Role of the Parathyroid Hormone Receptor in Osteoblast Support of Erythropoiesis

甲状旁腺激素受体在成骨细胞支持红细胞生成中的作用

• 批准号: 9696583
• 负责人: JOY Y WU
• 金额: $ 10万
• 依托单位: STANFORD UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-08-01 至 2019-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9696583
• 关键词: Abnormal Erythroblast; Adult; Anemia; B-Lymphocytes; Biology; Blood Cell Count; Blood Circulation; Bone Marrow; Cell Adhesion; Cells; Clinical; Cytometry; Data; Defect; Development; Endothelial Cells; Engraftment; Environment; Erythroblasts; Erythrocytes; Erythroid; Erythropoiesis; Erythropoietin; Event; Excision; Failure; Fluorescence-Activated Cell Sorting; Frequencies; G-Protein-Coupled Receptors; GTP-Binding Protein alpha Subunits, Gs; Growth Factor; Hematopoiesis; Hematopoietic; Hematopoietic stem cells; Hemorrhage; Homing; Hormones; Human; Immature B-Lymphocyte; Impairment; Lead; Light; Marrow; Messenger RNA; Metabolic; Modeling; Movement; Mus; Osteoblasts; Osteogenesis; Osteoporosis; Oxygen; PTH gene; Parabiosis; Parathyroid Hormone Receptor; Peripheral; Play; Population; Positioning Attribute; Production; Protein Deficiency; Proteins; Publishing; Receptor Signaling; Regulation; Reporting; Reticulocytes; Risk; Role; Signal Transduction; Site; Skeleton; Source; Spleen; Stress; Time; Tissues; VHL protein; Work; base; bone; bone loss; cytokine; innovation; interest; macrophage; migration; mouse model; novel; novel strategies; older men; osteoprogenitor cell; peripheral blood; progenitor; stem cell differentiation; trafficking

Project Summary Erythrocytes play a crucial role in the delivery of oxygen to meet the metabolic needs of tissues. Erythroid development occurs within the bone marrow, but when bleeding or erythrocyte destruction leads to a need for increased erythrocyte production (erythropoiesis), the spleen can become a secondary site for stress erythropoiesis. Within the bone marrow, the role of the osteoblast lineage in supporting hematopoietic stem cells and differentiation of hematopoietic lineages including B lymphocytes is now well established. Recent studies have expanded the contributions of the osteoblast lineage to the support of erythropoiesis as well, as osteoblasts are a potential source of the critical erythrocyte-regulating hormone erythropoietin (Epo). We have been interested in the role of signaling downstream of the parathyroid hormone receptor (PTH1R), a G protein- coupled receptor, in osteoblasts in regulating osteoblast support of erythropoiesis. In mice lacking PTH1R in the skeleton (PTH1R-OsxKO mice), we find a dramatic loss of erythrocytes in the spleen. The mechanisms that govern the migration of erythroid progenitors and erythroblasts from the bone marrow to the spleen in times of stress are largely undefined. Since these mice carry an osteoblast-specific deletion of PTH1R, the most likely model is that bone marrow erythropoiesis is sufficient at steady state, but unable to provide sufficient erythroid progenitors to the spleen during stress erythropoiesis. However, we find cells descended from osteoprogenitors in the spleen, therefore an impaired spleen environment in PTH1R-OsxKO mice may also be at work. Consistent with a defect in osteoblastic regulation of erythropoiesis, in preliminary studies we find a significant decrease in expression of Epo mRNA in bones of PTH1R-OsxKO mice. We hypothesize that PTH1R signaling in osteoblast progenitors regulates bone marrow erythroid development and trafficking to the spleen. In this proposal we will systematically analyze the following steps in PTH1R-OsxKO mice: 1) bone marrow commitment, differentiation and proliferation of erythroid progenitors and erythroblasts; 2) exit of marrow erythroblasts from the bone marrow to enter the peripheral circulation; 3) homing of circulating erythroid progenitors to the spleen, followed by engraftment and expansion within the splenic microenvironment. Together the accomplishment of the proposed studies will pinpoint the site(s) of dysregulation of spleen hematopoiesis in PTH1R-OsxKO mice, and may shed light upon the mechanisms that govern stress erythropoiesis as well as further clarifying a role for osteoblasts in the support of bone marrow erythropoiesis.

项目摘要 红细胞在氧气的递送中起着至关重要的作用，以满足组织的代谢需求。红细胞 发育发生在骨髓内，但是当出血或红细胞破坏会导致需要 增长了红细胞的产生（红细胞生成），脾脏可以成为压力的次要部位 红细胞生成。在骨髓中，成骨细胞谱系在支撑造血茎中的作用 现在已经确定了包括B淋巴细胞在内的造血谱系的细胞和分化。最近的 研究扩大了成骨细胞谱系对促红细胞生成的支持的贡献。 成骨细胞是临界红细胞调节激素促红细胞生成素（EPO）的潜在来源。我们有 对甲状旁腺激素受体（PTH1R）下游信号传导的作用感兴趣，G蛋白 耦合受体，在成骨细胞中调节成骨细胞对红细胞生成的支持。在缺乏pth1r的小鼠中 骨骼（pth1r-osxko小鼠），我们发现脾脏中的红细胞损失巨大。机制 控制着红细胞祖细胞和红细胞从骨髓到脾的迁移 压力的时间在很大程度上是不确定的。由于这些小鼠具有pth1r的成骨细胞特异性缺失，所以 最有可能的模型是，骨髓红细胞生成在稳态上足够，但无法提供 在压力红细胞生成期间，足够的红细胞祖细胞。但是，我们发现细胞下降 从脾脏中的骨基因生成剂，因此PTH1R-OSXKO小鼠的脾脏受损可能 也在工作。与促红细胞生成的成骨细胞调节缺陷一致，在初步研究中 发现PTH1R-OSXKO小鼠骨骼中EPO mRNA的表达显着降低。我们假设这一点 成骨细胞祖细胞中的PTH1R信号传导调节骨髓红细胞发育和运输到 脾。在此提案中，我们将系统地分析PTH1R-OSXKO小鼠中的以下步骤：1） 骨髓的承诺，分化和红细胞祖细胞的扩散； 2）退出 骨髓骨髓骨髓细胞进入周围循环； 3）循环 脾脏的红斑祖细胞，然后在脾内植入和膨胀 微环境。拟议研究的完成将共同指出 PTH1R-OSXKO小鼠中脾脏造血的失调，并可能阐明 控制压力红细胞生成，并进一步阐明成骨细胞在支撑骨髓中的作用 红细胞生成。