Physicochemical Signaling in Osteoarthritis

描述（由申请人提供）：候选人有四个职业目标，第一，将我们的临床研究扩展到OA软骨下骨的理化信号；二是培养临床科学家的临床研究方法和循证医学；第三，在骨科住院医师中建立临床医生-科学家的学术轨道，包括公共卫生硕士学位；第四，指导初级教师实现独立资助。我们最近以布朗/VA恢复和再生医学中心和NIH COBRE资助的形式开发了新的资源，包括两者的高级导师，这将增强我们将个人转变为独立研究者的能力。研究计划侧重于了解软骨下骨在OA中的作用。最近的观察结果激发了人们对骨性关节炎发生和/或进展中骨和软骨之间关系的兴趣：(1)骨性水肿与骨性关节炎的疼痛有关，(2)骨性水肿严重的关节中软骨病变的进展更大，(3)骨性关节炎中的成骨细胞发生代谢变化并分泌刺激骨重塑和软骨降解的细胞因子，(4)局灶性AVN发生在骨性关节炎中，这表明了共同的机制。(5)骨性关节炎发生骨内高血压和缺氧。众所周知，成骨细胞对其物理化学环境的变化具有高度的反应性，并在压力、流体流动和缺氧的情况下改变其细胞因子的表达谱。我们的初步观察表明，灌注变化发生在早期实验和人类OA中，并且与软骨病变具有时间和空间关系。同样清楚的是，骨性关节炎中的成骨细胞以可能与骨重塑和软骨降解增加相关的方式改变其细胞因子表达谱。这些研究的长期目标是了解成骨细胞和软骨下骨在OA中的作用，特别是在软骨降解中的作用。这些研究的假设是OA软骨下骨的灌注、压力和pO2的扰动与骨重塑和软骨降解具有功能关系，并且是调节成骨细胞表达的理化信号机制的一部分。由于我们拥有一位知识渊博、忠诚的导师、坚实的基础设施、有趣的研究问题、转化能力、强有力的合作，并且已经制定了一项计划，以引入循证骨科，并培养了一批对以患者为导向的研究感兴趣的临床医生和科学家。我们增加了重要的新项目倡议和个人，以增强我们培养独立调查员的能力。

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.