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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：
7493414
负责人：
Elizabeth G Sweeney
金额：
$ 5.04万
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/7493414
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 Disruption 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 Range Reverse Transcriptase Polymerase Chain Reaction Rheumatoid Arthritis Severities Signal Transduction Skeletal Development Skeletal system Stem Cell Development Stem cells Stromal Cells Testing Time Tissues Transgenes Transgenic Organisms Transplantation Week Wild Type Mouse cartilage matrix protein cell type congenic cytokine disease phenotype insight leukemia/lymphoma progenitor scaffold 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).

这一建议将表征软骨内成骨之间的联系，其中肥大的软骨是