Role of the BMP4 Dependent Stress Erythropoiesis Pathway in Short-Term Radioprote

描述(申请人提供)：成人骨髓红细胞生成主要是动态平衡，在成人一生中不断产生新的红细胞。然而，在胎儿发育期间和成人对急性贫血的反应中，情况截然不同。在这些时候，应激性红细胞生成占主导地位，迅速产生大量新的红细胞。人们对调节人类应激性红细胞生成的机制知之甚少。我的实验室利用小鼠的应激性红细胞生成模型，证明了BMP4依赖的信号是应激性红系祖细胞在急性贫血恢复过程中迅速扩张所必需的。这些祖细胞比骨髓稳定状态的祖细胞具有更大的潜力快速产生大量新的红细胞。在这项建议中，我们将利用一个强大的实验系统，利用骨髓移植后立即恢复红系的强大实验系统，进一步表征BMP4依赖的应激性红细胞生成途径。我们的初步数据显示，这种恢复是由红系短期放射防护细胞介导的，这种细胞利用BMP4依赖的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过程中调节脾BMP4表达的机制。在第二个目标中，我们将研究Hedgehog和BMP4信号在脾中应激红系祖细胞的指定和扩张中的作用。而在第三个目标中，我们将研究Hedgehog、BMP4和低氧对SC1、GATA2和GATA1的调节。这些研究将提供关于应激性红细胞生成调节的关键基本信息，这些信息可以被建立在此基础上开发治疗贫血的新疗法。与公共卫生相关：该项目概述了旨在调查在紧急需要时调节新红细胞快速产生的机制的实验。从这项工作中收集的信息将为贫血和其他血液疾病的新疗法的开发提供关键的基本信息。

DESCRIPTION (provided by applicant): 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. PUBLIC HEALTH RELEVANCE: This project outlines experiments designed to investigate the mechanisms that regulate the rapid production of new red blood cells at times of acute need. The information gathered from this work will provide key basic information for the development of new therapies for anemia and other blood diseases.