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: 10330592
• 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/10330592
• 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; 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; Lead; Length; Listeria; Liver X Receptor; 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; 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; Tumor-infiltrating immune cells; Variant; Virulence; Virulence Factors; arginase; bead chip; chronic infection; disparity reduction; efficacy testing; exome; extracellular; genetic variant; genome-wide; health disparity; high risk; improved; improved outcome; inhibitor; low socioeconomic status; macrophage; 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.

项目摘要 非裔美国人的幽门螺杆菌感染高6倍，比非西班牙裔白人人口高。然而， 这种差异的基因基因仍然难以捉摸。我们发现氨基的人类TP53基因变体 酸47主要存在于非洲血统的人群中。包含S47变体的巨噬细胞有缺陷 在铁铁作用中，M2极化并显示出HP和其他细菌的生产性感染。巨噬细胞自适应 反应对于消除HP感染至关重要，并且在导致胃炎的慢性感染中受到抑制。 我们的合作者基思·威尔逊（Keith Wilson）博士报道了HP在抑制巨噬细胞中激活ARG2的作用 回复。无偏的WT和S47巨噬细胞蛋白质组学揭示了肝X受体的明显差异 激活，精氨酸酶II活性，感染，铁运输和抗菌防御机制，调节 免疫反应并直接影响细菌感染的结局。尽管已知P53调节免疫 响应，我们是第一个发现引起分布的确切遗传变异的人。我们将逆转HP 通过深入的机械和治疗研究，非洲裔美国人的感染差异具有S47 SNP。 我们的人类研究将与该项目具有翻译相关性。我们将测试〜500 hp血清阳性非洲人 S47和其他SNP的流行率的美国样本。然后，我们将专注于改善巨噬细胞 使用肝X受体（LXR）激动剂的反应，HP清除率并降低S47小鼠中慢性胃发育不良。 我们将测试LXR激活是否可以改善具有不同病毒的多种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，以“微调”其对巨噬细胞的活性 激活并消除肝脂肪变性的UNESE效应。 由于在细胞外和巨噬细胞中都发现了HP，因此免疫细胞的特定定义将是 用于区分巨噬细胞在幽门螺杆菌发病机理中的其他组织环境的作用。这些 研究将通过WT和S47小鼠之间的骨髓互换来验证。我们将测试巨噬细胞 调节和组织环境更多。我们将优先和测试与LXR相关的途径 作为精氨酸酶途径（ARG2，SLC7A2），铁运输（TFRC，SLC40A1，FTH1）和先天免疫蛋白（TLR3和 TLR7）作为新的治疗靶标。最后，我们将测试巨噬细胞调节因素（Notch1和 MTOR），能量代谢（通过二甲双胍从Ox-Phos转换为糖酵解）和多胺途径 （DFMO-聚丙胺合成抑制剂）在微调LXR激动剂中引起的抗炎逆转 S47小鼠的极化，HP感染的清除和胃发育不全的降低。 该建议将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）提供了几种治疗途径，以提高HP感染和胃炎的清除。 该项目是人类研究的个性化医学研究的垫脚石，以解决这种健康差异。惠普 NIDDK认为感染在非裔美国人少数群体中至关重要。