Signaling Pathway in Ah Receptor-Dependent Control of Hematopoietic Stem Cells

描述(申请人提供)：造血干细胞(HSCs)具有自我更新和分化为所有血系的能力。保持静止、自我更新、增殖和分化之间的平衡，正是为了在生物体的一生中以及在对压力、组织损伤和病原体的反应期间保持多谱系世代。尽管造血干细胞中这些过程的失调对人类健康有巨大的影响，但这种平衡是如何调节的还不是很清楚。最近的数据支持这一新的假设，即芳香烃受体(AhR)是HSCs的生理调节因子。这些数据支持AhR通过抑制过度或不必要的增殖和促进HSC静止而起到负调控作用的观点。虽然我们的实验室已经做了很多工作来了解HSC中AhR干扰的生物学机制，但我们还没有发现AhR调节的信号通路，这些信号通路定义了HSC的正常功能，并在AhR失调条件下的功能改变中发挥作用。我们假设Wnt和/或HIF信号通路在AhR介导的HSCs调控中起关键作用。我们还假设，HSCs中AhR表达的失调，通过破坏这些途径，导致氧化DNA损伤的积累，最终限制自我更新，导致过早衰老。结合分子和细胞生物学技术、独特的动物模型和信号通路分析，我们将确定HSC中AhR调节的信号通路，这些信号通路定义了AhR的功能，并可能在调节失调的条件下导致HSC衰老和造血系统疾病。

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) 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. While our lab has done much work to understand the biology associated with AhR disruption in HSCs, we have not yet identified AhR-regulated signaling pathways that define normal HSC function as well as play a role in altered function under conditions of AhR dysregulation. We hypothesize that the Wnt and/or HIF signaling pathways are critical for AhR-mediated regulation of HSCs. We also hypothesize that dysregulation of AhR expression in HSCs, through disruption of these pathways, results in accumulation of oxidative DNA damage that eventually restricts self-renewal and causes premature senescence. Using a combination of molecular and cell biology techniques, unique animal models, and signaling pathway analyses, we will determin AhR-regulated signaling pathways in HSCs that define AhR function and that may lead to, under conditions of dysregulation, to HSC senescence and hematopoietic disease.