylase (HDC) converts L-histidine to histamine, a biogenic amine that functions in numerous physiologic processes, but has increasingly been linked to immune regulation. Work from our laboratory using HDC-EGFP BAC transgenic reporter mice has demonstrated that HDC is highly expressed in CD11b+Ly6G+ immature myeloid cells (IMCs) that exhibit cell surface markers similar to myeloid-derived suppressor cells (MDSCs) or tumor-associated neutrophils (TAN). These HDC-expressing cells are recruited early on in an AOM/DSS model of colorectal carcinogenesis. HDC-/- mice that are deficient in histamine production exhibit markedly increased inflammatory responses to AOM/DSS and thus increased colon carcinogenesis, due largely to deficient myeloid maturation. HDC-/- mice show increased circulating CD11b+Ly6G+ IMCs and decreased mature neutrophils and macrophages, due to a requirement for histamine for normal maturation and differentiation of CD11b+Ly6G+ myeloid progenitors. Transplant of HDC deficient bone marrow to wild type recipients results in increased CD11b+Ly6G+ cell mobilization and reproduces the cancer susceptibility phenotype. CD11b+Ly6G+ IMCs from HDC-KO mice show increased proinflammatory cytokine expression and induce greater growth of colon cancer xenografts. IMCs accumulate in early stages of mouse and human colonic neoplasia, due to downregulation of HDC gene expression by cancer cells leading to inhibition of myeloid cell maturation, suggesting a novel mechanism by which tumors promote an active tumor microenvironment. Taken together, these data indicate key roles for HDC/histamine in myeloid cell differentiation, and CD11b+Ly6G+ IMCs in early colon cancer development. We are proposing four specific aims: (1) Are HDC-expressing CD11b+Gr1+ cells myeloid precursors that give rise to mature monocytes and granulocytes and other cell types? We will utilize HDC-BAC-Cre-ERTM mice developed in our laboratory to trace the development and differentiation of the myeloid cell lineage, both in vitro and in vivo. (2) How are HDC-expressing IMCs recruited during carcinogenic stimuli? We will examine the role of IL-1beta, IL-6, and RAGE ligands (S100A8/A9), and test the effect of IL-1beta blockade and RAGE deletion on IMC recruitment. (3) How do tumors downregulate HDC to inhibit myeloid cell differentiation and maturation? We will examine changes in methylation of the HDC CpG promoter sites during co-culture of IMCs with tumor cells, and explore the possible role of TGF-beta in modulating myeloid cell differentiation. (4) Are HDC-expressing IMC cells critical to the initiation and promotion of colorectal cancer? HDC-BAC-Cre-ERTM mice will be crossed to Ikkbeta F/F and DTR F/F mice, and we will also explore the importance of histamine in carcinogenesis.

描述(申请人提供)：组氨酸脱羧酶(HDC)将L-组氨酸转化为组胺，组胺是一种生物胺，在许多生理过程中发挥作用，但越来越多地与免疫调节有关。我们实验室使用HDC-EGFP BAC转基因报告鼠的工作表明，HDC在CD11b+Ly6G+未成熟髓系细胞(IMCs)中高表达，其细胞表面标志类似于髓系抑制细胞(MDSCs)或肿瘤相关中性粒细胞(TAN)。这些表达HDC的细胞在大肠癌变的AOM/DSS模型早期被招募。组胺产生不足的HDC-/-小鼠对AOM/DSS的炎症反应显著增加，从而增加了结肠癌的发生，这主要是由于髓系成熟不足所致。HDC-/-小鼠表现出循环CD11b+Ly6G+IMC增加，成熟中性粒细胞和巨噬细胞减少，这是因为CD11b+Ly6G+髓系祖细胞的正常成熟和分化需要组胺。将HDC缺陷的骨髓移植给野生型受者，可增加CD11b+Ly6G+细胞的动员，并重现癌症易感性表型。来自HDC-KO小鼠的CD11b+Ly6G+IMCs表现出促炎症细胞因子的表达增加，并诱导结肠癌异种移植瘤生长。在小鼠和人类结肠肿瘤的早期阶段，由于癌细胞下调HDC基因的表达导致髓系细胞成熟受抑，IMCs积聚，这表明肿瘤促进活跃的肿瘤微环境的新机制。综上所述，这些数据表明HDC/组胺在髓系细胞分化中的关键作用，以及CD11b+Ly6G+IMCs在早期结肠癌发展中的关键作用。我们提出了四个特定的目标：(1)HDC表达CD11b+Gr1+细胞是否是导致成熟单核细胞、粒细胞和其他细胞类型的髓系前体细胞？我们将利用我们实验室培育的HDC-BAC-CRE-ERTM小鼠在体外和体内追踪髓系细胞的发育和分化。(2)在致癌刺激过程中，表达HDC的IMCs是如何募集的？我们将检测IL-1β、IL-6和RAGE配体(S100A8/A9)的作用，并检测IL-1β阻断和RAGE缺失对IMC募集的影响。(3)肿瘤如何下调HDC以抑制髓系细胞的分化和成熟？我们将检测在IMCs与肿瘤细胞共培养过程中HDC CpG启动子位置甲基化的变化，并探索转化生长因子-β在调节髓系细胞分化中的可能作用。(4)HDC表达的IMC细胞在结直肠癌的发生和发展中起关键作用吗？HDC-BAC-CRE-ERTM小鼠将与IKKbeta F/F和DTR F/F小鼠杂交，我们还将探索组胺在癌症发生中的重要性。