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

摘要 职业发展：这份K01申请描述了一项为期5年的培训计划，以支持我的职业生涯 发展成为一名独立的临床医生-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)翻译研究项目的长期目标 再生。这一K01奖项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 临床应用中的发现，可使患有疼痛和致残性退行性TMD障碍的患者受益。 (3)积极参与指导下一代临床医生/科学家，推动纳入 代表不足的人进入卫生专业和头面部研究。为了达到列出的目标，我 已经组建了一个由颅面翻译研究专家组成的多学科指导团队， 牙科医学院肌肉骨骼健康以及在促进多样性方面的学术领导地位。 科学：TMJ-OA是一种退行性关节疾病，其特征是关节软骨丢失和硬化。 软骨下骨，导致疼痛和残疾。有一种尚未得到满足的临床需求，即开发治疗方法 对TMJ具有合成代谢作用的干预措施，可以防止或逆转TMJ软骨的退变。 我们已经确认FDA批准的间歇性甲状旁腺激素(i-PTH)治疗可以促进 TMJ骨软骨组织中的合成代谢反应。我们的目标是深入了解蜂窝和 这些效应产生的分子机制。我们的中心假设是FGFR3是主宰 I-PTH给药引起的TMJ合成代谢反应的调节。这一假设将是 通过以下特定目标进行测试：特定目标1A：确定FGFR3信号在合成代谢中的作用 甲状旁腺激素在TMJ微循环中的作用。我们将在αSMA中删除表达FGFR3的细胞 并测定FGFR3功能丧失在有或无I-R的情况下的影响。 PTH。我们还将注射可溶性FGFR3来挽救FGFR3的条件性删除，以确认这一信号 是i-PTH效应的主要调节者。目的1B：确定FGFR3的分子机制 调节I-PTH的体外合成代谢作用。MCC原代软骨细胞中FGFR3的表达 使用RNA沉默和特异性FGFR3抑制剂将抑制胶原转基因报告鼠。特定的 目的：探讨间歇性甲状旁腺激素在软骨损伤修复模型中的作用。三元组的MCC 转基因小鼠将受到伤害，动物将接受注射i-PTH或生理盐水以了解 甲状旁腺激素在肾小细胞癌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.