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

描述（由申请人提供）：成人骨髓红细胞生成主要是体内平衡的，在整个成人生活中不断产生新的红细胞。然而，在胎儿发育期间和对成人急性贫血的反应情况是截然不同的。在这些时候，应激性红细胞生成占主导地位，它迅速产生大量的新红细胞。对人类应激性红细胞生成的调节机制知之甚少。我的实验室利用小鼠模型进行应激性红细胞生成，并证明在急性贫血恢复过程中，BMP4依赖信号是应激性红细胞祖细胞特殊种群快速扩张所必需的。与骨髓稳态祖细胞相比，这些祖细胞具有快速产生大量新红细胞的更大潜力。在本研究中，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的红细胞，进一步表征BMP4依赖性应激红细胞生成途径。我们的初步数据表明，这种恢复是由红细胞短期放射保护细胞介导的，它利用BMP4依赖性应激红细胞生成途径。在第一个目标中，我们将研究骨髓移植恢复过程中脾脏中BMP4表达的调节机制。在第二个目标中，我们将研究Hedgehog和BMP4信号在脾脏中应激红细胞祖细胞的特异和扩增中的作用。而在第三个目标中，我们将研究Hedgehog、BMP4和缺氧对Scl、Gata2和Gata1的调控。这些研究将为研究应激性红细胞生成的调控提供关键的基础信息，为开发治疗贫血的新疗法奠定基础。公共卫生相关性：本项目概述了旨在研究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础信息。

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.