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

项目摘要 非裔美国人的H.幽门螺杆菌（Hp）感染比非西班牙裔白色人群;然而， 这种差异的潜在基因仍然难以捉摸。我们发现人类TP 53基因的氨基酸变异 Acid 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 在铁下垂中，M2极化并显示出更多的Hp和其它细菌的生产性感染。巨噬细胞适应性 应答对于消除Hp感染是必不可少的，并且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，报道了幽门螺杆菌激活Arg 2在抑制巨噬细胞中的作用。 反应无偏WT和S47巨噬细胞蛋白质组学显示肝X受体 激活，辅酶II活性，炎症，铁转运和抗菌防御机制，调节 免疫反应和直接影响细菌感染结果。尽管已知p53可以调节免疫 我们是第一个发现导致差异的确切遗传变异的人。我们将逆转Hp 通过深入的机制和治疗研究，研究了具有S47 SNP的非裔美国人的感染差异。 我们的人类研究将为这个项目提供翻译相关性。我们将检测约500名Hp血清阳性的非洲人， 美国样本中S47和其他SNP的患病率。然后我们将重点提高巨噬细胞 使用肝X受体（LXR）激动剂，在S47小鼠中， 我们将测试LXR激活是否改善具有不同毒力的多种Hp菌株的这些结果。此外，委员会认为， 我们将生成一个巨噬细胞结合LXR的全基因组图谱，以“微调”其对巨噬细胞的活性， 激活并消除不希望的肝脂肪变性的影响。 由于Hp在细胞外和巨噬细胞内均存在，因此免疫细胞的特异性耗竭将是一个重要的因素。 用于区分巨噬细胞在H. pylori发病机制这些 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。我们将优先考虑和测试与LXR相关的途径， 如蛋白酶途径（Arg 2，Slc 7a 2），铁转运（Tfrc，Slc 40 a1，Fth 1）和先天免疫蛋白（TLR 3和 TLR 7）作为新的治疗靶点。最后，我们将测试巨噬细胞调节因子（NOTCH 1和 mTOR）、能量代谢（通过代谢酶从ox-phos转换为糖酵解）和多胺途径 （DFMO-多胺合成抑制剂）在微调LXR激动剂诱导的抗炎逆转中的作用 S47小鼠中的极化、Hp感染的清除和胃发育不良的减少。 这一建议将：a）提高我们对幽门螺杆菌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类研究的垫脚石，以解决这种健康差距。HP NIDDK认为感染在非裔美国人少数民族中至关重要。

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.