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Principal Investigator: Lawrence, B Paige
Institute Receiving Award University Of Rochester
Location Rochester, NY
Grant Number R01ES004862
Funding Organization National Institute of Environmental Health Sciences
Award Funding Period 01 Jul 1990 to 31 Aug 2021
DESCRIPTION (provided by applicant):  : Hematopoietic stem cells (HSCs) have the ability to self-renew and differentiate into all blood lineages. A balance among quiescence, self-renewal, proliferation, and differentiation is precisely maintained to preserve multi-lineage generation throughout the organism's lifetime, and during responses to stress, tissue damage, and pathogens. Although the dysregulation of these processes in HSCs has immense implications for human health, how this balance is regulated is not well understood. Recent data support the novel hypothesis that the aryl hydrocarbon receptor (AHR), a bHLH transcription factor, is a physiological regulator of HSCs. These data support the contention that AHR acts as a negative regulator by curbing excessive or unnecessary proliferation and promoting HSC quiescence. These data also support an overall hypothesis that AHR dysregulation, and thus disruption of the quiescence-proliferation balance, through xenobiotic/chemotherapeutic exposure or genetic/epigenetic events, has an important role in the etiology and progression of hematopoietic disease. Much data also indicates that the regulation of AHR expression is a key rate-limiting element controlling downstream AHR signaling events in HSCs. Yet, virtually nothing is known about how this occurs or the identity of signals from HSCs or other cells that regulate this process. Here we will test the hypothesis that Ahr gene expression is regulated by HSC-intrinsic and -extrinsic factors, and this regulation is essential for the balance between HSC quiescence and proliferation. Using a combination of molecular and cell biology techniques and unique animal models, we will determine 1) if the presence of the AHR in bone marrow niche cells has a role in the regulation of Ahr expression in HSCs and/or control of HSC function, 2) if the down- regulation of Ahr is absolutely necessary for HSC to transit from quiescence to proliferation, and 3) the mechanism(s) responsible for Ahr down-regulation.
Science Code(s)/Area of Science(s) Primary: 17 - Stem Cell Biology and Cellular Differentiation
Publications See publications associated with this Grant.
Program Officer Leslie Reinlib
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