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Purinergic Regulation of Bone Metabolism

Purinergic Regulation of Bone Metabolism
骨代谢的嘌呤能调节
批准号:
8698897
负责人:
BRUCE Neil CRONSTEIN
金额:
$13.03万
依托单位国家:
美国
项目类别:
财政年份:
2013
资助国家:
美国
项目状态:
已结题
起止时间:
2013-09-18 至 2015-03-31

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中文摘要
翻译
嘌呤核苷腺苷调节心率等生理功能
英文摘要
The purine nucleoside adenosine regulates such physiologic functions as heart rate, vasodilation and inflammation and receptors for adenosine have been targeted for such diverse conditions as Parkinson's Disease and, indirectly, Rheumatoid Arthritis. Few studies have addressed the role of adenosine and its receptors in bone metabolism despite clear demonstrations of bony pathology in children with marked elevations in adenosine levels due to adenosine deaminase deficiency. We had previously observed that adenosine A1 receptors regulate the stimulated formation of multinucleated giant cells by cultured human peripheral blood monocytes and therefore determined whether adenosine A1 receptors also regulated formation of osteoclasts, a related form of multinucleated giant cell. We were surprised to find, in preliminary studies, that either blockade or knockout of adenosine receptors prevents osteoclast formation in vitro. Moreover, adenosine A1 receptor knockout mice have increased bone formation in vivo and adenosine receptor blockade blocks bone loss in ovariectomized mice. Preliminary studies further demonstrate that blockade of adenosine A1 receptors in vitro alters signaling events required for osteoclastogenesis. We propose four aims to confirm and expand on our preliminary findings. In the first aim we will examine the role of adenosine and adenosine A1 receptors in osteoclast function and bone remodeling and confirm and expand on our preliminary studies. The second aim is to determine the biochemical basis for adenosine generation during bone remodeling using animals deficient in the enzymes that convert extracellular adenine nucleotides to adenosine (NPP-1, TNAP, CD39 and CD73). The third aim is to dissect the mechanism by which adenosine A1 receptors modulate the formation and function of osteoclasts in vitro using a combination of molecular techniques and inhibitors of signaling enzymes. The demonstration that adenosine A1 receptors play a critical role in regulating the formation and function of osteoclasts suggests a novel therapeutic target for the treatment of disorders characterized by osteoclast-mediated bone resorption. One of the most pressing public health problems for the aging population is the increasing fragility and brittleness of bones, osteoporosis; brittle and de-mineralized bones are much more susceptible to fractures which are a major problem for the elderly. We have discovered that adenosine, a substance which is present in almost all bodily fluids, can bind to a receptor which is critical for formation and function of osteoclasts, the cells that break down bone. We propose to investigate the role of these adenosine receptors in regulating bone remodeling and the mechanism by which adenosine and its receptor modulate osteoclast function. The studies proposed here are directly relevant to human disease and may lead to the rapid development of new therapies for the treatment and prevention of osteoporosis and the resulting susceptibility to fractures that is so common in the elderly.¿
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Clinical and Translational Science Award
Engineering Personalized Devices for Craniomaxillofacial Defects
  • 批准号:
    10116988
  • 项目类别:
  • 资助金额:
    $38.58万
  • 财政年份:
    2019
  • 负责人:
    BRUCE Neil CRONSTEIN
  • 依托单位:
Clinical and Translational Science Award
Clinical and Translational Science Award
国内基金
海外基金
鼠伤寒沙门菌5'-nucleotidase在致病过程中的作用机制研究
  • 批准号:
    --
  • 项目类别:
    --
  • 资助金额:
    50万元
  • 批准年份:
    2023
  • 负责人:
    廖成水
  • 依托单位: