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Mechanistically linking skeletogenesis and hematopoiesis

骨骼发生和造血的机制连接

基本信息

批准号：
7546958
负责人：
Elizabeth G Sweeney
金额：
$ 5.2万
依托单位：
UNIVERSITY OF PENNSYLVANIA
依托单位国家：
美国
项目类别：
财政年份：
2006
资助国家：
美国
起止时间：
2006-12-01 至 2009-11-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7546958
关键词：
Aplastic Anemia Autoimmunity B-Lymphocytes Biological Assay Birth Bone Marrow Bone Marrow Involvement Bone Marrow Transplantation Cartilage Cells Chondrocytes Coculture Techniques Collagen Collagen Type X Data Defect Development Disease Dwarfism Elements Environment Epiphysial cartilage Exclusion Exhibits Failure Gene Silencing Generations Glycosaminoglycans Growth Growth Factor Hematopoiesis Hematopoietic Hematopoietic stem cells Heparan Sulfate Proteoglycan Hypocellular Bone Marrow Immune Immune System Diseases Immune system Immunity In Vitro Interleukin-3 Knockout Mice Lead Link Lymphocyte Function Lymphoid Tissue Malignant Neoplasms Marrow Metabolism Mus Mutation Neonatal Organ Osteoblasts Pancytopenia Perinatal Proteoglycan Reverse Transcriptase Polymerase Chain Reaction Rheumatoid Arthritis Severities Signal Transduction Skeletal Development Stem Cell Development Stem cells Stromal Cells Testing Time Tissues Transgenes Transgenic Organisms Transplantation Wild Type Mouse cartilage matrix protein cell type congenic cytokine disease phenotype insight leukemia/lymphoma progenitor scaffold skeletal skeletogenesis substantia spongiosa

项目摘要

This proposal will characterize the link between endochondral ossification, where hypertrophic cartilage is replaced by bone and marrow, and the development of a functional immune system. To do this, collagen X transgenic (Tg) and knock-out mice (KO) mice will be used since the disease phenotype involves growth plate defects, which lead to an altered marrow environment and aberrant hematopoiesis. It is proposed that collagen X and other matrix molecules, e.g. glycosaminoglycans and heparan sulfate proteoglycans, provides a structural network that sequesters cytokines in hypertrophic cartilage, and disruption of this network may cause inappropriate signaling at the growth plate/marrowjunction leading to an altered marrow environment and defective hematopoiesis. To test this, 1) The involvement of the bone marrow resident cells, e.g. stromal cells, hypertrophic cartilage, and/or osteoblasts, from the collagen X mice in the disease phenotype will be confirmed with bone marrow transplants, 2) Further, the collagen X mouse marrow environment will be assayed for support of hematopoiesis in vitro, function of lymphocytes will be tested, and the marrow resident cells will be assayed individually for the ability to support hematopoiesis. 3) Finally, a mechanism will be explored that links aberrant cytokine expression, due to decompartmentalization of the hypertrophic network, to altered hematopoiesis via real-time RT-PCR of growth plate and marrow tissue from collagen X mice. Resulting data may elucidate how a hematopoietic marrow is established, and which skeletal defects might contribute to marrow alterations and hematopoietic disorders. Understanding the relationship between skeletal development and hematopoiesis may reveal which skeletal defects contribute to marrow alterations, leading to hematopoietic disorders and impaired immunity, such as bone marrow failure and immune dysfunction (e.g. aplastic anemia, rheumatoid arthritis), autoimmunity, as well as certain cancers (e.g. leukemia, lymphoma).

这项建议将描述软骨内骨化，其中肥大的软骨，被骨骼和骨髓所取代，以及功能性免疫系统的发展。为此，胶原蛋白X 将使用转基因（Tg）和敲除小鼠（KO）小鼠，因为疾病表型涉及生长板缺陷，导致骨髓环境改变和异常造血。拟将胶原X和其它基质分子，例如糖胺聚糖和硫酸乙酰肝素蛋白聚糖，提供了一个结构网络，在肥大的软骨中隔离细胞因子，网络可能导致生长板/骨髓连接处的不适当信号传导，导致骨髓改变环境和造血缺陷。为了验证这一点，1）骨髓居民的参与细胞，例如基质细胞、肥大软骨和/或成骨细胞，来自疾病中的胶原X小鼠表型将通过骨髓移植来证实，2）此外，胶原X小鼠骨髓移植物将通过骨髓移植来证实。将测定环境对体外造血的支持，将检测淋巴细胞功能，并单独测定骨髓驻留细胞支持造血的能力。3)最后，将探索一种机制，该机制将异常细胞因子的表达联系起来，这是由于细胞的去部分化，通过生长板和骨髓组织的实时RT-PCR检测肥大网络对改变的造血作用从胶原X小鼠。结果数据可以阐明造血骨髓是如何建立的，骨骼缺陷可能导致骨髓改变和造血功能障碍。了解骨骼发育和造血之间的关系可能会揭示哪些骨骼缺陷导致骨髓改变，导致造血功能紊乱和免疫力受损，如骨髓衰竭和免疫功能障碍（例如再生障碍性贫血、类风湿性关节炎）、自身免疫，以及某些癌症（例如白血病、淋巴瘤）。