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(Hp)感染率是非西班牙裔白人的6倍；然而， 造成这种差距的根本基因(S)仍然难以捉摸。我们发现人类TP53基因在氨基上的一个变异 酸47主要存在于非洲人后裔中。含有S47变异的巨噬细胞是有缺陷的 在铁性下垂中，M2两极分化，显示出更多的Hp和其他细菌的感染。巨噬细胞适应性 这种反应对于消除幽门螺杆菌感染至关重要，在导致胃炎的慢性感染中被抑制。 我们的合作者基思·威尔逊博士报告了幽门螺杆菌激活Arg2在抑制巨噬细胞中的作用 回应。无偏倚WT和S47巨噬细胞蛋白质组学显示肝脏X受体存在显著差异 激活、精氨酸酶II活性、炎症、铁运输和抗菌防御机制 免疫应答并直接影响细菌感染的结局。虽然已知P53可以调节免疫 我们是第一个发现造成差异的确切基因变异的人。我们将逆转惠普 通过深入的机制和治疗研究非裔美国人与S47 SNP之间的感染差异。 我们的人体研究将给这个项目带来翻译上的相关性。我们将检测~500个HP阳性的非洲人 美国样本的S47和其他SNP的流行情况。然后我们将专注于改善巨噬细胞 使用肝X受体(LXR)激动剂对S47小鼠的反应、幽门螺杆菌清除和减少慢性胃异型增生。 我们将测试LXR激活是否可以改善具有不同毒力的多个HP菌株的结果。此外， 我们将制作一张LXR与巨噬细胞结合的全基因组图谱，以“微调”其在巨噬细胞上的活性 激活和消除肝脏脂肪变性的不良影响。 由于幽门螺杆菌既存在于细胞外，也存在于巨噬细胞内，因此免疫细胞的特异性耗竭 用于区分巨噬细胞和其他组织环境在幽门螺杆菌致病中的作用。这些 研究将通过WT和S47小鼠之间的骨髓交换来验证。我们将测试巨噬细胞 调节和组织环境的更多。我们将对与LXR相关的路径进行优先排序和测试 精氨酸酶途径(Arg2，Slc7a2)，铁转运(Tfrc，Slc40a1，Fth1)和天然免疫蛋白(TLR3，Fth1) TLR7)作为新的治疗靶点。最后，我们将检测巨噬细胞调节因子(NOTCH1和 MTOR)、能量代谢(二甲双胍从氧化-磷酸转换为糖酵解)和多胺途径 (DFMO-多胺合成抑制剂)在微调LXR激动剂诱导抗炎逆转中的作用 S47小鼠极化，清除幽门螺杆菌感染，减少胃不典型增生。 这一建议将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来改善HP感染和胃炎的清除。 该项目是个性化医学人体研究的垫脚石，以解决这一健康差距。幽门螺杆菌 NIDDK认为感染在非裔美国少数民族中至关重要。