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）：成人骨髓红细胞生成主要是稳态的，在整个成年过程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，情况却截然不同。此时，应激性红细胞生成占主导地位，会迅速产生大量新红细胞。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，应激性红细胞祖细胞特殊群体的快速扩张需要 BMP4 依赖性信号。与骨髓稳态祖细胞相比，这些祖细胞具有更大的潜力快速产生大量新红细胞。在本提案中，我们将通过利用骨髓移植后立即进行红细胞恢复的强大实验系统，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，这种恢复是由红系短期辐射防护细胞介导的，这些细胞利用 BMP4 依赖性应激红细胞生成途径。第一个目标是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 信号在脾脏应激红系祖细胞的规范和扩张中的作用。在第三个目标中，我们将研究Hedgehog、BMP4和缺氧对Scl、Gata2和Gata1的调节。这些研究将提供有关应激性红细胞生成调节的关键基本信息，可在此基础上开发治疗贫血的新疗法。公共卫生相关性：该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。这项工作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础信息。