Molecular Epidemiology of B cell Activation, DNA Repair & HIV-Associated Lymphoma

描述（由申请人提供）：本提案描述了一个为期五年的短期计划，旨在为Shehnaz K博士提供额外的具体培训和指导研究经验。侯赛因使她能够实现其长期目标，即成功开始癌症分子流行病学独立学术研究员和科学家的职业生涯，重点研究与感染相关的癌症。Hussain博士获得了Sc.M.约翰霍普金斯的流行病学博士在流行病学上，W.西雅图，曾是卡罗林斯卡学院的博士后，目前是加州大学洛杉矶分校流行病学系新任命的助理教授。Hussain博士将在包括张博士在内的经验丰富和支持性的跨学科导师团队的帮助下实现她的学术生涯目标（癌症分子流行病学），Martinez-Maza（癌症免疫学），Detels（艾滋病毒/艾滋病流行病学）和Sinsheimer（统计遗传学）;一个明确和有指导的职业发展计划，包括赠款和手稿写作，在计算生物学，生物信息学，复杂的数据分析，以及全基因组关联研究的设计/进行中的问题，以及湿实验室培训;由多个中心，部门和UCLA学校组成的强大和协作的机构环境;以及定义明确的研究项目，很有可能发展成为独立的研究计划。Hussain博士研究项目的主要假设是，B细胞活化相关基因的不良基因型将与艾滋病毒相关非霍奇金淋巴瘤（AIDS-NHL）风险增加相关。Hussain博士将在两个描述良好的HIV队列（MACS和WIHS）中进行巢式病例对照研究。候选基因中的TagSNPs，按推定的功能性优先，将在AIDS-NHL病例和匹配的对照中进行基因分型。将利用多变量逻辑回归模型和基于路径的统计方法来确定tagSNPs和单倍型与AIDS-NHL风险之间的关联，并检查这些关联是否被其他遗传、分子或流行病学因素修饰。该项目将整合高通量技术，创新的统计方法和丰富的先前收集的数据，以扩大我们对NHL病因的理解。 公共卫生相关性：非霍奇金淋巴瘤（NHL）在美国构成了重要的公共卫生负担，发病率和死亡率稳步上升，平均寿命损失年数很高，突出表明了这一点。不幸的是，NHL的确切原因在很大程度上仍然未知。NHL的HIV感染者，谁是在NHL的风险非常高的病因学研究，将告知未来的风险评估，检测和预防NHL的策略。

DESCRIPTION (provided by applicant): This proposal describes a five-year program designed in the short-term to provide additional specific training and mentored research experience to Dr. Shehnaz K. Hussain to enable her to achieve her long-term goal of successfully launching a career as an independent academic researcher and scientist in cancer molecular epidemiology with a focus on infection-related cancers. Dr. Hussain received a Sc.M. in epidemiology from Johns Hopkins, a Ph.D. in epidemiology from U. W. Seattle, was a postdoc at the Karolinska Institute, and is currently a newly appointed Assistant Professor in the UCLA Department of Epidemiology. Dr. Hussain will meet her academic career goals with the help of a highly experienced and supportive interdisciplinary team of mentors including Drs. Zhang (cancer molecular epidemiology), Martinez-Maza (cancer immunology), Detels (HIV/AIDS epidemiology), and Sinsheimer (statistical genetics); a clear and directed career development plan including grant and manuscript writing, didactic training in computational biology, bioinformatics, complex data analysis, and issues in the design/conduct of genome wide association studies, and wet-lab training; a strong and collaborative institutional environment consisting of multiple centers, departments, and schools of UCLA; and a well-defined research project with a high possibility of being developed into an independent research program. The main hypothesis of Dr. Hussain's research project is that adverse genotypes of B cell activation-related genes will be associated with increased risk of HIV-associated non-Hodgkin's lymphoma (AIDS-NHL). Dr. Hussain will conduct a nested case-control study in two well-described HIV cohorts, the MACS and WIHS. TagSNPs in candidate genes, prioritized by putative functionality, will be genotyped in AIDS-NHL cases and matched controls. Multivariate logistic regression models and pathway-based statistical methods will be utilized to determine the association between tagSNPs and haplotypes and AIDS-NHL risk, and to examine whether these associations are modified by other genetic, molecular, or epidemiological factors. This project will integrate high-throughput technologies, innovative statistical methods, and a wealth of previously collected data to extend our understanding of NHL etiology. PUBLIC HEALTH RELEVANCE: Non-Hodgkin's lymphoma (NHL) poses an important public health burden in the U.S., which is underscored by the steady rise in incidence and mortality and high number of average years of life lost. Unfortunately, the exact causes of NHL are still largely unknown. Etiological studies of NHL in HIV infected individuals, who are at very high risk of NHL, will inform future strategies for risk assessment, detection, and prevention of NHL.