Role of African-centric TP53 variant in higher H. pylori prevalence in African Americans

以非洲为中心的 TP53 变异在非裔美国人中较高的幽门螺杆菌患病率中的作用

• 批准号: 10541244
• 负责人: Daniel Thomas Claiborne
• 金额: $ 60.03万
• 依托单位: WISTAR INSTITUTE
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-01-20 至 2025-12-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10541244
• 关键词: ARG2 gene; Acute; Address; Affect; African; African American; African American population; African ancestry; Agonist; Alleles; Amino Acids; Anti-Bacterial Agents; Anti-Inflammatory Agents; Asian population; Avena sativa; Bacteria; Bacterial Infections; Binding; Biological; Bone Marrow; Caucasians; Cells; Chronic; Clinical; Code; Cohort Studies; Communication; Communities; DL-alpha-Difluoromethylornithine; DNA; Data; Disparity; Dysplasia; East Asian; Energy Metabolism; Environment; European; FRAP1 gene; FTH1 gene; Fatty Liver; Gastric Intraepithelial Neoplasia; Gastritis; Genes; Genetic Polymorphism; Genus Mycobacterium; Glycolysis; Goals; Helicobacter Infections; Helicobacter pylori; High Prevalence; Hispanic Populations; Human; Immune; Immune response; Incidence; Individual; Infection; Inflammation; Inflammatory Response; Innate Immune Response; Iron; Iron Overload; Length; Listeria; Liver X Receptor; Macrophage; Macrophage Activation; Maps; Messenger RNA; Metformin; Minority; Modeling; Molecular; Mucin 1 protein; Mucous Membrane; Mus; NOTCH1 gene; National Institute of Diabetes and Digestive and Kidney Diseases; Nature; Not Hispanic or Latino; Outcome; Paper; Pathogenesis; Pathway interactions; Peroxisome Proliferator-Activated Receptors; Persons; Phenotype; Polyamines; Population; Prevalence; Productivity; Proteins; Proteomics; Receptor Activation; Regulation; Reporting; Research Design; Role; Sampling; Socioeconomic Status; Stomach; TLR1 gene; TLR3 gene; TLR7 gene; TP53 gene; Testing; Therapeutic; Therapeutic Studies; Tissues; Tumor Suppressor Genes; Variant; Virulence; Virulence Factors; arginase; bead chip; chronic infection; disparity reduction; efficacy testing; exome; extracellular; genetic variant; genome-wide; health disparity; high risk; immune cell infiltrate; improved; improved outcome; inhibitor; low socioeconomic status; mouse model; multi-ethnic; new therapeutic target; novel therapeutics; personalized medicine; racial difference; receptor; response; seropositive; socioeconomics; synergism; therapeutic evaluation

Project Summary African Americans have a 6-fold higher H. pylori (Hp) infection than the non-Hispanic white population; however, underlying gene(s) for this disparity remain elusive. We discovered that a human TP53 gene variant at amino acid 47 exists predominantly in people of African descent. Macrophages containing the S47 variant are defective in ferroptosis, M2 polarized and show more productive infections by Hp and other bacteria. Macrophage adaptive response is essential for eliminating Hp infection and is suppressed in chronic infections that lead to gastritis. Our collaborator, Dr. Keith Wilson, reported the role of Arg2 activation by Hp in suppressing the macrophage response. Unbiased WT and S47 macrophage proteomics revealed marked differences in Liver X Receptor activation, arginase II activity, inflammation, iron transport and antibacterial defense machinery which regulate immune response and directly affect outcomes of bacterial infections. Although p53 is known to regulate immune response, we are the first to discover the exact genetic variant causing the disparities. We will reverse the Hp infection disparities in African Americans with the S47 SNP by in-depth mechanistic and therapeutic study. Our human studies will give translational relevance to this project. We will test ~500 Hp seropositive African American samples for the prevalence of S47 and other SNPs. Then we will focus on improving macrophage response, Hp clearance and reduce chronic gastric dysplasia in S47 mice using Liver X Receptor (LXR) agonists. We will test if LXR activation improves these outcomes for multiple Hp strains with differing virulence. Moreover, we will generate a genome-wide map of macrophage binding of LXR to ‘fine tune’ its activity on macrophage activation and eliminate undesired effect of hepatic steatosis. Since Hp is found both extracellularly and within macrophages, specific depletion of immune cells will be used to distinguish the role of macrophages from other tissue environment in H. pylori pathogenesis. These studies will be validated by bone marrow swaps between WT and S47 mice. we will test macrophage regulation and tissue environment for more. We will prioritize and test pathways associated with LXR such as arginase pathway (Arg2, Slc7a2), iron transport (Tfrc, Slc40a1, Fth1) and innate immune proteins (TLR3 and TLR7) as novel therapeutic targets. Lastly, we will test macrophage regulatory factors (NOTCH1 and mTOR), energy metabolism (switching from ox-phos to glycolysis by Metformin) and polyamine pathway (DFMO-polyamine synthesis inhibitor) in fine tuning LXR agonist induced reversal of anti-inflammatory polarization in S47 mice, clearance of Hp infection and reduction of gastric dysplasia. This proposal will a) improve our understanding of the biological mechanism for the disparity in Hp infection in African Americans and b) provide several therapeutic avenues to improve clearance of Hp infection and gastritis. This project is a stepping stone for human studies in personalized medicine to address this health disparity. Hp infection has been deemed of critical importance in the African American minority, by the NIDDK.

项目概要 非裔美国人的幽门螺杆菌 (Hp) 感染率是非西班牙裔白人的 6 倍；然而， 造成这种差异的潜在基因仍然难以捉摸。我们发现人类 TP53 基因的氨基变异 酸 47 主要存在于非洲人后裔中。含有 S47 变体的巨噬细胞有缺陷 在铁死亡中，M2 极化并显示出更有效的 Hp 和其他细菌感染。巨噬细胞适应性 反应对于消除幽门螺杆菌感染至关重要，并且在导致胃炎的慢性感染中受到抑制。 我们的合作者 Keith Wilson 博士报告了 Hp 激活 Arg2 在抑制巨噬细胞中的作用 回复。无偏见的 WT 和 S47 巨噬细胞蛋白质组学揭示了肝脏 X 受体的显着差异 激活、精氨酸酶 II 活性、炎症、铁转运和抗菌防御机制 免疫反应并直接影响细菌感染的结果。尽管 p53 已知可调节免疫 响应，我们是第一个发现导致差异的确切遗传变异的人。我们将扭转HP 通过深入的机制和治疗研究，了解 S47 SNP 在非裔美国人中的感染差异。 我们的人体研究将为该项目提供转化相关性。我们将测试约 500 Hp 血清反应呈阳性的非洲人 美国 S47 和其他 SNP 流行率样本。然后我们将重点改善巨噬细胞 使用肝脏 X 受体 (LXR) 激动剂，可以改善 S47 小鼠的反应、Hp 清除并减少慢性胃发育不良。 我们将测试 LXR 激活是否可以改善具有不同毒力的多种 Hp 菌株的这些结果。而且， 我们将生成 LXR 巨噬细胞结合的全基因组图谱，以“微调”其对巨噬细胞的活性 激活并消除肝脂肪变性的不良影响。 由于 Hp 存在于细胞外和巨噬细胞内，因此免疫细胞的特异性耗竭将被 用于区分巨噬细胞与其他组织环境在幽门螺杆菌发病机制中的作用。这些 研究将通过 WT 和 S47 小鼠之间的骨髓交换进行验证。我们将测试巨噬细胞 调节和组织环境更多。我们将优先考虑并测试与 LXR 相关的途径，例如 如精氨酸酶途径（Arg2、Slc7a2）、铁转运（Tfrc、Slc40a1、Fth1）和先天免疫蛋白（TLR3 和 TLR7）作为新的治疗靶点。最后，我们将测试巨噬细胞调节因子（NOTCH1 和 mTOR）、能量代谢（通过二甲双胍从氧化磷转变为糖酵解）和多胺途径 （DFMO-多胺合成抑制剂）微调 LXR 激动剂诱导的抗炎逆转 S47 小鼠中的极化、Hp 感染的清除和胃发育不良的减少。 该提案将 a) 提高我们对 Hp 感染差异的生物学机制的理解 非裔美国人和 b) 提供了多种治疗途径来改善幽门螺杆菌感染和胃炎的清除。 该项目是个性化医疗人类研究的垫脚石，以解决这种健康差异。马力 NIDDK 认为感染对于非裔美国少数民族至关重要。