Project 1

项目1

基本信息

批准号：
9336273
负责人：
Corey Casper
金额：
$ 26.89万
依托单位：
FRED HUTCHINSON CANCER RESEARCH CENTER
依托单位国家：
美国
项目类别：
财政年份：
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/9336273
关键词：
Acquired Immunodeficiency Syndrome Adult Africa South of the Sahara Alleles Anatomy Biological Markers Cell Cycle Classification Cohort Studies Complementarity Determining Regions Data Development Disease Epitopes Etiology Evaluation Evolution Genes Genetic Polymorphism Genetic Variation Genetic study Genome Genomics Goals Grouping HIV HIV-1 Heterogeneity Human Herpesvirus 8 Immune Evasion Immune response Immunoglobulin Variable Region In complete remission Individual Infection Inflammation Kaposi Sarcoma Malignant Neoplasms Molecular Morbidity - disease rate Natural History Oncogenic Viruses Oral Outcome Pathogenesis Patients Persons Phylogenetic Analysis Plasma Play Population Progressive Disease Recording of previous events Residual state Role Sampling Sequence Analysis Site Source Specimen Stable Disease Swab Technology Time Treatment outcome Uganda Variant Viral Viral Genes Viral Genome Virus adaptive immune response angiogenesis base cancer risk chemotherapy co-infection cohort follow-up genome sequencing insight mortality new therapeutic target partial response predictive marker response targeted sequencing targeted treatment treatment response tumor tumorigenesis virus genetics whole genome

项目摘要

Kaposi sarcoma (KS) is the most common HIV-associated malignancy worldwide and causes significant morbidity and mortality, particularly in sub-Saharan Africa. Human herpesvirus-8 (HHV-8) is the etiologic agent of KS, but the natural history of progression from asymptomatic HHV-8 infection to KS development is poorly understood. Viral genomic diversity plays an important role in the risk of cancer and response to treatment in some oncogenic viruses, but HHV-8 genomic heterogeneity has been described in only limited regions of the viral genome and the potential contribution of HHV-8 diversity to KS pathogenesis and treatment outcomes is unknown. The overarching goal of this project is to provide the first comprehensive description of HHV-8 genome diversity, at the individual and population level, and to evaluate the association of HHV-8 polymorphisms with disease state and therapeutic response. Using state-of-the-art molecular technologies, we propose to determine sequence diversity over the whole HHV-8 genome in specimens from well-annotated cohorts of HHV-8/HIV-1 co-infected persons with and without KS in Uganda. In Aim 1, we will comprehensively characterize HHV-8 diversity to define common polymorphisms and phylogenetic groupings across the cohort population. In Aim 2, we will perform single-genome sequence analysis of polymorphic HHV-8 regions in additional paired oral, plasma and tumor specimens within individuals to determine whether multiple viral variants coexist and whether there is compartmentalization of variants in different anatomic sites. In Aim 3, we will explore associations of HHV-8 polymorphisms with KS disease state and treatment outcomes to identify polymorphisms with potential biologic significance, which may ultimately serve as predictive or treatment-selective biomarkers or targets of therapy.

Kaposi Sarcoma（KS）是全球最常见的HIV相关性恶性肿瘤，引起了显着的发病率和死亡率，尤其是在撒哈拉以南非洲。人类疱疹病毒8（HHV-8）是KS的病因学药，但是从无症状HHV-8感染到KS发育的自然历史知之甚少。病毒基因组多样性在某些致癌病毒的癌症风险和对治疗的反应中起着重要作用，但是仅在有限的病毒基因组的有限区域中描述了HHV-8基因组异质性，而HHV-8多样性对KS发病机理和治疗的潜在贡献尚不清楚。该项目的总体目标是在个体和人群水平上提供对HHV-8基因组多样性的首次全面描述，并评估HHV-8多态性与疾病状态和治疗反应的关联。我们建议使用最先进的分子技术，以确定来自乌干达和没有KS的HHV-8/HIV-1共同感染者的良好宣布同类群体中的整个HHV-8基因组的序列多样性。在AIM 1中，我们将全面地表征HHV-8多样性，以定义整个队列种群中常见的多态性和系统发育组。在AIM 2中，我们将对个体内其他配对的口腔，血浆和肿瘤样本中的多态性HHV-8区域进行单基因组序列分析，以确定多种病毒变体是否共存以及是否存在不同解剖位点中变体的分区化。在AIM 3中，我们将探索HHV-8多态性与KS疾病状态和治疗结果的关联，以鉴定具有潜在生物学意义的多态性，最终可能是预测性或治疗选择性生物标志物或治疗靶标。