Center for Integrative Research on Childhood Leukemia and the Environment

 描述(由申请人提供)：儿童白血病与环境综合研究中心(CLOCK)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者、家庭和公共卫生组织了解白血病的危险因素来支持预防工作。在过去的半个世纪里，儿童ALL的发病率在儿童中稳步上升，其中拉丁裔的发病率最高。这一快速增长有力地支持了环境暴露在儿童ALL病因中的作用，无论是单独的还是与遗传和表观遗传因素结合在一起的。现有的生物学和流行病学研究表明，儿童ALL通常在子宫中开始，胎儿接触致癌化学物质可能在疾病的病因中发挥作用。鉴于这些发现和在国际生物多样性圈第一个周期中开发的新的实验室方法，下一个周期的首要主题是确定在不同族裔人群中对儿童造成更多宫内化学风险的因素，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将通过使用加州公共卫生部存档的孕妇怀孕血液样本和新生儿血点来整合以人口为基础的研究和基础研究，并将利用正在进行的两项研究--加州儿童白血病研究和加州母婴出生队列--的资源。对这些项目的综合统计分析将评估宫内化学暴露、免疫状态、遗传学和表观遗传学在所有病因中的相互作用。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，并支持新职业发展调查员的研究职业发展。项目1将评估宫内化学品暴露对儿童ALL风险的影响，同时考虑到母亲和新生儿免疫状态的作用，通过母亲怀孕血清和新生儿血点中的免疫调节细胞因子来衡量。项目2将描述孕妇和新生儿的内源性和外源性化学物质暴露的总体特征，以确定儿童ALL的新的宫内危险因素。将应用分析小分子和蛋白质加合物的新方法，并对以前发现与ALL相关的小分子进行有针对性的分析。项目3将结合构成遗传学，确定化学、免疫和饮食因素对DNA甲基化的干扰，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，该模型有发展成类似于儿童ALL的老鼠的倾向。社区外联和翻译核心(核心B)将有助于包括拉丁裔在内的各种受众的环境健康素养，并为制定儿童中所有人的预防方案提供科学基础。

 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.