A Role of the Ah Receptor in Hematopoiesis: Model Characterization

描述(由申请人提供)：人类接触多环芳烃和二恶英与淋巴瘤和白血病的发展有关。这些化学物质的作用是由一种基因调节蛋白--芳香烃受体(AhR)介导的。小鼠体内持续的AhR激活会导致造血干细胞(HSCs)数量和功能的改变。来自AhR零等位基因(AhR-KO)小鼠的初步数据也提供了证据，表明AhR在HSCs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。在这个提案中，我们将开始检验AhR在造血干细胞自我更新和增殖中发挥重要作用的具体假设。为此，有必要进一步确定AhR-KO小鼠中HSCs的表型和功能特征。利用这一小鼠模型和多种流式细胞术方法，我们将确定AhR-KO小鼠体内的HSCs是否具有高增殖率，并将鉴定表现出这一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，我们将通过一次和连续移植，评估来自AhR-KO小鼠的HSCs进行多系重建的能力和动力学。公共卫生相关性：进一步了解调节HSC自我更新和分化的过程是预防和治疗人类各种白血病和其他血液系统疾病的基础。了解是什么调节了正常情况下令人难以置信的骨髓再生能力，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包括癌症在内的各种疾病密切相关，癌症的发病率随着年龄的增长而增加。

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.