The effect of parathyroid hormone on modeling-based bone formation

甲状旁腺激素对建模骨形成的影响

• 批准号: 8967724
• 负责人: Xiaowei Sherry Liu
• 金额: $ 13.28万
• 依托单位: UNIVERSITY OF PENNSYLVANIA
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-07-09 至 2019-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8967724
• 关键词: Ablation; Advisory Committees; Affect; Alendronate; Animal Model; Animals; Antibodies; Biochemical; Biological Assay; Biology; Biology of Aging; Biomechanics; Biomedical Engineering; Bone Diseases; Bone Resorption; Bone Surface; Cells; Cellular biology; Clinical Trials; Collagen Fiber; Combined Modality Therapy; Core Facility; Coupling; Doctor of Philosophy; Environment; Equilibrium; Equipment; Faculty; Foundations; Fracture; Funding; Future; Gene Expression; Goals; Grant; Growth; Health; Histology; Homeostasis; Hormones; Housing; Image; Image Analysis; Immunohistochemistry; Individual; Institution; International; Interruption; Investigation; Journals; Knowledge; Laboratories; Laboratory Research; Light; Measurement; Mechanics; Mentors; Metabolic Bone Diseases; Methods; Modeling; Molecular; Molecular Biology; Molecular and Cellular Biology; Monkeys; Mono-S; Mus; Musculoskeletal; Orthopedics; Osteoblasts; Osteoclasts; Osteocytes; Osteogenesis; Osteopenia; Osteoporosis; Parathyroid Hormone Receptor; Parathyroid gland; Physiology; Play; Positioning Attribute; Postdoctoral Fellow; Production; Recombinants; Regulation; Research; Research Personnel; Research Project Grants; Research Training; Risk; Role; Scientist; Series; Signal Transduction; Site; Skeletal Development; Specimen; TNFSF11 gene; Tamoxifen; Techniques; Testing; Therapeutic; Therapeutic Effect; Time; Tissues; Training; Universities; Writing; X-Ray Computed Tomography; aged; base; beta catenin; bisphosphonate; bone; bone cell; bone imaging; bone strength; career; career development; clinical investigation; dentin matrix protein 1; drug mechanism; graduate student; human PTH protein; imaging modality; in vivo; in vivo imaging; innovation; lecturer; medical schools; mouse model; neutralizing antibody; novel; protein expression; public health relevance; receptor; research study; response; responsible research conduct; skills; symposium; translational medicine; young adult

 DESCRIPTION (provided by applicant): Candidate: I obtained my Ph.D in Biomedical Engineering. My post-doc training focused on clinical investigations of changes in bone microstructure that affect bone strength and fracture risk in osteopenia, osteoporosis, and other metabolic bone diseases. My long-term goal is to develop as an independent research investigator able to combine the fields of bone imaging and biomechanics with bone cell and molecular biology. Thus, my specific objective here is to obtain training in cell and molecular biology and in vivo animal models in order to uncover and clarify the overall mechanisms behind PTH-induced, modeling-based bone formation. By combining my expertise in innovative imaging and image analyses with cellular, molecular and in vivo animal approaches, the proposed research project promises to represent a major new first attempt to understand the direct modeling component of PTH's anabolic action at the local level. Mentor and Advisory Committee: The primary Mentor Dr. Louis Soslowsky, an international leader in mechanical adaptation of musculoskeletal tissue, will serve as my mentor for both career development and scientific content. The co-Mentor Dr. Maurizio Pacifici, a world-renowned scientist in skeletal development and growth, will serve as scientific mentor. The advisory committee consists of Dr. Xu Cao at the Johns Hopkins University, who will advise on bone modeling and remodeling; Dr. Paola Divieti Pajevic at the Harvard Medical School, who will advise on PTH receptor and osteocyte signaling; and Dr. Ling Qin at my local institution, who will provide hands-on training in cellular and molecular experiment skills. Environment: The research/training environment at Penn includes 15,500 ft2 of shared lab space in the McKay Orthopaedic Research Laboratory; multiple shared experimental facilities, including an in vivo and a specimen micro computed tomography (µCT) scanner, histology core facilities, equipment for cellular and molecular biology, and mechanical testing core facilities; numerous vivarium facilities available to investigators for both conventional and barrier housing options; numerous seminars and lecturers, and career development courses. Training Plan: The training plan includes research training in the Mentors' and advisors' laboratories in techniques utilizing genetically-modified mouse models, and cell and molecular measurements using histology, biochemical assays, and immunohistochemistry. The training plan also includes courses in the molecular biology of aging, grant writing, career development, and responsible conduct of research; attendance at several seminar series pertinent to candidate's research training; journal clubs; and presentations at a minimum of 2 national conferences per year. Research: Current osteoporosis treatments aim to elicit an anti-catabolic or anabolic bone response. However, due to bone formation-resorption coupling mechanisms, drugs inhibiting bone resorption often inhibit formation, and those increasing formation also increase resorption, thereby limiting their potential benefits. In contrast, several studies including those we recently performed, suggest that pre-treatment with bisphosphonates followed by intermittent recombinant human parathyroid hormone 1-34 (iPTH) treatment may result in modeling-based bone formation, i.e., bone formation with minimal activation of resorption. Through this mechanism, a combination therapy of iPTH and anti-catabolic agents could activate bone formation with minimal concomitant bone resorption, thus eliciting an overall beneficial effect stronger than current mono- therapies. However, results from clinical trials have been highly variable. Controversies remain, due in part to unclear mechanisms of PTH's role in controlling modeling-based bone formation. Recent studies suggested that PTH acts on osteocytes to control the balance between resorption and formation through the regulation of Sost/sclerostin, RANKL and OPG in osteocytes. Interestingly, treatment with a sclerostin-neutralizing antibody was recently found to induce strong modeling-based bone formation. iPTH has been shown to down-regulate sclerostin production, leading to our central hypothesis that iPTH regulates modeling-based bone formation and does so partially by acting on osteocytes and influencing their signaling activity. According, Aim 1 is to characterize modeling-based bone formation on trabecular and cortical bone surfaces in response to iPTH in a young and old mouse model. We will exploit our novel 3D, µCT-based, in vivo bone dynamic imaging approaches, combined with 2D histological methods, to allow characterization of modeling- and remodeling- based bone formation at individual sites with unparalleled sensitivity and accuracy. Aim 2 is to delineate the roles of the PTH receptor (PPR) in osteocytes and osteoblasts in iPTH-induced, modeling-based bone formation. Here we will determine whether this anabolic response requires expression of PPR in osteocytes or osteoblasts. Dmp1-CreER; PPRfl/fl and OCN-CreER; PPRfl/fl mice will be treated with tamoxifen to induce PPR deficiency in osteocytes and osteoblasts, respectively. Their responses to iPTH and combined iPTH and alendronate treatment will be evaluated. We anticipate that this investigation will shed light on more efficient therapeutic strategies for osteoporosis that favor formation over resorption. Institutional Commitment to the Candidate: The candidate holds a tenure-track faculty position at Penn, which has provided laboratory space, start-up funding, and support for graduate students and post-docs.

 描述（由申请人提供）：候选人：我获得了生物医学工程博士学位。我的博士后培训集中在临床研究的变化，影响骨强度和骨折风险的骨质减少，骨质疏松症，和其他代谢性骨骼疾病的骨微观结构。我的长期目标是发展成为一名独立的研究调查员，能够将骨成像和生物力学领域与骨细胞和分子生物学相结合。因此，我在这里的具体目标是获得细胞和分子生物学和体内动物模型的培训，以揭示和澄清PTH诱导的，基于模型的骨形成背后的整体机制。通过将我在创新成像和图像分析方面的专业知识与细胞，分子和体内动物方法相结合，拟议的研究项目有望代表一个主要的新的首次尝试，以了解PTH在局部水平的合成代谢作用的直接建模成分。导师及顾问委员会：主要导师Louis Soslowsky博士是肌肉骨骼组织机械适应的国际领导者，他将担任我的职业发展和科学内容的导师。共同导师Maurizio Pacifici博士是骨骼发育和生长领域的世界知名科学家，他将担任科学导师。咨询委员会包括约翰霍普金斯大学的曹旭博士，他将为骨建模和重塑提供建议;哈佛医学院的保拉迪维蒂·帕耶维奇博士，他将为PTH受体和骨细胞信号传导提供建议;以及我当地机构的秦玲博士，他将提供细胞和分子实验技能的实践培训。工作环境：在宾夕法尼亚大学的研究/培训环境包括15,500平方英尺的共享实验室空间在麦凯骨科研究实验室;多个共享实验设施，包括在体内和标本微计算机断层扫描（µCT）扫描仪，组织学核心设施，细胞和分子生物学设备，和机械测试核心设施;为研究人员提供了许多饲养设施，可供选择传统和隔离式住房;许多研讨会和讲座以及职业发展课程。培训计划：培训计划包括在导师和顾问实验室进行的研究培训，内容包括利用遗传修饰小鼠模型的技术，以及使用组织学、生化测定和免疫组织化学进行的细胞和分子测量。培训计划还包括衰老分子生物学课程，赠款写作，职业发展和负责任的研究行为;参加与候选人研究培训有关的几个系列研讨会;期刊俱乐部;每年至少2次全国会议的演讲。研究：目前的骨质疏松症治疗旨在引起抗分解代谢或合成代谢骨反应。然而，由于骨形成-吸收偶联机制，抑制骨吸收的药物通常抑制骨形成，而那些增加骨形成的药物也增加骨吸收，从而限制了它们的潜在益处。相比之下，包括我们最近进行的研究在内的几项研究表明，用双膦酸盐预治疗，然后间歇性重组人甲状旁腺激素1-34（iPTH）治疗可能导致基于建模的骨形成，即，骨形成和最小的再吸收激活。通过这种机制，iPTH和抗分解代谢药物的联合治疗可以激活骨形成，同时伴有最小的骨吸收，从而产生比当前单一治疗更强的总体有益作用。然而，临床试验的结果差异很大。争议仍然存在，部分原因是PTH在控制基于模型的骨形成中的作用机制尚不清楚。最近的研究表明，PTH作用于骨细胞，通过调节骨细胞中的Sost/sclerostin、RANKL和OPG来控制骨吸收和形成之间的平衡。有趣的是，最近发现用硬化蛋白中和抗体治疗可诱导强的基于建模的骨形成。iPTH已显示下调硬化蛋白的产生，导致我们的中心假设，即iPTH调节基于建模的骨形成，并且部分通过作用于骨细胞并影响其信号传导活性来实现。因此，目的1是表征在年轻和老年小鼠模型中响应iPTH的小梁和皮质骨表面上基于建模的骨形成。我们将利用我们的新型3D、基于µ CT的体内骨动态成像方法，结合2D组织学方法，以无与伦比的灵敏度和准确度对各个部位的基于建模和重塑的骨形成进行表征。目标二是界定 PTH受体（PPR）在iPTH诱导的成骨细胞和成骨细胞中，基于模型的骨形成。在这里，我们将确定这种合成代谢反应是否需要在骨细胞或成骨细胞中表达PPR。将用他莫昔芬处理Dmp 1-CreER; PPRfl/fl和OCN-CreER; PPRfl/fl小鼠以分别诱导骨细胞和成骨细胞中的PPR缺陷。将评价他们对iPTH以及iPTH和阿仑膦酸钠联合治疗的反应。我们预计，这项调查将揭示更有效的治疗骨质疏松症的策略，有利于形成超过吸收。对候选人的机构承诺：候选人在宾夕法尼亚大学拥有终身教职，该大学为研究生和博士后提供实验室空间，启动资金和支持。