The BMP4 dependent stress erythropoiesis pathway in short-term radioprotection

成人骨髓红细胞生成主要是稳态的，在整个过程中不断产生新的红细胞。 成人生活然而，在胎儿发育期间和对成人急性贫血的反应中， 戏剧性的不同。在这些时候，应激性红细胞生成占主导地位，其迅速产生大量 新生红细胞数量。关于应激性红细胞生成的调节机制， 人类我的实验室利用应激红细胞生成的小鼠模型，并已证明BMP 4 依赖性信号是应激红细胞特化群体快速扩增所必需的 在急性贫血的恢复过程中。这些祖细胞具有更大的潜力， 比骨髓稳态祖细胞产生大量新的红细胞。在本提案中，我们 将进一步表征BMP 4依赖性应激红细胞生成途径， 在骨髓移植后立即恢复红细胞系的实验系统 移植我们的初步数据表明，这种恢复是由红细胞短期辐射防护介导的。 细胞，其利用BMP 4依赖性应激红细胞生成途径。在第一个目标中，我们将研究 在骨髓移植恢复期间调节脾脏中BMP 4表达的机制。在 第二个目标，我们将研究Hedgehog和BMP 4信号在特化和扩增中的作用。 应激红细胞祖细胞的数量而在第三个目标中，我们将研究Scl，Gata 2的调节 Hedgehog、BMP 4和缺氧对Gata1的影响。这些研究将提供有关 调节应激红细胞生成，这可以建立在开发新的疗法来治疗贫血。

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.