BMP4 Dependent Stress Erythropoiesis Pathway in Short-term Radioprotection

描述（由申请人提供）：贫血是一种导致严重发病率和死亡率的衰弱性疾病。这是一种由多种病因引起的常见疾病，对生活质量有显著的负面影响。在临床上，治疗贫血的方法是提高血红蛋白水平，改善向组织的氧气输送。然而，最近的研究表明，贫血的主要治疗方法，输血治疗和重组红细胞生成素（Epo）治疗，本身可以引起病理。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损耗的细胞。这个过程被称为稳态红细胞生成。在应对贫血挑战方面，情况有所不同。组织缺氧引发一种生理反应，旨在增加向组织的氧气输送。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。这是一种髓外过程，发生在胎儿肝脏和成人脾脏和肝脏的发育过程中。应激性红细胞生成利用一种特殊的红细胞祖细胞群，它不同于稳态祖细胞，因为它们可以迅速产生大量的新红细胞。应激性红细胞生成受与稳态红细胞生成无关的信号调节。我们之前的工作发现了一个表现出干细胞特性的应激红细胞祖细胞群体。这些细胞可以被连续移植到受辐照的小鼠体内，在那里它们维持红细胞生成而不影响其他谱系，直到存活的干细胞可以重新填充小鼠。移植的应激红细胞祖细胞建立了一个持久的应激反应室，可以对随后的贫血挑战作出反应。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。在本提案中，我们概述了旨在了解调节未成熟应激红细胞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贫血新疗法的途径中的转变。在Aim 1中，我们将研究来自微环境的信号调节未成熟干细胞（如应激祖细胞）增殖的机制。巨噬细胞是应激红细胞微环境的关键组成部分。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微环境。在最后的目的中，我们将研究巨噬细胞产生的分化信号促进从扩增性应激红细胞祖细胞向分化性应激红细胞祖细胞转变的机制。

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.