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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

基本信息

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
项目类别：
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

项目摘要

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.

项目总结