Role of Protein Kinase D in Age-Related Osteopenia

蛋白激酶 D 在年龄相关性骨质减少中的作用

基本信息

批准号：
8700283
负责人：
MARTIN L ADAMO
金额：
$ 22.43万
依托单位：
UNIVERSITY OF TEXAS HLTH SCIENCE CENTER
依托单位国家：
美国
项目类别：
财政年份：
2013
资助国家：
美国
起止时间：
2013-07-15 至 2017-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8700283
关键词：
Age Age-Months Age-Related Bone Loss Animals Architecture Attenuated Biology Biology of Aging Bone Density Bone Marrow Bone Morphogenetic Proteins Bone Resorption Bone remodeling Cell Aging Cell Culture Techniques DEXA Data Disease Exhibits Female Future Gender Goals Growth Factor In Vitro Insulin-Like Growth Factor I Knock-in Mouse Laboratories Left Life Longevity Mediator of activation protein Methodology Minerals Molecular Mus Osteoblasts Osteoclasts Osteogenesis Osteopenia Osteoporosis Outcome Physiological Protein Isoforms Protein Kinase C Publishing Reporting Resistance Resistance development Risk Role Scanning Signal Pathway Signal Transduction Stromal Cells Structure Testing Therapeutic Wild Type Mouse X-Ray Computed Tomography age related aged attenuation base bone bone mass bone morphogenetic protein 7 cell age density design in vivo innovation male middle age mineralization molecular imaging mouse model osteoblast differentiation osteoprogenitor cell protein kinase D public health relevance response

项目摘要

DESCRIPTION (provided by applicant): The goal of this project is to establish that protein kinase D (PKD) is a major regulator of bone formation in vivo and that attenuation of PKD activity leads to age-related osteopenia. Our published and preliminary data, as well as that of others, indicated that PKD activity is required for the in vitro differentiation and mineralizationof osteoblasts in response to bone morphogenetic proteins (BMPs) and that in aged animals there is in vitro and in vivo resistance to the bone forming actions of BMP-7. The recent availability of mouse models with deficiency of PKD1 or PKD2 catalytic activity has allowed us to obtain preliminary in vivo data indicating that the bone mineral density of pubertal PKD1 and PKD2 deficient mice is significantly reduced compared to their age- and gender-matched littermates. We will now test whether native bone of PKD1 and PKD2 deficient mice show diminished bone mineral density, impaired bone architecture, and age-related osteopenia, compared to wild-type controls throughout the life span. We will also determine whether the reduction in bone mineral density in these PKD deficient mice is due to alternations in bone formation or in bone resorption or both. This will be accomplished using cultured osteoprogenitor cells from these PKD1 and PKD2 deficient mice. We will utilize DEXA and CT scanning in young, middle aged and old mice to determine whether: 1) Native bone of younger PKD deficient mice exhibits attenuated mineral content and density as is observed in older wild type mice, and 2) BMP-7 induced ectopic bone, whose formation is attenuated in older mice, shows reduced activation of PKD in the old wild type mice, and whether young mice deficient in PKD catalytic activity exhibit attenuated bone formation similar to that seen in older wild type mice. Successful outcomes will provide proof of principal that PKD is a critical determinant of bone remodeling in the intact animal setting, and that age related reduction in the ability of growth factors to activate PKD in vivo has major consequences for age-related osteoporosis.

描述（由申请人提供）：该项目的目的是确定蛋白激酶D（PKD）是体内骨形成的主要调节剂，而PKD活性的衰减会导致与年龄相关的骨质减少症。我们的发布和初步数据以及其他数据表明，对骨形态发生蛋白（BMP）的体外分化和成骨细胞的矿化需要PKD活性，并且在衰老的动物中，体外有体外和对BMP-7骨形成骨形成作用的体外耐药性。最近的可用性 PKD1或PKD2催化活性缺乏的小鼠模型使我们能够获得初步的体内数据，这表明与年龄和性别匹配的小窝点相比，青春期PKD1和PKD2缺乏小鼠的骨矿物质密度显着降低。现在，与整个生命周期中的野生型对照相比，我们将测试PKD1和PKD2缺乏小鼠的天然骨是否显示出骨矿物质密度降低，骨骼结构受损和与年龄相关的骨质减少症。我们还将确定这些不足小鼠中骨矿物质密度的降低是由于骨形成或骨吸收或两者兼而有之。这将使用来自这些PKD1和PKD2缺乏小鼠的培养的骨基因细胞来完成。 We will utilize DEXA and CT scanning in young, middle aged and old mice to determine whether: 1) Native bone of younger PKD deficient mice exhibits attenuated mineral content and density as is observed in older wild type mice, and 2) BMP-7 induced ectopic bone, whose formation is attenuated in older mice, shows reduced activation of PKD in the old wild type mice, and whether young mice deficient in PKD催化活性表现出减弱的骨形成，类似于较老的野生型小鼠。成功的结果将证明PKD是完整动物环境中骨骼重塑的关键决定因素，并且与年龄相关的生长因子在体内激活PKD的能力的降低对年龄相关的骨质疏松症具有重大影响。