BMP4 Dependent Stress Erythropoiesis Pathway in Short-term Radioprotection

短期辐射防护中 BMP4 依赖性应激红细胞生成途径

基本信息

批准号：
8850435
负责人：
ROBERT Frank PAULSON
金额：
$ 31.07万
依托单位：
PENNSYLVANIA STATE UNIVERSITY, THE
依托单位国家：
美国
项目类别：
财政年份：
2009
资助国家：
美国
起止时间：
2009-07-01 至 2018-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8850435
关键词：
Acute Adult Anemia BFU-E BMP4 Bone Marrow Cells Clinic Coupled Data Development Dinoprostone Enzymes Epigenetic Process Erinaceidae Erythrocytes Erythroid Erythroid Progenitor Cells Erythropoiesis Erythropoietin Etiology Exhibits Extramedullary Fetal Liver Future GDF15 gene Genes Health Hemoglobin concentration result Hypoxia Individual Liver Morbidity - disease rate Mus Output Oxygen Pathology Pathway interactions Patients Physiological Population Process Production Property Quality of life Radioprotection Recombinant Erythropoietin Signal Pathway Signal Transduction Spleen Spleen Development Stat5 protein Stem cells Stress Therapeutic Intervention Time Tissues Transfusion Transplantation Work base biological adaptation to stress design effective therapy improved macrophage mortality progenitor programs recombinant human erythropoietin research study response self-renewal smoothened signaling pathway stem cell population targeted treatment therapy design tissue oxygenation

Acute Adult Anemia BFU-E BMP4 Bone Marrow Cells Clinic Coupled Data Development Dinoprostone Enzymes Epigenetic Process Erinaceidae Erythrocytes Erythroid Erythroid Progenitor Cells Erythropoiesis Erythropoietin Etiology Exhibits Extramedullary Fetal Liver Future GDF15 gene Genes Health Hemoglobin concentration result Hypoxia Individual Liver Morbidity - disease rate Mus Output Oxygen Pathology Pathway interactions Patients Physiological Population Process Production Property Quality of life Radioprotection Recombinant Erythropoietin Signal Pathway Signal Transduction Spleen Spleen Development Stat5 protein Stem cells Stress Therapeutic Intervention Time Tissues Transfusion Transplantation Work base biological adaptation to stress design effective therapy improved macrophage mortality progenitor programs recombinant human erythropoietin research study response self-renewal smoothened signaling pathway stem cell population targeted treatment therapy design tissue oxygenation

展开

项目摘要

DESCRIPTION (provided by applicant): Anemia is a debilitating condition that causes significant morbidity and mortality. It is a common condition caused by multiple etiologies and has a significant negative impact on quality of life. In the clinic, treatments for anemia are designed to raise hemoglobin levels and improve oxygen delivery to the tissues. Recent work, however, suggests that the primary therapies for anemia, transfusion therapy and treatment with recombinant erythropoietin (Epo), can themselves cause pathology. These observations underscore the need to develop new, effective long term therapies to treat anemia. In healthy individuals, the bone marrow constantly generates new erythrocytes to replaced worn out cells. This process is referred to as steady state erythropoiesis. In response to anemic challenge, the situation is different. Tissue hypoxia initiates a physiological response designed to increase oxygen delivery to the tissues. At these times stress erythropoiesis predominates. Most of what we know about stress erythropoiesis comes from the study of murine stress erythropoiesis. It is an extramedullary process that takes place in the fetal liver during development and the adult spleen and liver. Stress erythropoiesis utilizes a specialized population of erythroid progenitors that are distinct from steady state progenitors in that they can rapidly generate large numbers of new erythrocytes. Stress erythropoiesis is regulated by signals not associated with steady state erythropoiesis. Our previous work identified a population of stress erythroid progenitors that exhibit stem cell properties. These cells could be serially transplanted into irradiated mice, where they maintained erythropoiesis without contribution to other lineages until surviving stem cells could repopulate the mouse. The transplanted stress erythroid progenitors establish a durable stress response compartment that can then respond to subsequent anemic challenges. Thus a better understanding of the mechanisms that regulate stress erythropoiesis will identify new targets for therapeutic intervention. In this proposal, we outline experiments designed to understand the mechanisms that regulate the expansion of immature stress erythroid progenitors and the signals that promote their differentiation as these regulatory points represent transitions in the pathway that could be exploited in the development of new therapies for anemia. In Aim 1, we will investigate the mechanism by which signals from the microenvironment regulate the expansion of immature stem cell like stress progenitors. Macrophages are key components of the stress erythroid microenvironment. In the second aim, we will examine how Epo alters the macrophage microenvironment by inhibiting the production of signals that promote expansion and self-renewal and activating signals that promote differentiation. In the final aim, we will examine the mechanism by which differentiation signals generated by macrophages promote the transition from amplifying stress erythroid progenitors to differentiating stress erythroid progenitors.

描述（由申请人提供）：贫血是一种令人衰弱的疾病，会导致明显的发病率和死亡率。这是由多种病因引起的常见条件，对生活质量产生了重大负面影响。在诊所中，贫血的治疗旨在提高血红蛋白水平并改善向组织的氧气递送。然而，最近的工作表明，重组红细胞生成素（EPO）的贫血，输血疗法和治疗的主要疗法本身会引起病理。这些观察结果强调了开发新的，有效的长期疗法以治疗贫血的必要性。在健康的个体中，骨髓不断产生新的红细胞以替换破旧的细胞。该过程称为稳态红细胞生成。为了应对贫血挑战，情况有所不同。组织缺氧引发了一种生理反应，旨在增加向组织的氧气递送。在这些时候，压力红细胞生成为主导。我们对压力红细胞生成的大多数知识都来自对鼠压力红细胞生成的研究。这是一种在发育期间在胎儿肝脏中发生的耗尽过程，成人脾脏和肝脏。压力红细胞生成利用了与稳态祖细胞不同的红骨祖细胞的专业人群，因为它们可以迅速产生大量的新红细胞。压力红细胞生成受到与稳态红细胞生成无关的信号的调节。我们以前的工作确定了表现出干细胞特性的一系列应力红细胞祖细胞。这些细胞可以连续移植到辐照的小鼠中，在那里它们保持红血病，而无需对其他谱系贡献，直到存活的干细胞可以重新填充小鼠为止。移植的应力红细胞祖细胞建立一个耐用的应力反应室，然后可以应对随后的贫血挑战。因此，更好地理解调节压力红细胞生成的机制将确定治疗干预的新目标。在该提案中，我们概述了旨在了解调节未成熟应激红系祖细胞扩张的机制，以及促进其分化的信号，因为这些调节点代表了途径中可以利用的途径中的过渡，这些途径可以利用贫血新疗法的发展。在AIM 1中，我们将研究微环境中信号调节未成熟干细胞（如应力祖细胞）的扩展的机制。巨噬细胞是应力红细胞微环境的关键组成部分。在第二个目标中，我们将研究EPO如何通过抑制信号的产生来改变巨噬细胞微环境，从而促进扩展和自我更新和激活促进分化的信号。在最终目的中，我们将研究巨噬细胞产生的分化信号促进从扩增压力粒子祖细胞到区分应力红细胞祖细胞的过渡。