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.
|Boule, Lisbeth A; Burke, Catherine G; Jin, Guang-Bi et al. (2018) Aryl hydrocarbon receptor signaling modulates antiviral immune responses: ligand metabolism rather than chemical source is the stronger predictor of outcome. Sci Rep 8:1826|
|Franchini, Anthony M; Lawrence, B Paige (2018) Environmental exposures are hidden modifiers of anti-viral immunity. Curr Opin Toxicol 10:54-59|
|Boulé, Lisbeth A; Chapman, Timothy J; Hillman, Sara E et al. (2018) Developmental Exposure to a Mixture of 23 Chemicals Associated With Unconventional Oil and Gas Operations Alters the Immune System of Mice. Toxicol Sci 163:639-654|
|Yee, Min; Domm, William; Gelein, Robert et al. (2017) Alternative Progenitor Lineages Regenerate the Adult Lung Depleted of Alveolar Epithelial Type 2 Cells. Am J Respir Cell Mol Biol 56:453-464|
|De Jesús Andino, Francisco; Lawrence, B Paige; Robert, Jacques (2017) Long term effects of carbaryl exposure on antiviral immune responses in Xenopus laevis. Chemosphere 170:169-175|
|Unnisa, Zeenath; Singh, Kameshwar P; Henry, Ellen C et al. (2016) Aryl Hydrocarbon Receptor Deficiency in an Exon 3 Deletion Mouse Model Promotes Hematopoietic Stem Cell Proliferation and Impacts Endosteal Niche Cells. Stem Cells Int 2016:4536187|
|Bennett, John A; Singh, Kameshwar P; Unnisa, Zeenath et al. (2015) Deficiency in Aryl Hydrocarbon Receptor (AHR) Expression throughout Aging Alters Gene Expression Profiles in Murine Long-Term Hematopoietic Stem Cells. PLoS One 10:e0133791|
|Singh, Kameshwar P; Bennett, John A; Casado, Fanny L et al. (2014) Loss of aryl hydrocarbon receptor promotes gene changes associated with premature hematopoietic stem cell exhaustion and development of a myeloproliferative disorder in aging mice. Stem Cells Dev 23:95-106|
|Gasiewicz, Thomas A; Singh, Kameshwar P; Bennett, J Allen (2014) The Ah receptor in stem cell cycling, regulation, and quiescence. Ann N Y Acad Sci 1310:44-50|
|Budinsky, R A; Schrenk, D; Simon, T et al. (2014) Mode of action and dose-response framework analysis for receptor-mediated toxicity: The aryl hydrocarbon receptor as a case study. Crit Rev Toxicol 44:83-119|
Showing the most recent 10 out of 42 publications