The role of FGFR3 in the effects of PTH in the Mandibular Condyle

摘要 职业发展：这份K 01申请描述了一个为期5年的培训计划，以支持我的职业生涯 作为一名独立的临床科学家。我的目标是扩大我的研究经验，以实现我的 指导颞下颌关节骨关节炎（TMJ-OA）转化研究项目的长期目标 再生这个K 01奖将为我提供必要的指导和保护时间，以实现 以下目标：（1）完成具体目标1和2中概述的研究。(2)翻译基础研究 这些发现应用于临床，可以使患有疼痛和致残性退行性TMD疾病的患者受益。 (3)积极参与指导下一代临床医生/科学家，促进包括 少数人进入卫生专业和颅面研究。为了实现上述目标，我 组建了一个由颅面转化研究专家组成的多学科指导团队， 肌肉骨骼健康以及在牙科医学院的多样性促进学术领导。 科学：TMJ-OA是一种退行性关节疾病，其特征是软骨丢失和关节硬化。 软骨下骨，造成疼痛和残疾。存在未满足的临床需求，以开发治疗性药物。 对TMJ进行合成代谢的干预，可以预防或逆转TMJ软骨的退化。 我们已经确定，FDA批准的治疗，间歇性甲状旁腺激素（I-PTH），促进 TMJ骨软骨组织中的合成代谢反应。我们的目标是深入了解细胞， 这些效应的分子机制。我们的中心假设是FGFR 3是 由于I-PTH给药，在TMJ中观察到的合成代谢反应的调节剂。这一假设将是 具体目的1A：确定FGFR 3信号传导在合成代谢中的作用， I-PTH给药对TMJ MCC的影响。我们将删除αSMA表达细胞中的FGFR 3， 下颌髁突软骨（MCC），并确定FGFR 3功能丧失的影响，有和没有I- PTH。我们还将注射可溶性FGFR 3以拯救条件性缺失的FGFR 3，以确认这种信号传导 是I-PTH作用的主要调节剂。目的1B：确定FGFR 3通过其调节细胞凋亡的分子机制。 在体外调节I-PTH的合成代谢作用。FGFR 3在来自三重的MCC的原代软骨细胞中的表达 将使用RNA沉默和特异性FGFR 3抑制剂抑制胶原转基因报告小鼠。具体 目的2：评价间歇性甲状旁腺激素在软骨损伤和修复模型中的作用。三重MCC 转基因报告小鼠将被损伤，并且动物将接受注射I-PTH或盐水以了解 I-PTH在MCC早期和延迟愈合中的作用。

Abstract Career Development: This K01 application describes a 5-year training program to support my career development as an independent clinician-scientist. My goal is to expand my research experience to achieve my long-term goal of directing a translational research program in temporomandibular joint osteoarthritis (TMJ-OA) regeneration. This K01 award will provide me with the guidance and protected time necessary to achieve the following goals: (1) To complete the studies outlined in Specific Aims 1 and 2. (2) To translate the basic research findings into clinical applications that can benefit patients with painful and disabling degenerative TMD disorders. (3) To be actively involved in mentoring the next generation of clinician/scientists, promoting the inclusion of underrepresented individuals into health professions and craniofacial research. To achieve the listed goals, I have assembled a multidisciplinary mentoring team of experts in craniofacial translational research, musculoskeletal health as well as academic leadership in diversity promotion in the School of Dental Medicine. Science: TMJ-OA is a degenerative joint disease characterized by cartilage loss and sclerosis of the subchondral bone, causing pain and disability. There is an unmet clinical need to develop therapeutic interventions that are anabolic for the TMJ which could prevent or reverse degeneration of the TMJ cartilage. We have identified that the FDA approved treatment, intermittent parathyroid hormone (I-PTH), promotes anabolic responses in the osteochondral tissues of the TMJ. Our goal is to gain insights into the cellular and molecular mechanisms by which these effects are exerted. Our central hypothesis is that FGFR3 is the master regulator of the anabolic response observed in the TMJ due to I-PTH administration. This hypothesis will be tested by following specific aims: Specific Aim 1A: To determine the role of FGFR3 signaling in the anabolic effects of I-PTH administration in the MCC of the TMJ. We will delete FGFR3 in αSMA expressing cells in the mandibular condylar cartilage (MCC) and determine the effects of FGFR3 loss-of-function with and without I- PTH. We will also inject a soluble FGFR3 to rescue the FGFR3 conditional deleted to confirm that this signaling is the master regulator of the effects of I-PTH. Aim 1B: To define the molecular mechanism by which FGFR3 regulates the anabolic effects of I-PTH in vitro. FGFR3 in the primary chondrocytes from the MCC of triple collagen transgenic reporter mice will be inhibited using RNA silencing and specific FGFR3 inhibitor. Specific Aim 2: Evaluate the role Intermittent PTH plays in a model of cartilage injury and repair. The MCC of triple transgenic reporter mice will be injured and animals will receive either injected with I-PTH or saline to understand the role of I-PTH in early and delayed healing of the MCC.