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

BMP4 依赖性应激红细胞生成途径在短期 Radioprote 中的作用

• 批准号: 7730716
• 负责人: ROBERT Frank PAULSON
• 金额: $ 35.52万
• 依托单位: PENNSYLVANIA STATE UNIVERSITY, THE
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-07-01 至 2013-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7730716
• 关键词: Acute; Adult; Anemia; BMP4; Bone Marrow; Bone Marrow Cells; Bone Marrow Transplantation; Cells; Data; Defect; Development; Embryonic Development; Erinaceidae; Erythrocytes; Erythroid; Erythropoiesis; Family; Fetal Development; Fetal Liver; GDF15 gene; Generations; Growth Factor; Hematological Disease; Human; Hypoxia; Iron; Laboratories; Life; Mediating; Modeling; Mus; Mutant Strains Mice; Pathway interactions; Patients; Play; Population; Production; Radioprotection; Recovery; Regulation; Role; Signal Transduction; Spleen; Stress; System; Time; Transplantation; Up-Regulation; Work; absorption; design; information gathering; mutant; progenitor; public health relevance; research study; response; smoothened signaling pathway

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.

描述（由申请人提供）：成年骨髓红细胞生成主要是稳态的，在成年生活中不断产生新的红细胞。但是，在胎儿发育和对成年人急性贫血的反应过程中，情况大不相同。在这些时候，压力红细胞生成主要产生，这会迅速产生大量的新红细胞。关于调节人类压力红细胞生成的机制知之甚少。我的实验室利用鼠模型进行胁迫性红细胞生成，并证明在从急性贫血中恢复过程中，依赖BMP4依赖性信号是迅速扩张的胁迫粒红细胞祖细胞所必需的。这些祖细胞比骨髓稳态祖细胞具有更大的快速产生新红细胞的潜力。在此提案中，我们将通过利用强大的实验系统来进一步表征BMP4依赖性压力红细胞生成途径，该系统在骨髓移植后立即利用红细胞恢复。我们的初步数据表明，这种恢复是由红系短期辐射保护细胞介导的，该细胞使用BMP4依赖性应力红细胞生成途径。在第一个目标中，我们将检查在从骨髓移植中恢复过程中调节脾脏中BMP4表达的机制。在第二个目标中，我们将研究刺猬和BMP4信号在脾脏中应力红细胞祖细胞的规范和扩展中的作用。在第三个目标中，我们将研究刺猬，BMP4和缺氧的SCL，GATA2和GATA1的调节。这些研究将提供有关压力红细胞生成的调节的关键基本信息，这些信息可以建立在开发新疗法以治疗贫血的基础上。公共卫生相关性：该项目概述了旨在调查调节急需需求时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开发贫血和其他血液疾病的新疗法提供关键的基本信息。