A Role of the Ah Receptor in Hematopoiesis: Model Characterization

描述（由申请人提供）：人类暴露于多环芳烃和二恶英与淋巴瘤和白血病的发生有关。这些化学物质的作用是由基因调节蛋白，芳烃受体（AhR）介导的。小鼠中持续的AhR激活导致造血干细胞（HSC）的数量和功能改变。来自Ahr空等位基因（AhR-KO）小鼠的初步数据也提供了证据，表明AhR在HSC的调节中具有生理作用。总体假设是AhR失调在包括白血病在内的许多造血系统疾病中起作用。在这个提议中，我们将开始测试特定的假设，即AhR在HSC的自我更新和增殖中具有重要作用。为此，有必要进一步确定AhR-KO小鼠中HSC的表型和功能特征。使用这种小鼠模型和各种流式细胞术方法，我们将确定AhR-KO小鼠中的HSC是否具有体内高增殖率，并将鉴定表现出这种特征的特定表型定义的细胞群。我们还将确定这些细胞在造血应激条件下的多谱系发育潜力。在第二个目标中，我们将通过初次和连续移植评估来自AhR-KO小鼠的HSC用于多谱系重建的能力和动力学。公共卫生相关性：进一步了解调控HSC自我更新和分化的过程对于预防和治疗人类各种白血病和其他造血系统疾病至关重要。了解是什么调节了骨髓通常令人难以置信的再生能力，也对骨髓移植、自身免疫性疾病和可能与癌症治疗相关的骨髓衰竭具有临床意义。此外，这些事件与衰老过程和各种疾病密切相关，包括癌症，其发病率随年龄增长而增加。

DESCRIPTION (provided by applicant): Human exposures to polycyclic aromtic hydrocarbons and dioxins have been linked to the development of lymphomas and leukemias. The actions of these chemicals are mediated by a gene regulatory protein, the aryl hydrocarbon receptor (AhR). Persistent AhR activation in mice results in altered numbers and function of hematopoietic stem cells (HSCs). Preliminary data from Ahr null-allele (AhR-KO) mice also provides evidence to indicate that the AhR has a physiological role in the regulation of HSCs. The overall hypothesis is that AhR dysregulation plays a role in a number of hematopoietic disorders including leukemia. In this proposal we will begin to test the specific hypothesis that the AhR has an important role in the self-renewal and proliferation of HSCs. To do this, it is necessary to further define the phenotypic and functional characteristics of HSCs in AhR-KO mice. Using this mouse model and a variety of flow cytometry approaches, we will determine if HSCs in AhR-KO mice have high proliferation rates in vivo, and will identify the specific phenotypically-defined cell populations exhibiting this characteristic. We will also define the multi-lineage developmental potential of these cells under hematopoietic stress conditions. In a second aim, we will assess by primary and serial transplantation, the ability and kinetics of HSCs from AhR-KO mice for multi-lineage reconstitution. PUBLIC HEALTH RELEVANCE: The further understanding of the processes regulating HSC self-renewal 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 treatment. Furthermore, these events are intimately tied with the process of aging and a variety of diseases, including cancer, whose incidence increases with age.