Human Genetic Variance and Cellular Responses to Sexually Transmitted Infections

人类遗传变异和细胞对性传播感染的反应

• 批准号: 8769306
• 负责人: Dennis Chun-Yone Ko
• 金额: $ 52.26万
• 依托单位: UNIVERSITY OF MARYLAND BALTIMORE
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/8769306
• 关键词: Address; Affect; Anti-Inflammatory Agents; Anti-inflammatory; Antibodies; Biological Markers; Cell Death; Cells; Cervicitis; Chlamydia trachomatis; Clinical; Communities; Complex; Disease; Disease Outcome; Dose; Drug Targeting; Ectopic Pregnancy; Environmental Risk Factor; Frequencies; Gardnerella; Genes; Genetic; Genetic Polymorphism; Genetic Variation; Genitourinary system; Genotype; Health; Human; Human Genetics; Immune response; In Vitro; Individual; Infection; Infertility; Inflammatory; Inflammatory Response; Lactobacillus; Lead; Liquid substance; Measurement; MicroRNAs; Microbe; Mission; Molecular; Neisseria gonorrhoeae; Organ; Outcome; Participant; Patients; Pelvic Inflammatory Disease; Phenotype; Physiology; Play; Population Genetics; Predisposition; Quality of life; Recurrence; Research; Resistance; Risk; Role; Severities; Severity of illness; Sexually Transmitted Diseases; Signal Transduction; Testing; United States National Institutes of Health; Vagina; Vaginal Douching; Variant; Woman; adverse outcome; clinical phenotype; clinically relevant; cohort; cytokine; genetic variant; genome wide association study; immunopathology; improved; lymphoblastoid cell line; member; men; microbial community; microbiome; novel; pathogen; reproductive; response; screening; trait

PROJECT SUMMARY Damage to reproductive organs as a result of inflammatory responses to STIs can lead to severe complications such as pelvic inflammatory disease, ectopic pregnancy and infertility. Multiple environmental factors including the infecting strain, dose and frequency of infections, and composition of the microbial communities in the urogenital tract contribute to the severity of disease manifestation and ensuing sequelae. Similarly, co-infection with other sexually transmitted pathogens may act synergistically to worsen disease. Finally, host genetics likely plays an important role in susceptibility to infection and ensuing immunopathologies. This project will address the role played by human genetic polymorphisms that regulate cellular interactions and responses to C. trachomatis alone or in the context of N. gonorrhoeae and vaginal microbiota components. We will identify and characterize genetic variants that affect STIs by applying two parallel and complementary approaches. First, we will use a discovery platform for genome-wide association studies (GWAS) of cellular traits called Hi-HOST (high throughput human in vitro susceptibility testing). Hi-HOST combines precise measurement of phenotypes in cells derived from hundreds of normal, genotyped individuals with genome-wide association to identify genetic differences that underlie the phenotypic variation. Furthermore, we propose to extend the Hi-HOST framework to examine how co-infection and the microbiota can act synergistically or antagonistically on the immune response and how human genetic differences can modulate these effects. Second, we will carry out GWAS of clinical traits and outcomes using the STING cohort. This dual approach will allow for study of human genetic variation in both the controlled experimental setting of identical infections with Hi-HOST and the more clinically relevant but complex setting of patients. We predict that overlap of SNPs identified by Hi-HOST and GWAS of the STING cohort will highlight human variation affecting both cellular infection phenotypes and clinical phenotypes and outcomes. Thus, we will determine not only which human genetic variants are associated with susceptibility to STIs but also intermediate phenotypes (such as cytokine levels, miRNA, and microbiota composition) that are likely responsible for the altered physiology. This will facilitate identification of biomarkers and possible drug targets, as well as specific genetic populations that might benefit most from targeted therapies.

项目摘要 由于对性传播感染的炎症反应，损坏生殖器官可能导致严重 并发症，例如骨盆炎性疾病，异位妊娠和不育。多个环境 包括感染菌株，感染的剂量和频率以及微生物组成的因素 泌尿生殖道的群落有助于疾病表现和随后的后遗症的严重程度。 同样，与其他性传播病原体的共同感染可能会协同作用对疾病恶化。 最后，宿主遗传学可能在感染和随后的易感性中起重要作用 免疫病理学。该项目将解决人类遗传多态性的作用 单独或在N。 淋病和阴道菌群成分。我们将识别并表征遗传变异 通过应用两种平行和互补方法来影响性传播感染。首先，我们将使用一个发现平台 全基因组关联研究（GWAS）的细胞性状称为Hi-host（高吞吐量人体外吞吐量 敏感性测试）。 Hi-Host结合了对数百个细胞中表型的精确测量 具有全基因组关联的正常的基因分型个体，以确定遗传差异 表型变异。此外，我们建议扩展HI-HOST框架以检查如何共同感染 微生物群可以在免疫反应上进行协同或拮抗作用，以及人类遗传 差异可以调节这些影响。其次，我们将使用临床特征和结果进行GWA 刺痛的队列。这种双重方法将允许研究受控的人类遗传变异 与Hi-Host相同感染的实验设置以及更临床相关但复杂的设置 患者。 我们预测，由刺刺和GWAS鉴定的SNP重叠将突出显示人类 影响细胞感染表型和临床表型和结果的变异。因此，我们会的 不仅确定哪些人类遗传变异与性传播感染的敏感性有关 可能是中间表型（例如细胞因子水平，miRNA和微生物群组成） 负责改变的生理学。这将有助于识别生物标志物和可能的药物靶标， 以及可能受益于靶向疗法的特定遗传种群。