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（由申请人提供）：神经胶质瘤是最致命的成人癌症之一；在过去的30年中，临床研究人员在治疗成功方面几乎没有收获。此外，除了电离辐射的作用和少量组成型遗传多态性外，对神经胶质瘤的原因几乎没有理解。神经胶质瘤中最近的一系列发现与免疫因子的作用有关：与健康对照组胶质瘤患者相比，胶质瘤患者报告的过敏较少，较低的Varicella病毒相关疾病的频率较低，并且过敏相关的IgE和细胞因子的水平改变了。大脑具有非常强大的免疫调节特性，诱发炎症的条件可能会因其密闭环境而损害大脑。大脑的免疫特权状态意味着中枢神经系统中的肿瘤免疫监视机制知之甚少。然而，与偏见和通用中枢神经系统使用的病原病毒为指导有关免疫反应在中枢神经系统恶性肿瘤中作用的研究提供了线索。水痘病毒（VZV）是一种神经性病毒，可以假设针对该病毒的免疫反应可能促进脑肿瘤的免疫监测。为了探索这一前提，我们将研究特定的VZV抗原在阐明抗体反应中的作用在神经胶质瘤病因（使用诊断前血清）和神经胶质瘤存活中（使用后诊断后血清）中的作用。诊断前标本来自嵌套在前列腺，肺，结直肠癌和卵巢癌筛查试验中的参与者（PLCO，n = 129例和516例对照），后诊断后诊断来自旧金山湾地区成人胶质瘤研究的病例（UCSF AGS，UCSF AGS，UCSF，UCSF，UCSF，n = 1000 glioma case a Glioma case complete Chess and Cheres and Cheres and Theres and Terme and Themor case complete and Tumor Data and Tumor data）。我们将测试针对所有69种构成VZV基因组的69种蛋白的特定抗VZV反应，以比较神经胶质瘤病例和对照组之间抗原库的身份和强度。我们将通过在诊断神经胶质瘤（PLCO）和神经胶质瘤存活（UCSF AGS）之前评估每个单独的VZV抗原和病例状态之间的病例对照差异来表征这种抗原反应。我们还将使用包括随机森林和PartDSA在内的多变量分析技术构建多VZV抗原谱。对于前4个信息丰富的抗原，我们将通过对这些蛋白质的完整线性表位映射进行进一步表征抗原特异性。我们还将使用PLCO诊断前病例（n = 39）和对照组（n = 78）评估这些反VZV反应的变异性，其中5个串行收集（以1年间隔）获得血清。蛋白质和肽水平的抗VZV反应将为神经胶质瘤病因和可能与神经胶质瘤抗原反应的单个抗原提供线索，从而增强对神经胶质作用中免疫反应及其临床相关性的了解。