Varicella virus antigens in glioma etiology and survival

水痘病毒抗原在神经胶质瘤病因学和生存中的作用

• 批准号: 9206483
• 负责人: Joseph Leo Wiemels
• 金额: $ 55.29万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-03-06 至 2019-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9206483
• 关键词: Address; Adult; Adult Glioma; Affect; Allergic; Antibodies; Antibody Response; Antigenic Specificity; Antigens; Area; Asthma; Biological Markers; Biological Response Modifiers; Blood; Brain; Brain Injuries; Brain Neoplasms; CD14 gene; Case-Control Studies; Cessation of life; Characteristics; Chickenpox; Clinical; Colorectal Cancer; Contracts; Data; Diagnosis; Diagnostic; Disease; Environment; Epidemiology; Epitope Mapping; Epitopes; Etiology; Exhibits; Foundations; Frequencies; Genetic; Genetic Polymorphism; Glioma; Gliomagenesis; Grant; Herpes zoster disease; Herpesvirus Type 3; Hypersensitivity; IgE; Immune; Immune response; Immune system; Immunity; Immunologic Factors; Immunologic Markers; Immunologic Monitoring; Immunological Models; Incidence; Individual; Inflammation; Investigation; Ionizing radiation; Logistic Regressions; Malignant Glioma; Malignant Neoplasms; Malignant neoplasm of brain; Malignant neoplasm of lung; Malignant neoplasm of prostate; Molecular; Odds Ratio; Open Reading Frames; Outcome; Participant; Pathogenicity; Patient Self-Report; Patients; Peptides; Phenotype; Property; Proteins; Questionnaires; RANK protein; Reaction; Reporting; Research; Research Personnel; Resources; Risk; Role; Sampling; San Francisco; Screening for Ovarian Cancer; Serologic tests; Serological; Serum; Societies; Solid; Specimen; Techniques; Testing; Time; Tropism; Viral Antigens; Viral Genome; Virus; Work; base; case control; clinically relevant; cohort; cytokine; follow-up; forest; immunoreaction; immunoregulation; instrument; lifetime risk; neurotropic virus; public health relevance; response; screening; success; time use; tumor

DESCRIPTION (provided by applicant): Gliomas are among the most deadly adult cancers; clinical researchers have made few gains in treatment success in the past 30 years. In addition, there is little understanding about the causes of glioma apart from the role of ionizing radiation and a small number of constitutive genetic polymorphisms. An additional recent array of findings in gliomas is related to the role of immune factors: when compared to healthy controls glioma patients report fewer allergies and lower frequencies of varicella-virus-related diseases, and have altered levels of allergy-related IgE and cytokines. The brain has very strong immunomodulatory properties, and inflammation-inducing conditions may damage the brain due to its confined environment. The immune privileged status of the brain means that tumor immunosurveillance mechanisms in the CNS are poorly understood; however, pathogenic viruses with tropism and access to the CNS provide clues to guide research on the role of immune response in CNS malignancies. Varicella Virus (VZV) is a neurotropic virus, and it is hypothesized that an immune response against the virus may facilitate immunosurveillance of brain tumors. To explore this premise, we will investigate the role of specific VZV antigens in elucidating antibody responses in glioma etiology (using pre-diagnostic sera) and in glioma survival (using post-diagnostic sera). Pre- diagnostic specimens are from participants nested within the Prostate, Lung, Colorectal, and Ovarian Cancer Screening Trial (PLCO, N = 129 cases, and 516 controls), and post-diagnostic are from cases in the San Francisco Bay Area Adult Glioma Study (UCSF AGS, N = 1000 glioma cases with complete treatment and tumor data). We will test for specific anti-VZV response against all 69 proteins that comprise the VZV genome to compare identities and intensities of the antigenic repertoire between glioma cases and controls. We will characterize this antigen response by assessing case-control differences between each individual VZV antigen and case status both before diagnosis of glioma (PLCO) and in glioma survival (UCSF AGS). We will also construct multi-VZV-antigen profiles using multivariable analytic techniques including random forests and partDSA. For the top 4 informative antigens, we will further characterize antigenic specificity by performing a complete linear epitope mapping of those proteins. We will also assess variability in these anti-VZV responses over time using PLCO pre-diagnostic cases (N = 39) and controls (N = 78) for whom 5 serially collected (at 1 year intervals) blood draw sera are available. Anti-VZV responses at the protein and peptide level will provide clues to glioma etiology and possibly individual antigens that cross-react with glioma antigens, providing an enhanced understanding of immune response in gliomagenesis and its clinical relevance.

描述(申请人提供)：胶质瘤是最致命的成人癌症之一；在过去的30年里，临床研究人员在治疗成功方面几乎没有取得什么进展。此外，除了电离辐射的作用和少量的结构性遗传多态性外，对胶质瘤的病因还知之甚少。最近在胶质瘤中的另一系列发现与免疫因素的作用有关：与健康对照组相比，胶质瘤患者报告的过敏反应和水痘病毒相关疾病的频率较低，并改变了与过敏相关的IgE和细胞因子的水平。大脑具有非常强的免疫调节特性，由于其受限的环境，炎症诱导的条件可能会损害大脑。脑的免疫特权状态意味着肿瘤的免疫监视机制在中枢神经系统中知之甚少；然而，具有趋向性和进入中枢神经系统的致病病毒为指导免疫反应在中枢神经系统恶性肿瘤中的作用提供了线索。水痘病毒(VZV)是一种嗜神经病毒，推测对该病毒的免疫反应可能有助于脑肿瘤的免疫监视。为了探索这一前提，我们将研究特定的VZV抗原在阐明胶质瘤病因学(使用诊断前血清)和胶质瘤生存(使用诊断后血清)中的抗体反应中的作用。诊断前样本来自前列腺癌、肺癌、结直肠癌和卵巢癌筛查试验的参与者(PLCO，N=129例，516名对照)，诊断后样本来自旧金山湾区成人胶质瘤研究(UCSF AGS，N=1000例有完整治疗和肿瘤数据的胶质瘤病例)。我们将针对构成VZV基因组的所有69种蛋白进行特异性抗VZV反应测试，以比较胶质瘤病例和对照组之间抗原库的特性和强度。我们将通过评估在胶质瘤诊断(PLCO)和胶质瘤存活率(UCSF AGS)之前的病例对照差异和病例状态来表征这种抗原反应。我们还将使用包括随机森林和部分DSA在内的多变量分析技术构建多个VZV抗原图谱。对于前4个信息量最大的抗原，我们将通过对这些蛋白质进行完整的线性表位映射来进一步表征抗原特异性。我们还将使用PLCO诊断前病例(N=39)和对照(N=78)评估这些抗VZV反应随时间的变异性，其中5例连续收集(每隔1年)抽血血清可用。在蛋白质和多肽水平上的抗VZV反应将提供胶质瘤病因学的线索，并可能提供与胶质瘤抗原交叉反应的单个抗原的线索，从而加深对胶质瘤形成中的免疫反应及其临床意义的理解。