Regulation of Skeletal Development and Mechanosensitivity by the α2δ1 Auxiliary Voltage Sensitive Calcium Channel Subunit

α2β1 辅助电压敏感钙通道亚基对骨骼发育和机械敏感性的调节

基本信息

批准号：
10402558
负责人：
Christian Stephen Wright
金额：
$ 3.43万
依托单位：
INDIANA UNIV-PURDUE UNIV AT INDIANAPOLIS
依托单位国家：
美国
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-05-01 至 2022-01-31
项目状态：
已结题

项目摘要

PROJECT SUMMARY/ABSTRACT The skeleton is highly sensitive to mechanical loading and unloading. Skeletal unloading increases bone marrow adiposity and accelerates the loss of bone quantity and quality. Conversely, skeletal loading decreases bone marrow adiposity and increases skeletal integrity. While this beneficial effect of skeletal loading is well- known, the specific cell types and the molecular mechanisms contributing to these effects are unclear. Preliminary data show that global deletion of the auxiliary α2δ1 voltage-sensitive calcium channel (VSCC) subunit results in osteopenia, impairing skeletal development, decreasing bone mass and bone formation, and increasing adiposity. As several cell types regulate bone formation and responses to skeletal loading, we hypothesize that the impaired activity of either osteocytes and/or bone marrow mesenchymal stem cells (MSCs) contribute to the decline in bone formation seen in global α2δ1 knockout mice. Thus, the proposed studies will examine the cell-specific mechanisms by which the auxiliary α2δ1 subunit regulates skeletal development and anabolic responses to loading. Using transgenic mouse models, α2δ1 will be selectively deleted in osteocytes and the limb-bud mesenchyme. Additionally, treatment with the neuropathic pain drug gabapentin, which binds α2δ1 will determine SA1) If deletion of α2δ1 in osteocytes or chronic GBP treatment impairs basal or load-induced bone formation with resultant loss in bone quality, and SA2) If deletion of α2δ1 in mesenchymal progenitors or chronic GBP treatment influences skeletal development, bone formation, and bone marrow adipogenesis. Additionally, Dr. Wright will conduct complementary RNA sequencing analyses and in vitro work to support in vivo results. Dr. Wright is a nutritional musculoskeletal scientist with considerable expertise in clinical dietary interventions, analytical analyses, and animal research whose long- term career goal is to become a NIH-funded, tenured faculty member who conducts innovative, translational musculoskeletal research. Dr. Wright is currently obtaining advanced training in molecular biology and animal modeling to complement his clinical background and develop the technical expertise needed to accomplish his career goals. Dr. Wright and his mentoring committee have developed a comprehensive training plan and research proposal that will build upon his previous research experience, and further expand his skills in basic biological research. Dr. Wright's primary training objectives include 1) Participating in professional development events; 2) Taking advanced didactic training courses; 3) Acquiring translational biomolecular research experience; 4) Learning new experimental techniques; and 5) Enhancing writing abilities. Collectively, these activities will expand Dr. Wright's knowledge and research abilities; providing him the crucial expertise necessary for a productive career. The F32 award will greatly aid in Dr. Wright's career development, providing the financial assistance and the protected time necessary to achieve these research and training objectives.

项目摘要/摘要骨骼对机械载荷和卸载高度敏感。骨骼卸载增加骨头骨髓肥胖和加速骨骼数量和质量的损失。相反，骨骼负载下降骨髓肥胖并增加骨骼完整性。虽然这种骨骼负荷的有益效果很好已知，尚不清楚导致这些作用的特定细胞类型和分子机制。初步数据表明，辅助α2Δ1电压敏感钙通道（VSCC）的全局缺失亚基导致骨质减少，骨骼发育障碍，骨骼质量和骨形成减少，以及增加肥胖。由于几种细胞类型调节骨骼形成和对骨骼负荷的反应，我们假设骨细胞和/或骨髓间充质干细胞的活性受损（MSC）有助于在全球α2Δ1基因敲除小鼠中看到的骨形成下降。那，提议研究将检查辅助α2Δ1亚基的细胞特异性机制开发和对加载的合成代谢响应。使用转基因小鼠模型，α2Δ1将有选择性在骨细胞和肢体细胞充质中删除。另外，用神经性疼痛药物治疗结合α2Δ1的加巴喷丁将确定sa1）如果在骨细胞或慢性GBP处理中删除α2Δ1 损害基本或负载引起的骨形成，导致骨质质量的损失，而SA2）如果删除了α2Δ1 间充质祖细胞或慢性GBP治疗会影响骨骼发育，骨骼形成和骨髓成生成。此外，赖特博士将进行完整的RNA测序分析并在体外工作以支持体内结果。赖特博士是一位营养肌肉骨骼科学家在临床饮食干预，分析分析和动物研究方面的大量专业知识，其长期很长任期职业目标是成为一名由NIH资助的终身教师，他们进行创新，翻译肌肉骨骼研究。赖特博士目前正在获得分子生物学和动物的高级培训建模以完成他的临床背景并发展完成他的技术专长职业目标。赖特博士及其心理委员会制定了一项全面的培训计划，研究建议将以他以前的研究经验为基础，并进一步扩大他的技能生物学研究。赖特博士的主要培训对象包括1）参加专业发展事件； 2）参加高级教学培训课程； 3）获取翻译生物分子研究经验； 4）学习新的实验技术； 5）增强写作能力。共同这些活动将扩大赖特博士的知识和研究能力；为他提供关键的专业知识有生产力的职业所必需的。 F32奖将极大地帮助赖特博士的职业发展，提供实现这些研究和培训目标所需的经济援助和受保护的时间。