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: 8588684
• 负责人: MARTIN L ADAMO
• 金额: $ 18.69万
• 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 2015-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8588684
• 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(申请人提供)：这个项目的目标是确定蛋白激酶D(PKD)是体内骨形成的主要调节因子，并且PKD活性的减弱会导致年龄相关性骨量减少。我们发表的和其他人的初步数据表明，在成骨细胞对骨形态发生蛋白(BMP)的体外分化和矿化过程中，PKD活性是必需的，在老年动物中，BMP-7在体外和体内对BMP-7的成骨作用存在抵抗。最近推出的 缺乏PKD1或PKD2催化活性的小鼠模型使我们能够获得初步的活体数据，表明青春期PKD1和PKD2缺陷小鼠的骨密度比年龄和性别匹配的小鼠显著降低。现在，我们将测试与野生型对照相比，PKD1和PKD2缺陷小鼠的天然骨是否表现出骨密度降低，骨结构受损，以及与年龄相关的骨量减少。我们还将确定这些PKD缺陷小鼠的骨密度降低是由于骨形成或骨吸收的变化，还是两者兼而有之。这将使用这些PKD1和PKD2缺陷小鼠的培养骨祖细胞来完成。我们将利用年轻、中年和老年小鼠的DEXA和CT扫描来确定：1)与老年野生型小鼠一样，年轻PKD缺陷小鼠的固有骨显示出矿物质含量和密度降低，2)BMP-7诱导的异位骨，其形成在老年野生型小鼠中有所减弱，显示PKD活性降低，以及PKD催化活性缺乏的年轻小鼠是否表现出与老年野生型小鼠相似的骨形成减弱。成功的结果将提供基本的证据，证明在完整的动物环境中，PKD是骨重建的关键决定因素，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后果。