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Notch Signaling and Bone Formation

Notch信号传导和骨形成

基本信息

批准号：
9791913
负责人：
Fanxin Long
金额：
$ 31.8万
依托单位：
CHILDREN'S HOSP OF PHILADELPHIA
依托单位国家：
美国
项目类别：
财政年份：
2018
资助国家：
美国
起止时间：
2018-09-25 至 2019-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9791913
关键词：
Notch Signaling Bone Formation

项目摘要

DESCRIPTION (provided by applicant): A fundamental understanding of the molecular mechanism governing osteoblast differentiation is essential for developing novel bone anabolic therapeutics. Physiological Notch signaling has emerged as a critical suppressive mechanism for osteoblast differentiation to ensure a proper pool of mesenchymal progenitors necessary for long-term bone homeostasis. Hyperactivation of NOTCH2 has recently been discover to cause Hajdu-Cheney syndrome (HCS) characterized by childhood osteoporosis, acroosteolysis and wormian bones. Where or not osteoblast or osteoclast defects are the primary cause for the disease has not been established. Moreover, an effective treatment for the disease is currently lacking. Elucidating the cellular basis for the disease and the relationship between NOTCH and other regulators of bone physiology will provide the basis for a rational design of therapeutics. I the current proposal, we test the hypothesis that suppression of osteoblast differentiation by hyperactive NOTCH2 is primarily responsible for HCS, and that stimulation of the bone anabolic WNT pathway may alleviate the bone defects associated with the disease. We further investigate the biochemical basis for the functional antagonism between NOTCH and WNT signaling. Overall, successful completion of this project is expected to provide novel mechanistic insights about the pathogenesis of HCS, and may open new avenues for effective treatments of the disease.

描述（由申请人提供）：对控制成骨细胞分化的分子机制的基本理解对于开发新的骨合成代谢疗法至关重要。生理Notch信号传导已成为成骨细胞分化的关键抑制机制，以确保长期骨稳态所需的适当的间充质祖细胞库。最近发现NOTCH 2的过度活化导致Hajdu-Cheney综合征（HCS），其特征在于儿童骨质疏松症、肢端骨质溶解和蠕虫骨。成骨细胞或破骨细胞缺陷是否是该疾病的主要原因尚未确定。此外，目前还缺乏有效的治疗方法。阐明该疾病的细胞基础以及NOTCH与其他骨生理调节因子之间的关系将为合理设计治疗方法提供基础。在目前的提议中，我们测试了这样的假设，即过度活跃的NOTCH 2抑制成骨细胞分化是HCS的主要原因，并且骨合成代谢WNT途径的刺激可以减轻与该疾病相关的骨缺损。我们进一步研究了NOTCH和WNT信号传导之间的功能性拮抗作用的生物化学基础。总的来说，该项目的成功完成有望为HCS的发病机制提供新的机制见解，并可能为有效治疗该疾病开辟新的途径。