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 红细胞在输送氧气以满足组织的代谢需求方面起着至关重要的作用。红系 发育发生在骨髓内，但当出血或红细胞破坏导致需要 增加红细胞生成（红细胞生成），脾脏可成为应激的次要部位 红细胞生成在骨髓中，成骨细胞谱系在支持造血干细胞中的作用 细胞和包括B淋巴细胞在内的造血谱系的分化现在已经很好地建立。最近 研究也扩大了成骨细胞谱系对支持红细胞生成的贡献， 成骨细胞是关键的红细胞调节激素促红细胞生成素（Epo）的潜在来源。我们有 一直对甲状旁腺激素受体（PTH 1 R）下游信号传导的作用感兴趣，PTH 1 R是一种G蛋白， 偶联受体，在成骨细胞中调节成骨细胞对红细胞生成的支持。在PTH 1 R缺乏的小鼠中， 在骨骼（PTH 1 R-OsxKO小鼠）中，我们发现脾脏中的红细胞显著减少。的机制 控制红系祖细胞和成红细胞从骨髓迁移到脾脏的细胞因子， 压力的时间在很大程度上是不确定的。由于这些小鼠携带成骨细胞特异性PTH 1 R缺失， 最可能的模型是骨髓红细胞生成在稳态下是足够的，但不能提供 在应激性红细胞生成期间向脾脏提供足够的红系祖细胞。然而，我们发现细胞 因此，PTH 1 R-OsxKO小鼠中受损的脾脏环境可能 也在工作。与成骨细胞调节红细胞生成的缺陷相一致，在初步研究中， 发现PTH 1 R-OsxKO小鼠骨中Epo mRNA的表达显著降低。我们假设 成骨细胞祖细胞中的PTH 1 R信号调节骨髓红系细胞发育和向成骨细胞的运输。 脾脏在本提案中，我们将系统地分析PTH 1 R-OsxKO小鼠的以下步骤：1）骨 红系祖细胞和成红细胞的骨髓定型、分化和增殖; 2）退出 骨髓成红细胞从骨髓进入外周循环; 3）循环的归巢 将红系祖细胞移植到脾脏，然后在脾脏内植入和扩增。 微环境拟议研究的完成将确定 PTH 1 R-OsxKO小鼠脾造血功能失调，并可能揭示其机制， 控制应激性红细胞生成以及进一步阐明成骨细胞在支持骨髓中的作用 红细胞生成