Novel Growth Factor Regulators of Early Erythropoieisis

早期红细胞生成的新型生长因子调节剂

基本信息

批准号：
9916811
负责人：
Allon Moshe Klein
金额：
$ 63.78万
依托单位：
UNIV OF MASSACHUSETTS MED SCH WORCESTER
依托单位国家：
美国
项目类别：
财政年份：
2018
资助国家：
美国
起止时间：
2018-04-15 至 2022-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9916811
关键词：
Acute Address Adult Altitude Anemia Area BFU-E Biological Biological Process Blood Bone Marrow CFU-E Cells Chronic Clinical Colony-forming units Complex Development Diamond-Blackfan anemia Disease Dysmyelopoietic Syndromes Erythroblasts Erythrocytes Erythroid Erythropoiesis Erythropoietin Etiology Failure Genetic Transcription Glucocorticoids Growth Factor Growth Factor Receptors Hematopoietic Hematopoietic stem cells Hemorrhage Hormones Human Hypoxia IL17 gene In Vitro Inflammation Interleukin-17 Investigation Laboratories Life Ligands Mediating Molecular Mus Output Oxygen Pathway interactions Pharmaceutical Preparations Phase Physiology Population Process Publications Regulation Resistance Role Scheme Series Signal Pathway Signal Transduction Stress Structure Technology Testing Time Tissues Work base cytokine erythroid differentiation extracellular genome-wide hematopoietic hierarchy in vivo in vivo Model inhibitor/antagonist irradiation mouse genetics mouse model myelodysplastic anemia novel progenitor prospective receptor response single-cell RNA sequencing stem cell differentiation stem cells

项目摘要

Project Summary Erythropoiesis is the tightly regulated process by which red blood cells are formed from hematopoietic stem cells. Clinically, the only erythropoiesis-stimulating agents available for the treatment of anemia are the hormone erythropoietin (Epo), and glucocorticoids, leaving a gap where they are ineffective or contraindicated. In this inter-disciplinary project, we will use in vivo mouse models of erythropoietic stress, mouse genetics, and cutting-edge scRNA-Seq approaches to explore a largely uncharted area of non-Epo growth factor signaling and regulatory mechanisms in early erythroid progenitors. We will specifically focus on a potent new regulator that we have discovered: the cytokine IL-17, which we found stimulates both human and mouse erythroid progenitors, acting specifically through its receptor IL-17RA. We first identified IL17 as a novel erythropoietic regulator by overcoming an important technical challenge in studying erythropoiesis. Until recently, a major challenge in identifying novel erythropoietic regulators was a lack of information about the earliest stages of erythroid differentiation from stem cells. Early progenitors could only be defined retrospectively by their erythroid colony forming potential, namely “burst” forming units and colony forming units [BFU-e(rythroid) and CFU-e respectively]. FACS-based schemes could enrich for BFU-e/ CFU-e, but not purify them. We have now, for the first time, prospectively isolated distinct early stages of erythropoiesis, guided by novel single cell RNA sequencing (scRNA-Seq) technology and using FACS. We found that these newly defined progenitors express multiple growth factor receptors that were not previously recognized as erythroid regulators, and we identified an erythropoietic regulatory role for the first three such growth-factor receptors that we tested, including IL-17. Our project is structured around three aims: we will determine IL-17 pathway components involved in erythropoietic control, the cell biological and transcriptional responses to IL-17 in erythroid and non-erythroid blood progenitors, and finally, we will investigate the ability of IL-17RA activation to modulate erythropoiesis in mice in stress and disease, including anemic conditions. In the process, we will apply scRNA-seq technology to reveal the dynamic structure of the hematopoietic/erythropoietic hierarchies in physiology, disease and during stress, and the sensitivity of these stem and progenitor cell hierarchies to IL-17 signaling.

项目概要红细胞生成是造血干形成红细胞的严格调节过程临床上，唯一可用于治疗贫血的红细胞生成刺激剂是激素促红细胞生成素 (Epo) 和糖皮质激素，留下了无效或禁忌的空白。在这个跨学科项目中，我们将使用红细胞生成应激、小鼠遗传学和尖端的 scRNA-Seq 方法探索非 Epo 生长因子信号传导的很大程度上未知的领域我们将特别关注一种有效的新调节剂。我们发现：细胞因子 IL-17，我们发现它可以刺激人类和小鼠的红细胞祖细胞，通过其受体 IL-17RA 特异性发挥作用。我们克服了一项重要的技术挑战，首次将 IL17 确定为一种新型红细胞生成调节剂。直到最近，研究红细胞生成的一个主要挑战是识别新的红细胞生成调节因子。缺乏有关早期祖细胞分化为红细胞的最早阶段的信息。仅通过其红系集落形成潜力（即“爆发”形成单位）回顾性地定义集落形成单位[分别为 BFU-e（红细胞）和 CFU-e]。 CFU-e，但没有纯化它们，我们现在第一次前瞻性地分离了不同的早期阶段。红细胞生成，由新型单细胞 RNA 测序 (scRNA-Seq) 技术引导并使用 FACS。发现这些新定义的祖细胞表达以前没有的多种生长因子受体被认为是红细胞调节因子，我们确定了前三个这样的红细胞生成调节作用我们测试的生长因子受体，包括 IL-17。我们的项目围绕三个目标构建：我们将确定参与的 IL-17 通路成分红细胞生成控制，红细胞和非红细胞对 IL-17 的细胞生物学和转录反应血液祖细胞，最后，我们将研究 IL-17RA 激活调节红细胞生成的能力在此过程中，我们将应用 scRNA-seq 技术。揭示生理、疾病和造血/红细胞生成层次的动态结构压力期间，以及这些干细胞和祖细胞层次结构对 IL-17 信号传导的敏感性。