Physicochemical Signaling in Osteoarthritis

应聘者描述(由申请者提供)：应聘者有四个职业目标，第一，将我们的临床研究扩展到骨关节炎软骨下骨的理化信号；第二，在临床研究方法和循证医学方面培训临床医生-科学家；第三，在骨科住院医师中建立学术临床医生-科学家轨道，包括公共卫生硕士学位；以及第四，指导初级教员实现独立资助。我们最近开发了新的资源，形式为布朗/退伍军人管理局恢复和再生医学中心和NIH Cobre赠款，包括这两个项目的资深导师，这将增强我们将个人转变为独立研究人员的能力。该研究计划重点了解软骨下骨在骨性关节炎中的作用。骨和软骨之间的关系在骨性关节炎的发生和/或进展中的关系最近被以下观察激发了兴趣：(1)骨性关节炎患者的骨髓水肿与疼痛有关，(2)有明显骨髓水肿的关节软骨病变进展较大。成骨细胞在骨性关节炎中经历代谢变化，并分泌细胞因子，刺激骨重建和软骨降解。局灶性房室结出现在骨性关节炎，提示共同的机制，和(5)骨性关节炎时会出现骨内高压和低氧。众所周知，成骨细胞对其物理化学环境的变化高度敏感，并在压力、液体流动和低氧条件下改变其细胞因子的表达谱。我们的初步观察表明，早期实验性和人类骨性关节炎都会出现血流灌注的变化，并且与软骨损伤存在时间和空间上的关系。同样清楚的是，骨性关节炎中的成骨细胞改变了其细胞因子的表达谱，这可能与骨重建和软骨降解的增加有关。这些研究的长期目标是了解成骨细胞和软骨下骨在骨关节炎中的作用，特别是在软骨退化中的作用。这些研究的假设是，骨关节炎软骨下骨的灌流、压力和氧分压的改变与骨重建和软骨降解有关，是调节成骨细胞表达的物理化学信号机制的一部分。延长第二阶段的资金应该会产生不成比例的红利，因为我们有一位知识渊博、尽职尽责的导师、坚实的基础设施、有趣的研究问题、翻译能力、强大的合作，并制定了一项计划，引入循证骨科，培养一支对以患者为导向的研究感兴趣的临床医生-科学家队伍。我们增加了重大的新项目倡议和个人，以增强我们产生独立调查人员的能力。

DESCRIPTION (provided by applicant): The candidate has four career goals, first to extend our clinical studies to physicochemical signaling in subchondral bone in OA; second to train clinician-scientists in clinical research methods and evidence-based medicine; third to establish an academic clinician-scientist track in the orthopaedic residency including an MPH degree; and fourth, mentoring junior faculty to achieve independent funding. We have recently developed new resources in the form of the Brown/VA Center for Restorative and Regnerative Medicine and an NIH COBRE grant, including senior mentorees in both, that will enhance our ability to transition individuals to independent investigator status. The research plan focuses understanding the role of subchondral bone in OA. Interest in the relationships between bone and cartilage in the initiation and/or progression of OA has been stimulated recently by observations that (1.) bone marrow edema is related to pain in OA, (2.) the progression of cartilage lesions is greater in joints with significant bone marrow edema, (3.) osteoblasts in OA undergo metabolic changes and secrete cytokines which stimulate both bone remodeling and cartilage degradation, (4.) focal AVN occurs in OA, suggesting common mechanisms, and (5.) intraosseous hypertension and hypoxia occur in OA. It is well established that osteoblasts are highly responsive to changes in their physicochemical environment and alter their cytokine expression profile in response to pressure, fluid flow, and hypoxia. Our preliminary observations indicate that changes in perfusion occur in both early experimental and human OA and bear a temporal and spatial relationship to cartilage lesions. It is clear also that osteoblasts in OA change their cytokine expression profile in ways that may be associated with increased bone remodeling and cartilage degradation. The long-term goal of these studies is to understand the role of the osteoblast and subchondral bone in OA, particularly in cartilage degradation. The hypothesis of these studies is that perturbations in perfusion, pressure and pO2 that occur in OA subchondral bone bear a functional relationship to bone remodeling and cartilage degradation and are part of a physicochemical signaling mechanism regulating osteoblast expression. Renewal of funding for the second period should yield disproportionate dividends, since we have a knowledgeable, committed mentor, solid infrastructure, interesting research questions, translational capability, strong collaborations, and have developed a plan to introduce evidence-based orthopaedics and develop a cadre of clinician-scientists interested in patient-oriented research. We have added major new program initiatives and individuals that enhance our ability to produce independent investigators.