Human exposures to polycyclic aromatic hydrocarbons and dioxins have been linked to the development of lymphomas and leukemias. The actions of these chemicals are mediated through a gene regulatory protein, the aryl hydrocarbon receptor (AhR). Persistent AhR activation by dioxin in mice results in altered numbers and function of hematopoietic stem cells (HSCs). Data also indicate that lack of AhR in mouse HSCs results in altered HSC characteristics and hematopoietic disease. Our overall hypothesis is that that AhR has an intrinsic role in the regulation of HSCs and that its dysregulation leads to and/or contributes to hematopoietic disease. In this proposal we will test the specific hypothesis that the AhR, through its ability to control specific gene targets, has an intrinsic role in the ability of HSCs to sense environmental (niche) signals and regulate the balance between HSC quiescence and proliferation. To address this and to define a role of AhR in HSC biology, we will use models of persistent AhR activation and AhR loss. Using radiation-reconstitution chimeric mice we will determine if HSCs are direct targets for AhR activation that result in altered HSC function. Using a combination of microarray and qRT-PCR analysis, we will determine the gene expression profile in HSCs from dioxin treated mice, and will define alterations in signaling pathways that affect HSC function following persistent activation. Using both AhR null-allele and conditional AhR knock-out mice, we will determine how AhR loss affects HSC function. Microarray analysis of HSCs lacking an AhR will define the molecular basis for altered HSC characteristics and function following AhR loss. Finally, several ex vivo approaches will be used to determine if down-regulation of the Ahr gene is necessary for the progression of HSCs from quiescence to proliferation.
The further understanding of the processes regulating HSC self-renewal, proliferation, and differentiation are fundamental to the prevention and treatment of a variety of leukemias and other hematopoietic diseases in humans. Understanding what regulates the normally incredible regenerative capacity of bone marrow also has clinical implications for bone marrow transplantation, autoimmune disease, and bone marrow failure that may be associated with cancer treatments. Furthermore, these events are intimately tied with the process of aging and a variety of diseases, including cancer, whose incidence increases with age.
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