Mechanistically linking skeletogenesis and hematopoiesis

骨骼发生和造血的机制连接

• 批准号: 7223094
• 负责人: Elizabeth G Sweeney
• 金额: $ 4.88万
• 依托单位: UNIVERSITY OF PENNSYLVANIA
• 依托单位国家: 美国
• 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/7223094
• 关键词: bone marrow; cartilage; collagen; cytokine; hematopoiesis; lead

DESCRIPTION (provided by applicant): 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/marrow junction 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).

描述（由申请人提供）：该提案将描述软骨内骨化（肥大软骨被骨骼和骨髓取代）与功能性免疫系统发育之间的联系。为此，将使用胶原蛋白 X 转基因 (Tg) 和基因敲除小鼠 (KO) 小鼠，因为该疾病表型涉及生长板缺陷，从而导致骨髓环境改变和造血异常。建议胶原蛋白 X 和其他基质分子，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，将细胞因子隔离在肥大软骨中，该网络的破坏可能会导致生长板/骨髓连接处的不适当信号传导，从而导致骨髓环境改变和造血缺陷。为了测试这一点，1）骨髓驻留细胞的参与，例如骨髓细胞。来自疾病表型中的胶原蛋白 X 小鼠的基质细胞、肥大软骨和/或成骨细胞将通过骨髓移植得到证实，2) 此外，将测定胶原蛋白 X 小鼠骨髓环境以支持体外造血、功能将测试淋巴细胞，并单独检测骨髓驻留细胞支持造血的能力。 3）最后，将通过对胶原X小鼠的生长板和骨髓组织进行实时RT-PCR，探索一种机制，将由于肥大网络的去区室化而导致的异常细胞因子表达与造血功能改变联系起来。由此产生的数据可以阐明造血骨髓是如何建立的，以及哪些骨骼缺陷可能导致骨髓改变和造血障碍。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会导致骨髓改变，从而导致造血障碍和免疫力受损，例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）。