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Mapping the Pathway of PAH-Induced Bone Marrow B Cell Apoptosis
EPA Grant Number: F5D10699Title: Mapping the Pathway of PAH-Induced Bone Marrow B Cell Apoptosis
Investigators: Emberley, Jessica K.
Institution: Boston University
EPA Project Officer: McClure, Karen
Project Period: September 6, 2005 through June 30, 2007
Project Amount: $94,980
RFA: STAR Graduate Fellowships (2005)
Research Category: Academic Fellowships
Description:
Objective:Many studies indicate that environmentally ubiquitous chemicals, such as polycyclic aromatic hydrocarbons (PAH), adversely affect the mature immune system. However relatively few have addressed how PAH affect the developing immune system and what molecular mechanisms are responsible for these effects. The primary goal of these studies is to determine the molecular mechanisms by which environmental chemicals impair immune system development using the prototypic PAH 7,12-dimethylbenz[α]anthracene (DMBA). In particular, t hese studies will elucidate the molecular events responsible for DMBA-induced bone marrow B cell apoptosis and serve as a basis for mechanistic studies on immunotoxicity mediated by xenobiotics in general. My hypothesis is that caspase-8 and mitochondrial activation are both necessary for optimal PAH-induced pro/pre-B cell apoptosis.
Approach:The following aspects of DMBA-induced pro/pre-B cell apoptosis will be investigated: the mechanism of caspase-8 activation, the importance of caspase-8 activation, the mechanism of mitochondrial activation, and the mechanism of mitochondrial activation and caspase-8 activation linkage. These studies will be performed using DMBA to induce apoptosis of developing B cells in a well-characterized in vitro murine model of B cell development involving non-transformed, stromal cell-dependent primary and cloned bone marrow B cells from wild type and gene knockout mice. Caspase-dependent and JNK-mediated mechanisms of caspase-8 activation will be tested. Caspase-8-dominant negative cell lines will be used to determine the importance of caspase-8 activation. C aspase-2, p53, Bax, and JNK will be examined as possible activators of the mitochondria. Possible pathways linking caspase-8 and mitochondrial activation, such as Bid cleavage and a caspase feedback loop, will also be investigated.
Expected Results:I expect to find that caspase-8 and the mitochondria are both activated during DMBA-induced pro/pre-B cell apoptosis, and that both are necessary for maximal apoptosis. Further, I expect the mitochondria to be activated before caspase-8, likely in a caspase-independent manner. If this is correct then I expect caspase-8 to be activated by a caspase cascade activated by the mitochondria. By determining the molecular changes resulting from PAH exposure our ability to predict consequences of human exposure to these pollutants and design rational strategies to block these effects will improve.
Supplemental Keywords:PAH, DMBA, environmental pollutant, xenobiotic, B cell, immunotoxicity, immune system, bone marrow, immune development, apoptosis, caspase,
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Scientific Discipline, Health, PHYSICAL ASPECTS, Risk Assessments, Analytical Chemistry, Health Risk Assessment, Physical Processes, Biochemistry, Environmental Chemistry, chemical mixtures, immune response, immune systems, molecular mechanisms, immunotoxicology, bioaccumulation, ecological risk assessment, environmental mutagens, cell apoptosis, human health risk, toxicology, exposure, PAH, complex mixtures, human exposure