Discovering Infection-mediated Pathways of Glioma Etiology and Prognosis by Leveraging Multiplex Serology and Immunogenomics

利用多重血清学和免疫基因组学发现神经胶质瘤病因和预后的感染介导途径

• 批准号: 10522917
• 负责人: Stephen Starko Francis
• 金额: $ 66.91万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-09-01 至 2026-08-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10522917
• 关键词: 19q; Adult Glioma; Affect; Alleles; Amino Acid Motifs; Amino Acid Sequence; Amino Acids; Antibody Response; Antigenic Variation; Antigens; Area; BK Virus; Binding; Biological Assay; Cells; Clinical Data; Cytomegalovirus; Data; Detection; Development; Etiology; Foundations; Genes; Genetic; Genetic Polymorphism; Genetic Variation; Genome; Glioma; Gliomagenesis; HHV-6A; HLA Antigens; Haplotypes; Herpesviridae; Herpesvirus Type 3; Histocompatibility Antigens Class I; Human; Human Herpesvirus 4; Human Herpesvirus 7; Immune response; Immunogenomics; Individual; Infection; Infectious Agent; International; Intervention; Link; Malignant Neoplasms; Malignant neoplasm of brain; Manuscripts; Maps; Measurement; Measures; Mediating; Mediation; Meta-Analysis; Modeling; Mutate; Mutation; Nucleotides; Outcome; Pathogenesis; Pathway interactions; Patients; Pattern; Peptides; Play; Polyomaviridae; Polyomavirus; Predisposition; Prevention; Prognosis; Proteins; Risk; Risk Factors; Role; Sampling; Serology; Serology test; Serum; Simian virus 40; Simplexvirus; Technology; Testing; Therapeutic; Time; Toxoplasma gondii; Viral; Viral Antigens; Virus; Virus Diseases; case control; co-infection; epidemiologic data; epidemiology study; genetic architecture; innovation; interest; member; modifiable risk; nanopore; novel therapeutics; pathogen; predictive modeling; prognostic; response; survival outcome; synergism

PROJECT SUMMARY Gliomas account for 80% of all malignant brain tumors and have an extremely poor prognosis, with a 5-year survival of 5.1%. The etiology of glioma remains poorly understood, with few established modifiable risk factors. Multiple studies have implicated infections in the development of glioma, however the underlying mechanisms and putative causal pathogens remain unclear. In addition to risk, there is also accumulating evidence from studies investigating novel therapeutics suggesting that immune response to infection may be prognostic in glioma patients. Previous epidemiologic studies have investigated a limited number of pathogens using serological assays that only allowed detection. We seek to conduct a large serologic study measuring 41 antigens from all 12 infections previously associated with glioma using assays that provide quantitative measures of antibody response. Our study will include 1000 glioma case-control pairs with extensive clinical and epidemiologic data. In Aim 1 we will estimate the effect of each individual infection on glioma risk and survival and also examine grouped patterns of co-infections. In Aim 2, we will employ innovative long read sequencing technology to detail all polymorphisms in human leukocyte antigen (HLA) class I and II genes in the same set of subjects. Genetic variation in the HLA region plays a pivotal role in regulating immune response to viral challenge and has been previously linked to glioma risk and progression. We will investigate a range of functional HLA polymorphisms, including antigen-presenting classical alleles and amino acid residues, with respect to glioma risk and survival. In Aim 3, we will integrate serological and HLA sequencing data to delineate host genetic mechanisms of immune response to infection and subsequent effects on glioma endpoints. This will allow us to develop comprehensive immunogenomic models for predicting glioma risk and survival. Taken together, the proposed study will contribute new, high-quality data that will significantly advance our understanding of glioma pathogenesis, as well as inform avenues for prevention and improvement of outcomes in glioma patients.

项目概要 胶质瘤占所有恶性脑肿瘤的80%，预后极差，5年生存期极差。 生存率为5.1%。神经胶质瘤的病因仍然知之甚少，几乎没有确定的可改变的危险因素。 多项研究表明感染与神经胶质瘤的发展有关，但其潜在机制 假定的致病病原体仍不清楚。除了风险之外，还有越来越多的证据来自 调查新疗法的研究表明，对感染的免疫反应可能是预后的 神经胶质瘤患者。先前的流行病学研究使用以下方法调查了有限数量的病原体 血清学检测仅允许检测。我们寻求进行一项大型血清学研究，测量 41 使用提供定量测量的检测方法检测先前与神经胶质瘤相关的所有 12 种感染的抗原 的抗体反应。我们的研究将包括 1000 个神经胶质瘤病例对照对，具有广泛的临床和 流行病学数据。在目标 1 中，我们将评估每种感染对神经胶质瘤风险和生存的影响 并检查合并感染的分组模式。在目标 2 中，我们将采用创新的长读测序 详细描述同一组中人类白细胞抗原 (HLA) I 类和 II 类基因的所有多态性的技术 科目。 HLA 区域的遗传变异在调节病毒攻击的免疫反应中发挥着关键作用 之前已被认为与神经胶质瘤的风险和进展有关。我们将研究一系列功能性 HLA 与神经胶质瘤有关的多态性，包括抗原呈递经典等位基因和氨基酸残基 风险和生存。在目标 3 中，我们将整合血清学和 HLA 测序数据来描述宿主遗传 对感染的免疫反应机制以及随后对神经胶质瘤终点的影响。这将使我们能够 开发综合免疫基因组模型来预测神经胶质瘤风险和生存。综合起来， 拟议的研究将提供新的高质量数据，这将显着增进我们对神经胶质瘤的理解 发病机制，以及为神经胶质瘤患者的预防和改善结果提供信息。