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

FGFR3 在下颌髁突 PTH 影响中的作用

• 批准号: 10576359
• 负责人: Eliane Dutra
• 金额: $ 18.68万
• 依托单位: UNIVERSITY OF CONNECTICUT SCH OF MED/DNT
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-04-01 至 2025-03-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10576359
• 关键词: Address; Affect; Affinity; Anabolism; Animals; Basic Science; Binding; Cartilage; Cartilage injury; Cells; Chondrocytes; Clinical; Clinical Management; Collagen; Data; Degenerative polyarthritis; Dental Schools; Development; Disease; Euthanasia; Extracellular Matrix; FDA approved; FGF2 gene; FGFR3 gene; Fibroblast Growth Factor; Fibroblast Growth Factor Receptor 1; Fibroblast Growth Factor Receptor 2; Foundations; Future; Gender; Goals; Health; Health Occupations; Hypertrophy; Impaired healing; In Vitro; Individual; Intervention; Leadership; Ligands; Logic; Mandible; Mandibular Condyle; Medicine; Mentored Research Scientist Development Award; Mentors; Modeling; Molecular; Mus; Musculoskeletal; Musculoskeletal Diseases; National Institute of Dental and Craniofacial Research; Natural regeneration; Nature; PTH gene; Pain; Patients; Pharmacy (field); Play; Process; Proliferating; Proliferation Marker; Proteins; Publishing; RNA Interference; Receptor Protein-Tyrosine Kinases; Reporter Genes; Reporting; Research; Role; Saline; Science; Scientist; Sclerosis; Signal Transduction; Skeletal Development; Stimulus; Temporomandibular Joint; Temporomandibular Joint Disorders; Temporomandibular joint osteoarthritis; Testing; Therapeutic Intervention; Time; Tissues; Training Programs; Transgenic Organisms; Translating; Translational Research; United States; United States National Institutes of Health; biomechanical test; career development; cartilage regeneration; cartilage repair; chondroprotection; clinical application; clinical development; clinically relevant; condylar cartilage; craniofacial; disability; experience; experimental study; in vivo; inhibitor; injured; insight; loss of function; mRNA Expression; microCT; mineralization; multidisciplinary; next generation; novel; novel therapeutic intervention; osteochondral tissue; palliative; prevent; repaired; response; subchondral bone; transcriptome sequencing; translational research program

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.

抽象的 职业发展：此K01应用程序描述了一项为期5年的培训计划，以支持我的职业 作为独立的临床科学家的发展。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）的转化研究计划的长期目标 再生。该K01奖将为我提供实现的指导和受保护的时间 以下目标：（1）完成特定目的1和2中概述的研究。（2）翻译基础研究 临床应用的发现，可以使患有疼痛和残疾的退化性TMD疾病的患者受益。 （3）积极参与心理下一代临床/科学家，促进包括 代表人数不足的个人是卫生专业人员和颅面研究。为了实现列出的目标，我 已经组建了一个多学科指导团队，专家专家 肌肉骨骼健康以及牙科医学学院多样性促进方面的学术领导力。 科学：TMJ-OA是一种退化性关节疾病，其特征是软骨丧失和硬化症 软骨下骨，导致疼痛和残疾。有未满足的临床需要开发治疗 TMJ合成代谢的干预措施，可以防止或逆转TMJ软骨变性。 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的骨软骨组织中的合成代谢反应。我们的目标是洞悉细胞和 这些作用的分子机制。我们的中心假设是FGFR3是主人 由于I-PTH给药，在TMJ中观察到的合成代谢反应的调节剂。这个假设将是 通过以下特定目的测试：特定目标1a：确定FGFR3信号在合成代谢中的作用 I-PTH给药在TMJ的MCC中的影响。我们将在αSMA表达细胞中删除FGFR3 下颌do孔软骨（MCC），并确定有或没有I-的功能丧失的效果 pth。我们还将注入固体FGFR3以挽救有条件删除的FGFR3以确认该信号传导 是I-PTH效果的主调节器。 AIM 1B：定义FGFR3的分子机制 调节体外I-PTH的合成代谢作用。三倍的MCC的主要软骨细胞中的FGFR3 使用RNA沉默和特异性FGFR3抑制剂将抑制胶原蛋白转基因报告基因小鼠。具体的 AIM 2：在软骨损伤和修复模型中评估间歇性PTH的作用。三倍的MCC 转基因记者小鼠将受伤，动物将接受I-Pth注射或盐水以了解 I-PTH在MCC早期和延迟愈合中的作用。