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.

Public Health Relevance

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.

Agency
National Institute of Health (NIH)
Institute
National Institute of Environmental Health Sciences (NIEHS)
Type
Research Project (R01)
Project #
5R01ES004862-19
Application #
8367826
Study Section
Special Emphasis Panel (ZRG1-DKUS-C (90))
Program Officer
Reinlib, Leslie J
Project Start
1990-07-01
Project End
2014-10-31
Budget Start
2012-11-01
Budget End
2013-10-31
Support Year
19
Fiscal Year
2013
Total Cost
$363,273
Indirect Cost
$128,145
Name
University of Rochester
Department
Public Health & Prev Medicine
Type
Schools of Dentistry
DUNS #
041294109
City
Rochester
State
NY
Country
United States
Zip Code
14627
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
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
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
Feng, F; Silvin, C J; Fiore, N C et al. (2012) 17ýý-Estradiol (E-2) administration to male (NZB ýý SWR)Fýýý mice results in increased Id(LN)Fýýý-reactive memory T-lymphocytes and accelerated glomerulonephritis. Lupus 21:288-301
Casado, Fanny L; Singh, Kameshwar P; Gasiewicz, Thomas A (2011) Aryl hydrocarbon receptor activation in hematopoietic stem/progenitor cells alters cell function and pathway-specific gene modulation reflecting changes in cellular trafficking and migration. Mol Pharmacol 80:673-82
Casado, Fanny L; Singh, Kameshwar P; Gasiewicz, Thomas A (2010) The aryl hydrocarbon receptor: regulation of hematopoiesis and involvement in the progression of blood diseases. Blood Cells Mol Dis 44:199-206
Laiosa, Michael D; Mills, Jeffrey H; Lai, Zhi-Wei et al. (2010) Identification of stage-specific gene modulation during early thymocyte development by whole-genome profiling analysis after aryl hydrocarbon receptor activation. Mol Pharmacol 77:773-83
Gasiewicz, Thomas A; Singh, Kameshwar P; Casado, Fanny L (2010) The aryl hydrocarbon receptor has an important role in the regulation of hematopoiesis: implications for benzene-induced hematopoietic toxicity. Chem Biol Interact 184:246-51
Singh, Kameshwar P; Casado, Fanny L; Opanashuk, Lisa A et al. (2009) The aryl hydrocarbon receptor has a normal function in the regulation of hematopoietic and other stem/progenitor cell populations. Biochem Pharmacol 77:577-87
Singh, Kameshwar P; Wyman, Amber; Casado, Fanny L et al. (2009) Treatment of mice with the Ah receptor agonist and human carcinogen dioxin results in altered numbers and function of hematopoietic stem cells. Carcinogenesis 30:11-9

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