Core C ? Mouse Model Service Core The overarching theme of the proposed research is to identify additional in utero chemical factors that increase the risk for childhood ALL in an ethnically-diverse population, and understand how these and previously identified chemicals increase risk via immunologic, genetic and epigenetic mechanisms. In order to assess how suspected chemical risk factors can contribute to leukemogenesis, we propose a Service Core to test the impact of such exposures in a mouse model of human childhood ALL, our ETV6- RUNX1 (TEL-AML1) Cdkn2a null model. Such exposure studies not only permit a direct assessment of the impact of chemical risk factors on leukemic transformation, they also enable mechanistic in vivo laboratory studies at the level of molecule, cell, tissue and organism to understand the effects of such exposures on immune system development and carcinogenesis. Because biological assessments of the effects of chemicals are included in the experimental aims of Project 1 and Project 3, we propose a core to enable coordinated analyses. Housing mice centrally, and using groups of these mice to assess the impact of exposures on all aspects under study, will produce essential economies of effort and cost, as compared to duplicating studies within separate Projects. It is only through this economy of effort and cost that we will be able to achieve project aims within the proposed budgetary framework. In the Core, pregnant female mice will be exposed to chemical risk factors, both previously identified and those newly implicated through work in Project 2. Subsequent to exposure, the Core will collect blood samples from the pregnant females (and unexposed pregnant controls), which Project 1 will use to assess chemically- induced changes in immunomodulatory cytokines. Blood samples will be provided from the newborn offspring for similar studies of the impact of exposures on the immune system of newborns, and DNA from these pups will be assessed for methylation changes in Project 3. Samples from these offspring will also be collected 5 weeks after birth to assess persistent changes in immunomodulatory cytokines (in Project 1), methylation changes of immune cells (in Project 3), and immature bone marrow B-cell numbers (for Projects 1 and 3). The Core will also follow and will diagnose disease in separate cohorts of exposed and unexposed mice in order to establish the leukemogenic potential of prenatal chemical exposures implicated in human studies. The Projects will work together, under the administrative leadership of Core A, to perform coordinated analyses: results of planned human and mouse studies will be used to delineate how pre-natal chemical exposures impact the immune system and epigenetic DNA methylation to contribute to childhood ALL.
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