CONTROL OF OSTEOGENESIS AND ADIPOGENESIS BY EBF

EBF 对成骨和脂肪生成的控制

基本信息

批准号：
7913053
负责人：
MARK C HOROWITZ
金额：
$ 30.79万
依托单位：
YALE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2007
资助国家：
美国
起止时间：
2007-09-01 至 2012-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7913053
关键词：
Adipocytes Adoptive Transfer Affect Age Alkaline Phosphatase Anabolic Agents Animals Architecture B cell differentiation B-Cell Development B-Lymphocytes Binding Biochemical Biochemistry Bone Development Bone Marrow Bone Marrow Cells Bone Morphogenetic Proteins Breeding Caliber Calvaria Cell Count Cell Culture Techniques Cell Lineage Cell surface Cells Characteristics Chondrocytes Collagen Type I Collagen Type X Cyclophosphamide DEXA DNA Binding Data Defect Development EMSA Employee Strikes Enzyme-Linked Immunosorbent Assay Epiphysial cartilage Exhibits Fatty acid glycerol esters Fluorescent Probes Fracture Gene Expression Gene Targeting Gene Transfer Genes Genetic Genetic Transcription Goals Hematopoietic Hematopoietic stem cells Histology Immune Implant In Situ Hybridization In Vitro LacZ Genes Lead Length Leptin Link Lipids Macrophage Colony-Stimulating Factor Marrow Measurement Measures Mesenchymal Mesenchymal Stem Cells Minerals Modeling Molecular Mus Mutant Strains Mice Neonatal Northern Blotting Oncogene Deregulation Osteoblasts Osteocalcin Osteoclasts Osteogenesis Osteoid Osteopenia Parathyroid Hormones Pathway interactions Phenotype Play Postmenopausal Osteoporosis Postpartum Period Property Prosthesis Proteins Rattus Retroviridae Reverse Transcriptase Polymerase Chain Reaction Role Series Serum Signal Pathway Signal Transduction Site Skeletal Development Source Spleen Staging Staining method Stains Stem cells Sternum Stromal Cells TNFSF11 gene Time Tissues Transplantation Weight Western Blotting Work adipocyte differentiation age related bone bone mass bone sialoprotein cell fate specification experience human PTH protein in vivo insight lipid biosynthesis long bone mRNA Expression mineralization mutant oil red O osteoblast differentiation osteogenic osteopontin precursor cell progenitor protein expression repaired research study response rib bone structure skeletal spine bone structure transcription factor

项目摘要

DESCRIPTION (provided by applicant): Osteoblasts, the cells that form bone, are mesenchymal in origin and like other mesenchymal lineages arise from pluripotential stem cells through a series of developmental transitions. The osteoblast developmental pathway is only partially understood, particularly in its early stages, where little is know about the cell fate decisions that lead to commitment to the osteoblast lineage. Adipocytes, the cells that produce fat, likely share a common early progenitor with osteoblasts, although little is known about the molecular control of this lineage bifurcation. Growing evidence indicates that transcription factors required for B lymphocyte development from hematopoietic stem cells are critical for proper skeletal development although as yet none have been implicated in osteoblast differentiation. We have discovered that Early B Cell Factor-1 (EBF-1), a transcription factor essential for B cell development, is expressed in osteoblasts and plays a critical role in controlling osteoblast development. EBF-1 deficient mice are runted, have increased bone formation parameters, and display a striking increase in numbers of osteoblasts. Remarkably, these mice also exhibit a dramatic expansion of adipocytes in the medullary canal of long bones. The central hypothesis underlying this proposal is that EBF-1 and its upstream regulatory and downstream target genes are critical for the control of osteoblast and adipocyte development. Our findings suggest that EBF-1 and EBF-1 deficient mice provide a unique opportunity to gain significant molecular insight into the development of these two lineages. The long-term goal of our work is to identify the mechanism(s) by which EBF-1 regulates osteogenesis and adipogenesis. The first step in achieving this goal is a careful analysis of the EBF-1 deficient mice at the histological, morphological, cellular, and molecular level, which will provide the information needed to formulate detailed molecular hypotheses for the role of EBF-1 in bone and fat cell development. Toward this end, we will pursue two Specific Aims: 1) To determine the bone phenotype of EBF-1 deficient mice; and 2) To characterize through a quantitative analysis the functional and molecular properties of EBF-1 deficient osteoblasts, osteoblast precursors, and adipocytes. We anticipate that these experiments will lead to new models for osteoblast development and hence for the potential to discover new anabolic pathways. Such information would be applicable to a wide variety of skeletal defects including age-related osteopenia, post-menopausal osteoporosis, fracture repair, and extended survival of prosthetic implants.

描述（由申请人提供）：成骨细胞，即形成骨骼的细胞，起源于间充质，并且像其他间充质谱系一样，由多能干细胞通过一系列发育转变产生。成骨细胞发育途径仅被部分了解，特别是在其早期阶段，人们对导致成骨细胞谱系定型的细胞命运决定知之甚少。脂肪细胞（产生脂肪的细胞）可能与成骨细胞共享一个共同的早期祖细胞，尽管人们对这种谱系分叉的分子控制知之甚少。越来越多的证据表明，造血干细胞发育成 B 淋巴细胞所需的转录因子对于骨骼的正常发育至关重要，尽管迄今为止尚未发现与成骨细胞分化有关的转录因子。我们发现早期 B 细胞因子-1 (EBF-1) 是 B 细胞发育必需的转录因子，在成骨细胞中表达，在控制成骨细胞发育中发挥着关键作用。 EBF-1缺陷小鼠身材矮小，骨形成参数增加，并且成骨细胞数量显着增加。值得注意的是，这些小鼠的长骨髓管中的脂肪细胞也出现了显着的扩张。该提议的核心假设是 EBF-1 及其上游调节基因和下游靶基因对于控制成骨细胞和脂肪细胞的发育至关重要。我们的研究结果表明 EBF-1 和 EBF-1 缺陷小鼠提供了独特的机会来获得对这两个谱系发育的重要分子洞察。我们工作的长期目标是确定 EBF-1 调节成骨和脂肪生成的机制。实现这一目标的第一步是在组织学、形态学、细胞和分子水平上对 EBF-1 缺陷小鼠进行仔细分析，这将为制定 EBF-1 在骨中作用的详细分子假设提供所需的信息。和脂肪细胞的发育。为此，我们将追求两个具体目标：1）确定EBF-1缺陷小鼠的骨表型； 2) 通过定量分析表征 EBF-1 缺陷的成骨细胞、成骨细胞前体和脂肪细胞的功能和分子特性。我们预计这些实验将带来成骨细胞发育的新模型，从而有可能发现新的合成代谢途径。这些信息适用于各种骨骼缺陷，包括与年龄相关的骨质减少、绝经后骨质疏松症、骨折修复和延长假体植入物的存活期。