Defining Estrogenic Regulation of Hematopoietic Stem Cell Formation and Function

描述（由申请人提供）：近几十年来，暴露于环境和饮食中破坏内分泌信号的物质急剧增加。虽然雌激素化合物对生殖系统功能的影响已经得到了很好的研究，但对其他器官，特别是造血系统的影响知之甚少。最终造血干细胞（HSCs）能够自我更新和分化，在个体的整个生命周期中产生各种成熟的血细胞谱系。由于遗传或获得性基因畸变，造血干细胞形成或分化的缺陷可导致骨髓衰竭和白血病。大多数参与HSC形成的基因在脊椎动物中是高度保守的，并且在成人中继续调节HSC的自我更新和分化。转录因子RUNX1是白血病染色体突变的常见靶标，在新生造血的所有位点都有表达，是哺乳动物HSC诱导所绝对需要的；Runx1在斑马鱼中表达保守。通过斑马鱼runx1表达修饰剂的化学筛选，主要研究人员确定了调节雌激素信号的化合物作为HSC形成的潜在调节剂。他们假设环境雌激素通过其雌激素功能对HSC的发展产生影响，并且暴露于这些化合物可能会产生长期的负面影响。他们的长期目标是了解环境雌激素影响造血的分子和细胞机制。本文的目的是表征环境雌激素暴露对斑马鱼和小鼠的HSC形成、增殖和功能在发育和损伤后恢复过程中的功能影响和脆弱期。核心假设是雌激素化合物在发育过程中多个不同时期影响HSC的形成，影响红细胞生成的原始波、血管造血生态位的形成和HSC的增殖。这一假设来源于他们的筛查结果和随后对不同时期对HSC形成的影响的评估。这项工作的基本原理是详细的

DESCRIPTION (provided by applicant): Exposure to substances in the environment and the diet that disrupt endocrine signaling has dramatically increased in recent decades. While the effects of estrogenic compounds on the function of the reproductive system has been well studied, much less is known about how other organs, particularly the hematopoietic system, are impacted. Definitive hematopoietic stem cells (HSCs) both self-renew and differentiate to produce each of the mature blood cell lineages for the entire lifespan of the individual. Defects in HSC formation or differentiation, as a result of inherited or acquired genetic aberrations, can lead to bone marrow failure and leukemia. Most genes involved in HSC formation are highly conserved across vertebrates, and continue to regulate HSC self-renewal and differentiation in the adult. The transcription factor RUNX1, a frequent target of chromosomal mutation in leukemia, is expressed in all sites of de novo hematopoiesis and is absolutely required for HSC induction in mammals; runx1 expression is conserved in zebra fish. Through a zebra fish chemical screen for modifiers of runx1 expression, the principal investigators identified compounds that modulate estrogen signaling as potential regulators of HSC formation. They hypothesize that environmental estrogens exert an effect on HSC development through their estrogenic function and that exposure to these compounds could have long-lasting negative effects. Their long-term goal is to understand the molecular and cellular mechanisms by which environmental estrogens affect hematopoiesis. The objective here is to characterize the functional implications and vulnerable periods of environmental estrogen exposure on HSC formation, proliferation and function during development and recovery after injury, in both zebra fish and mice. The central hypothesis is that estrogenic compounds impact HSC formation during multiple distinct periods during development, affecting the primitive wave of erythropoiesis, the formation of the vascular hematopoietic niche and HSC proliferation. This hypothesis has been derived from their screening results and subsequent evaluation of the different time periods contributing to HSC formation. The rationale for the work is that a detailed understanding of the impact of environmental estrogens on blood stem cell growth and proliferation will enable a deeper understanding of the consequences of exposure to environmental estrogenic compounds beyond their action on reproductive organs. In Specific Aim 1, they will investigate the effects of estrogen signaling on HSC specification and proliferation during hematopoietic development and recovery from injury in zebra fish. In particular, they will identify the cellular and molecular targets of estrogen action and the developmental stages during which the organism is particularly vulnerable to its effects. In Specific Aim 2, they will analyze the specific effects of xenoestrogens (bisphenol A), dietary phytoestrogens (genistein), and mycoestrogens (zearalenone) during HSC formation; they will demonstrate that these effects are mediated by specific activation of estrogen signaling. Using murine assays, they will examine how these compounds effect HSC function across vertebrate species. PUBLIC HEALTH RELEVANCE: Hematopoietic stem cells form the foundation of our blood and immune system; the formation and function of these cells are carefully controlled in the body. The proposed research will help to identify environmental factors that impact the birth and propagation of these stem cells. This work has great relevance for the identification of estrogenic compounds that lead to leukemia, and for recovery from bone marrow transplants.