SHP2 Regulation of the Plasticity of Bone Marrow Osterix+ Stroma

SHP2 对骨髓 Osterix 基质可塑性的调节

基本信息

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
项目类别：
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

项目摘要

(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.

（请保持言语，不要pdf）本节必须不超过30行文本。最近有报道称，主成骨转录因子Osterix的启动子在造血细胞中围绕围产期活性，而GFP+血细胞在TG（OSX-GFP：CRE）报告的低频中以低频循环。然而，目前尚无关于造血细胞特异性卵形表达的重要性，以及奥斯特质消耗是否可能影响造血。该提案中概述的工作建立在新的发现中，即OSX-GFP标志着一些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和消失。由于造血系统中的Osterix表达和功能在很大程度上未知，因此这些发现共同刺激了Osterix在造血干细胞（HSC）中暂时表达的假设，并且它们的生存和/或谱系投入和造血稳态是必需的。为了检验这个新的假设，我们提出了两个具体目标。在AIM 1中，我们将使用FACS分析中量化胚胎，产后和成人TG（OSX-GFP：CRE）小鼠中的GFP+血细胞的动力学来确定Osterix表达的动力学。在AIM 2中，我们将使用TG（MX1-CRE; OSXFX/FX）对P（i）（c）诱导的HSC中Osterix耗竭对细胞存活和多曲线分化的影响。这项创新的研究将导致对Osterix在造血系统中的调节作用的第一个描述，并提供有关Osterix功能障碍在血液中的影响的基本信息。成功完成提议的工作将对我们对造血调节的理解产生重大影响，并促进我们对骨架外组织中的卵巢的了解。