SHP2 Regulation of the Plasticity of Bone Marrow Osterix+ Stroma

SHP2 对骨髓 Osterix 基质可塑性的调节

• 批准号: 10701128
• 负责人: Wentian Yang
• 金额: $ 10万
• 依托单位: RHODE ISLAND HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-09-22 至 2024-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10701128
• 关键词: Adipocytes; Adult; Affect; Age; B-Lymphocytes; Biology; Blood; Blood Cell Count; Blood Cells; Blood Circulation; Blood Vessels; Bone Marrow; Bone marrow failure; CD19 gene; CD34 gene; Cell Lineage; Cell Survival; Cells; Cellular biology; Characteristics; Common Lymphoid Progenitor; Data; Development; Embryo; Endothelium; Erythrocytes; Foundations; Frequencies; Genetic; Goals; Health; Hematological Disease; Hematopoiesis; Hematopoietic; Hematopoietic System; Hematopoietic stem cells; Homeostasis; Knowledge; Lymphocyte; Lymphoid; Lymphopoiesis; Megakaryocytes; Mesenchymal; Mesenchymal Differentiation; Modality; Molecular; Mus; Myelogenous; Myeloid Cells; Nature; Neonatal; Osteoblasts; Osteogenesis; Outcome Study; PTPN11 gene; PTPRC gene; Pericytes; Perinatal; Phenotype; Population; PubMed; Regulation; Reporter; Reporting; Role; SLAM family receptor; Skeletal Development; Sorting - Cell Movement; Stromal Cells; T-Lymphocyte; Testing; Text; Time; Tissues; United States National Library of Medicine; Work; Zinc Fingers; bone; cohort; granulocyte; hematopoietic differentiation; hematopoietic stem cell differentiation; innovation; leukemia; novel; novel marker; novel therapeutics; osteoblast differentiation; osteogenic; peripheral blood; postnatal; progenitor; promoter; skeletal; stem; stem cell survival; stem cells; transcription factor; tumor; tumorigenic; virtual

(PLEASE KEEP IN WORD, DO NOT PDF) This section must be no longer than 30 lines of text. It has been recently reported that the promoter of the master osteogenic transcription factor, OSTERIX, is active perinatally in hematopoietic cells, and that GFP+ blood cells circulate at low frequency in Tg(Osx-GFP:Cre) reporter mice. However, nothing is currently known about the significance of the hematopoietic cell-specific OSTERIX expression, and whether OSTERIX depletion might impact hematopoiesis. The work outlined in this proposal builds on the novel findings that Osx-GFP marks some BM and peripheral blood cells, and the number of these GFP+ blood cells decreases and disappears during development and maturation. Since OSTERIX expression and function in the hematopoietic system remain largely unknown, these findings together stimulate the hypothesis that OSTERIX is temporarily expressed in hematopoietic stem cells (HSCs) and that it is required for their survival, and/or lineage commitment and hematopoietic homeostasis. To test this novel hypothesis, we propose two specific Aims. In Aim 1, we will determine the dynamics of OSTERIX expression by quantifying GFP+ blood cells in embryonic, postnatal, and adult Tg(Osx-GFP:Cre) mice using FACS analysis. In Aim 2, we will determine the impact of OSTERIX depletion in HSCs on cell survival and multilineage differentiation using Tg(Mx1-Cre;Osxfx/fx) upon p(I)(C) induction. This innovative study will result in the first-ever description of OSTERIX’s regulatory role in the hematopoietic system and provide foundational information on the effect of OSTERIX dysregulation in blood. Successful completion of the work proposed will have a significant impact on our understanding of the hematopoietic regulation by OSTERIX and advance our knowledge about OSTERIX in the extraskeletal tissues.

（请以 WORD 形式保存，请勿以 PDF 形式保存）此部分的文本长度不得超过 30 行。 最近有报道称，主成骨转录因子 OSTERIX 的启动子在围产期在造血细胞中活跃，并且 GFP+ 血细胞在 Tg(Osx-GFP:Cre) 报告小鼠中以低频率循环。然而，目前对于造血细胞特异性 OSTERIX 表达的意义以及 OSTERIX 消耗是否会影响造血功能尚不清楚。该提案中概述的工作建立在以下新发现的基础上：Osx-GFP 标记了一些 BM 和外周血细胞，并且这些 GFP+ 血细胞的数量在发育和成熟过程中减少并消失。由于 OSTERIX 在造血系统中的表达和功能仍然很大程度上未知，这些发现共同刺激了这样的假设：OSTERIX 在造血干细胞 (HSC) 中暂时表达，并且它是造血干细胞生存和/或谱系定型和造血稳态所必需的。为了检验这个新假设，我们提出了两个具体目标。在目标 1 中，我们将使用 FACS 分析对胚胎、出生后和成年 Tg(Osx-GFP:Cre) 小鼠中的 GFP+ 血细胞进行定量，从而确定 OSTERIX 表达的动态。在目标 2 中，我们将在 p(I)(C) 诱导时使用 Tg(Mx1-Cre;Osxfx/fx) 确定 HSC 中 OSTERIX 消耗对细胞存活和多谱系分化的影响。这项创新研究将首次描述 OSTERIX 在造血系统中的调节作用，并提供有关 OSTERIX 血液调节失调影响的基础信息。成功完成拟议的工作将对我们对 OSTERIX 造血调节的理解产生重大影响，并增进我们对 OSTERIX 在骨骼外组织中的了解。