The BMP4 dependent stress erythropoiesis pathway in short-term radioprotection

成人骨髓的红细胞生成主要是动态平衡的，始终不断地产生新的红细胞。 成年人的生活。然而，在胎儿发育期间和成人对急性贫血的反应中，情况是 截然不同。在这些时候，应激性红细胞生成占主导地位，这会迅速产生大量 新的红细胞数量。目前对应激性红细胞生成的调节机制知之甚少。 人类。我的实验室利用小鼠的应激性红细胞生成模型，并证明了BMP4 应激性红系特殊人群的快速扩张需要依赖信号 在急性贫血恢复过程中的祖细胞。这些祖先有更大的潜力迅速 比骨髓稳定状态的祖细胞产生大量新的红血球。在这份提案中，我们 将进一步表征BMP4依赖的应激红细胞生成途径 在紧接骨髓后的一段时间内利用红系恢复的实验系统 移植。我们的初步数据显示，这种恢复是由红系短期辐射防护所介导的。 利用BMP4依赖的应激红细胞生成途径的细胞。在第一个目标中，我们将研究 骨髓移植恢复过程中调节脾BMP4表达的机制。在……里面 第二个目标，我们将研究Hedgehog和BMP4信号在规范和扩展中的作用 脾中红系祖细胞的应激状态。在第三个目标中，我们将研究scl、gata2的监管。 Hedgehog、BMP4和低氧诱导的GATA1。这些研究将提供有关以下方面的关键基本信息 调节应激性红细胞生成，这可以建立在此基础上开发治疗贫血的新疗法。

Adult bone marrow erythropoiesis is primarily homeostatic, constantly producing new erythrocytes throughout adult life. However, during fetal development and in response to acute anemia in adults the situation is dramatically different. At these times stress erythropoiesis predominates, which rapidly produces large numbers of new erythrocytes. Little is known about the mechanisms that regulate stress erythropoiesis in humans. My laboratory utilizes a murine model for stress erythropoiesis and has demonstrated that BMP4 dependent signals are required for the rapid expansion of a specialized population of stress erythroid progenitors during the recovery from acute anemia. These progenitors have greater potential to rapidly generate large numbers of new erythrocytes than bone marrow steady state progenitors. In this proposal we will further characterize the BMP4 dependent stress erythropoiesis pathway by taking advantage of a robust experimental system that utilizes erythroid recovery during the period immediately following bone marrow transplant. Our preliminary data show that this recovery is mediated by erythroid short-term radioprotective cells, which utilize the BMP4 dependent stress erythropoiesis pathway. In the first aim, we will examine the mechanisms that regulate BMP4 expression in the spleen during the recovery from bone marrow transplant. In the second aim, we will examine the role of Hedgehog and BMP4 signaling in the specification and expansion of stress erythroid progenitors in the spleen. While in the third aim, we will examine the regulation of Scl, Gata2 and Gata1 by Hedgehog, BMP4 and hypoxia. These studies will provide key basic information concerning the regulation of stress erythropoiesis, which can be built upon to develop new therapies to treat anemia.