BMP4 Dependent Stress Erythropoiesis Pathway in Short-term Radioprotection

描述(由申请人提供)：贫血是一种使人衰弱的疾病，会导致严重的发病率和死亡率。它是一种由多种原因引起的常见疾病，对生活质量有显著的负面影响。在临床上，治疗贫血的目的是提高血红蛋白水平，改善对组织的氧气输送。然而，最近的研究表明，贫血的主要治疗方法，输血疗法和重组促红细胞生成素(EPO)治疗，本身就可以导致病理。这些观察结果强调了开发新的、有效的长期疗法来治疗贫血的必要性。在健康的个体中，骨髓不断地产生新的红细胞来取代破旧的细胞。这个过程被称为稳态红细胞生成。在应对疲软的挑战时，情况就不同了。组织缺氧启动了一种旨在增加组织氧气输送的生理反应。在这些时候，应激性红细胞生成占主导地位。我们对应激性红细胞生成的了解大多来自对小鼠应激性红细胞生成的研究。这是一个髓外过程，发生在发育过程中的胎儿肝脏和成人的脾和肝脏。应激性红细胞生成利用了一组特殊的红系祖细胞，这些红系祖细胞与稳定状态的红系祖细胞不同，因为它们可以迅速产生大量新的红细胞。应激性红细胞生成受与稳态红细胞生成无关的信号调控。我们之前的工作确定了一组具有干细胞特性的应激红系祖细胞。这些细胞可以连续移植到受辐射的小鼠体内，在那里它们维持红细胞生成，而不对其他血统做出贡献，直到存活的干细胞能够重新填充小鼠。移植的应激红系祖细胞建立了一个持久的应激反应隔间，然后可以对随后的贫血挑战做出反应。因此，更好地了解调节应激性红细胞生成的机制将为治疗干预确定新的靶点。在这项提案中，我们概述了旨在了解调节未成熟应激红系祖细胞扩张的机制和促进其分化的信号的实验，因为这些调节点代表了可用于开发新的贫血治疗方法的途径中的过渡。在目标1中，我们将研究来自微环境的信号调节未成熟干细胞样应激祖细胞扩张的机制。巨噬细胞是应激红系微环境的重要组成部分。在第二个目标中，我们将研究EPO如何通过抑制促进扩张和自我更新的信号的产生以及激活促进分化的信号来改变巨噬细胞的微环境。在最终目的中，我们将研究巨噬细胞产生的分化信号促进应激红系祖细胞从放大的应激红系祖细胞向分化的应激红系祖细胞转变的机制。

DESCRIPTION (provided by applicant): Anemia is a debilitating condition that causes significant morbidity and mortality. It is a common condition caused by multiple etiologies and has a significant negative impact on quality of life. In the clinic, treatments for anemia are designed to raise hemoglobin levels and improve oxygen delivery to the tissues. Recent work, however, suggests that the primary therapies for anemia, transfusion therapy and treatment with recombinant erythropoietin (Epo), can themselves cause pathology. These observations underscore the need to develop new, effective long term therapies to treat anemia. In healthy individuals, the bone marrow constantly generates new erythrocytes to replaced worn out cells. This process is referred to as steady state erythropoiesis. In response to anemic challenge, the situation is different. Tissue hypoxia initiates a physiological response designed to increase oxygen delivery to the tissues. At these times stress erythropoiesis predominates. Most of what we know about stress erythropoiesis comes from the study of murine stress erythropoiesis. It is an extramedullary process that takes place in the fetal liver during development and the adult spleen and liver. Stress erythropoiesis utilizes a specialized population of erythroid progenitors that are distinct from steady state progenitors in that they can rapidly generate large numbers of new erythrocytes. Stress erythropoiesis is regulated by signals not associated with steady state erythropoiesis. Our previous work identified a population of stress erythroid progenitors that exhibit stem cell properties. These cells could be serially transplanted into irradiated mice, where they maintained erythropoiesis without contribution to other lineages until surviving stem cells could repopulate the mouse. The transplanted stress erythroid progenitors establish a durable stress response compartment that can then respond to subsequent anemic challenges. Thus a better understanding of the mechanisms that regulate stress erythropoiesis will identify new targets for therapeutic intervention. In this proposal, we outline experiments designed to understand the mechanisms that regulate the expansion of immature stress erythroid progenitors and the signals that promote their differentiation as these regulatory points represent transitions in the pathway that could be exploited in the development of new therapies for anemia. In Aim 1, we will investigate the mechanism by which signals from the microenvironment regulate the expansion of immature stem cell like stress progenitors. Macrophages are key components of the stress erythroid microenvironment. In the second aim, we will examine how Epo alters the macrophage microenvironment by inhibiting the production of signals that promote expansion and self-renewal and activating signals that promote differentiation. In the final aim, we will examine the mechanism by which differentiation signals generated by macrophages promote the transition from amplifying stress erythroid progenitors to differentiating stress erythroid progenitors.