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中软骨下骨的理化信号传导;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MPH学位;第四，指导初级教师获得独立资助。我们最近开发了新的资源，以布朗/VA恢复和再生医学中心和NIH COBRE赠款的形式，包括两个机构的高级学员，这将提高我们将个人转变为独立研究者的能力。研究计划的重点是了解软骨下骨在OA中的作用。最近的观察结果激发了人们对骨和软骨在OA发生和/或发展中的关系的兴趣，这些观察结果是：（1）骨髓水肿与OA疼痛有关，（2.）软骨损伤的进展在具有显著骨髓水肿的关节中更大，（3.）OA中的成骨细胞经历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OA中，提示共同的机制，和（5.）骨内高压和缺氧发生在OA中。已经确定成骨细胞对它们的物理化学环境的变化高度响应，并且响应于压力、流体流动和缺氧而改变它们的细胞因子表达谱。我们的初步观察表明，灌注的变化发生在早期实验和人类OA和承担的时间和空间的关系，软骨病变。同样清楚的是，OA中的成骨细胞改变其细胞因子表达谱的方式可能与增加的骨重塑和软骨降解有关。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。这些研究的假设是，OA软骨下骨中发生的灌注、压力和pO 2的扰动与骨重建和软骨降解具有功能关系，并且是调节成骨细胞表达的物理化学信号机制的一部分。第二阶段的资金更新应该产生不成比例的红利，因为我们有一个知识渊博，坚定的导师，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，并培养一批对以患者为导向的研究感兴趣的临床科学家。我们增加了主要的新计划举措和个人，提高了我们培养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.