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

• 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
• 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

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）：本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因子，PKD活性减弱会导致年龄相关性骨质减少。我们发表的和初步的数据，以及其他人的数据表明，PKD活性是成骨细胞响应骨形态发生蛋白（BMP）的体外分化和矿化所必需的，并且在老年动物中，BMP-7的骨形成作用在体外和体内都存在抗性。最近推出的 具有PKD 1或PKD 2催化活性缺陷的小鼠模型使我们能够获得初步的体内数据，表明青春期PKD 1和PKD 2缺陷小鼠的骨矿物质密度与其年龄和性别匹配的同窝出生小鼠相比显著降低。我们现在将测试PKD 1和PKD 2缺陷小鼠的天然骨是否显示出骨矿物质密度降低，骨结构受损和年龄相关的骨质减少，与野生型对照组相比。我们还将确定这些PKD缺陷小鼠的骨密度降低是否是由于骨形成或骨吸收或两者的改变。这将使用来自这些PKD 1和PKD 2缺陷小鼠的培养的骨祖细胞来实现。我们将在年轻、中年和老年小鼠中使用DEXA和CT扫描来确定是否：1）较年轻的PKD缺陷小鼠的天然骨表现出减弱的矿物质含量和密度，如在较年长的野生型小鼠中观察到的，和2）BMP-7诱导的异位骨，其形成在较年长的小鼠中减弱，显示出在较年长的野生型小鼠中PKD的活化降低，以及PKD催化活性缺陷的年轻小鼠是否表现出类似于在老年野生型小鼠中所见的减弱的骨形成。成功的结果将提供PKD是完整动物环境中骨重建的关键决定因素的原则证据，并且与年龄相关的生长因子在体内激活PKD的能力降低对年龄相关性骨质疏松症具有重要影响。