Center for Integrative Research on Childhood Leukemia and the Environment

 儿童白血病与环境综合研究中心（CIRCLE）的目标是确定儿童急性淋巴细胞白血病（ALL）的原因，并通过教育卫生从业人员，家庭和公共卫生组织对白血病的风险因素来支持预防工作。在过去的半个世纪，儿童ALL的发病率稳步上升，其中拉丁美洲人的发病率最高。这种快速增加强烈支持环境暴露在儿童ALL病因中的作用，无论是单独还是与遗传和表观遗传因素相结合。现有的生物学和流行病学研究表明，儿童ALL往往是在子宫内启动和胎儿接触致癌化学品可能在疾病的病因学中发挥作用。鉴于这些发现和CIRCLE第一个周期开发的新实验室方法，下一个周期的首要主题是确定不同种族人群中儿童ALL的其他宫内化学风险因素，并了解化学品如何通过免疫学，遗传学和表观遗传学机制增加风险。CIRCLE将通过使用来自加州公共卫生部的存档孕妇血液标本和新生儿血点来整合基于人群的基础研究，并将利用两项正在进行的研究-加州儿童白血病研究和加州母婴出生队列的资源。项目的综合统计分析将评估子宫内化学品暴露、免疫状态、遗传学和表观遗传学在ALL病因学中的相互作用。核心A将提供中心活动的监督、协调和整合，建立外部咨询委员会，协调社区参与，与儿科健康专家合作，并支持新职业发展研究者的研究职业发展。项目1将评估宫内化学品暴露对儿童ALL风险的影响，同时考虑到母体和新生儿免疫状态的作用，通过母体妊娠血清和新生儿血斑中的免疫调节细胞因子进行测量。项目2将描述母体和新生儿生物标本中内源性和外源性化学品暴露的总体特征，以确定儿童ALL的子宫内新风险因素。将应用分析小分子和蛋白质加合物的新方法，并对先前发现与ALL相关的小分子进行靶向分析。项目3将确定化学、免疫和饮食因素对DNA甲基化的干扰，包括组成性遗传学，并将评估这些因素在儿童ALL综合风险分析中的作用。核心C将支持项目1、2、3，以阐明小鼠模型中的因果机制，该模型倾向于产生儿童ALL的小鼠类似物。社区外展和翻译核心（核心B）将有助于包括拉丁美洲人在内的各种受众的环境卫生知识，并为制定儿童ALL预防方案提供科学依据。

 DESCRIPTION (provided by applicant): The goal of the Center for Integrative Research on Childhood Leukemia and the Environment (CIRCLE) is to identify the causes of childhood acute lymphoblastic leukemia (ALL) and to support prevention efforts by educating health practitioners, families, and public health organizations on risk factors for leukemia. During the last half century, the incidence of childhood ALL has steadily increased in children, with the highest rates reported in Latinos. This rapid increase strongly supports the role of environmental exposures in the etiology of childhood ALL, either alone or in combination with genetic and epigenetic factors. Existing biological and epidemiological studies suggest that childhood ALL is often initiated in utero and fetal exposure to carcinogenic chemicals may play a role in the etiology of the disease. Given these findings and novel laboratory methods developed during CIRCLE's first cycle, the overarching theme for the next cycle is to identify additional in utero chemical risk factors for childhood ALL in an ethnically diverse population, and to understand how chemicals increase risk via immunological, genetic and epigenetic mechanisms. CIRCLE will integrate population-based and basic research by using archived maternal pregnancy blood specimens and neonatal blood spots from the California Department of Public Health, and will leverage resources from two ongoing studies - the California Childhood Leukemia Study and the California Mother-Child Birth Cohort. Integrated statistical analyses of the Projects will assess the interplay between in utero chemical exposures, immune status, genetics, and epigenetics in ALL etiology. Core A will provide oversight, coordination, and integration of Center activities, establish an External Advisory Committee, coordinate community engagement, collaborate with the Pediatric Health Specialist, and support the research career development of a new Career Development Investigator. Project 1 will evaluate the impact of in utero chemical exposures on the risk of childhood ALL, taking into account the role of maternal and neonatal immune status, as measured by immunomodulatory cytokines in maternal pregnancy sera and neonatal blood spots. Project 2 will characterize the totality of endogenous and exogenous chemical exposures in maternal and neonatal biospecimens to identify novel in utero risk factors for childhood ALL. New methods for profiling small molecules and protein adducts will be applied, and targeted analyses will be performed for small molecules previously found to be associated with ALL. Project 3 will determine the perturbation of DNA methylation by chemical, immune, and dietary factors, incorporating constitutive genetics, and will evaluate the role of these factors in integrated risk analyses of childhood ALL. Core C will support Projects 1, 2, 3 to elucidate causal mechanisms in a mouse model with a propensity to develop a mouse-analog of childhood ALL. The Community Outreach and Translation Core (Core B) will contribute to environmental health literacy in various audiences, including Latinos, and provide a scientific basis for developing prevention programs for ALL in children.