The Toll-like receptor pathway in Meniscal Injury and Osteoarthritis

简介（由申请人提供）：候选人：Carla R. Scanzello，医学博士，芝加哥拉什大学医学中心医学助理教授。她于2008年6月在特殊外科医院完成了风湿病学研究，最近被招募到该院医学部（风湿病科）。她对炎症在骨关节炎（OA）发病机制中的作用特别感兴趣，她作为风湿病学研究员开始认真地追求这一目标。在她的研究期间，她设计了一个研究项目，以表征OA患者滑膜中的滑膜细胞群和炎症介质。由于之前发表的大多数关于OA炎症的研究都集中在晚期疾病患者身上，因此她的项目旨在描述明确的早期疾病患者的炎症反应。这项工作产生了多篇手稿（一篇发表，一篇被接受，一篇正在准备），从这个项目中观察到的结果导致了本应用程序中提出的假设。该奖项将允许Scanzello博士在免疫学和软骨生物化学领域的特定实验室技术方面获得进一步的培训，以获得作为研究者的完全独立性。她致力于在基质生物化学和免疫学之间的交叉领域进行转化研究，因为它适用于OA病理生理学，最终目标是在早期阶段为这种常见疾病开发新的治疗方法。环境：斯坎泽洛博士最近接受了一个终身职位，以追求她成为一名独立研究者的目标。这个职位使她能够获得完成提案目标所需的资源。她将获得必要的资源，包括教师专业知识和支持，合适的指导，有成就的临床和研究合作者，充足的实验室空间和设备，并通过骨科获得适当的患者群体。她75%的时间用于研究，以避免过度的教学和行政要求。风湿病科致力于支持她努力获得独立，并支持研究技术人员帮助她实现她的目标。期望她将建立一个研究项目，专注于骨关节炎的炎症途径激活，这是一个刚刚开始出现的研究领域。研究：曾经认为主要是软骨退行性疾病，现在我们知道OA患者整个关节（包括骨、滑膜、半月板和关节周围软组织）都发生了改变。也许在OA关节中发生的最不为人所知的病理改变是滑膜内的炎症（SM）。这种炎症可能是疼痛的来源，并可能刺激某些患者关节退行性变的进展。然而，确切的炎症刺激在关节和下游介质仍然是未知的。我们最近证实，在大多数寻求手术干预的早期和晚期膝关节OA患者的关节中都可以检测到促炎细胞因子白细胞介素-15 (IL-15) 7。已知这种细胞因子是在某些先天免疫受体toll样受体（TLRs）激活后产生的，这暗示了它们在OA中的活性。IL-15先前未在OA中被证实，但它的存在暗示了tlr的激活。此外，IL-15可能具有与OA发病机制相关的功能，包括诱导与疾病相关的酶介质10,11。因此，我们计划验证TLR通路激活导致半月板损伤和早期OA情况下关节组织诱导IL-15的假设，进而验证IL-15参与OA滑膜反应和软骨降解特征。我们将通过以下具体目的来验证这一假设：具体目的1：证明TLR-2或TLR-4配体在早期膝关节OA和膝关节损伤患者中产生，并刺激IL-15的产生。特异性目标2：证明HA寡糖和tlr激活在与关节病理相关的细胞和组织产生IL-15中的作用。特异性目的3：建立IL-15对软骨、滑膜和半月板组织的作用。特异性目的4：在小鼠OA模型中验证IL-15和TLR激活在OA发病过程中起核心作用。我们希望这些研究能够更好地理解早期OA中特定炎症途径的刺激因素和后果，并最终开发出新的治疗方法来干扰这一途径。由于我们目前没有影响疾病进展的早期OA干预措施，因此确定早期疾病的重要途径至关重要。

DESCRIPTION (provided by applicant): Candidate: Carla R. Scanzello, MD PhD is an Assistant Professor of Medicine at Rush University Medical Center (Chicago). She has recently been recruited there to the Faculty of the Department of Medicine (Section of Rheumatology), having completed her Fellowship in Rheumatology at the Hospital for Special Surgery in June 2008. She has a particular interest in the role that inflammation plays in osteoarthritis (OA) pathogenesis, which she began to pursue in earnest as a Rheumatology Fellow. During her Fellowship she designed a research project to characterize synovial cell populations and inflammatory mediators in the synovium of OA patients. Since most previously published work on inflammation in OA had focused on patients with advanced disease, her project was designed to characterize the inflammatory reaction in patients with well-defined early disease. This work has resulted in multiple manuscripts (one published, one accepted, and one under preparation), and observations from this project have led to the hypothesis addressed in this application. This award will allow Dr. Scanzello to gain further training in specific laboratory techniques used in the fields of both Immunology and Cartilage Biochemistry, in order to gain full independence as an investigator. She is committed to pursuing a translational research career working at the intersection between matrix biochemistry and immunology as it applies to OA pathophysiology, with the ultimate goal of developing novel therapies for this common disease in its early stages. Environment: Dr. Scanzello has recently accepted a tenure-track position in pursuit of her goal of becoming an independent investigator. This position allows her the access to resources she will need to accomplish the goals of this proposal. Necessary resources she will have access to include faculty expertise and support, suitable mentorship, accomplished clinical and research collaborators, adequate laboratory space and equipment, and access to appropriate patient populations via the Orthopedics Department. 75% of her time is dedicated for research, with protection from excessive teaching and administrative requirements. The Section of Rheumatology is dedicated to support her efforts to gain independence, and is supporting a research technician to help her accomplish her goals. The expectation is that she will establish a research program with focus on inflammatory pathway activation in Osteoarthritis, an area of research that is just beginning to emerge. Research: Once considered primarily a degenerative cartilage condition, we now understand that the entire joint (including bone, synovium, menisci, and periarticular soft tissues) is altered in OA. Perhaps the least understood pathologic change that occurs in the OA joint is the inflammation within the synovial membrane (SM). This inflammation can be a source pain3, and may stimulate progression of joint degeneration in certain patients4. However the precise inflammatory stimuli in the joint and the downstream mediators remain unknown. We recently demonstrated that the pro-inflammatory cytokine interleukin-15 (IL-15) is detectable in the joints of most patients with knee OA seeking surgical intervention for both early and advanced disease7. This cytokine is known to be produced following activation of certain innate immune receptors, the Toll-like receptors (TLRs), implicating their activity in OA. IL-15 has not been documented in OA previously, but its presence implicates activation of TLRs. Furthermore, IL-15 has functions that may be relevant to OA pathogenesis including induction of enzymatic mediators10,11implicated in disease. Therefore, we plan to test the hypothesis that TLR pathway activation leads to induction of IL-15 by joint tissues in the setting of meniscal injury and early OA, and furthermore that IL-15 contributes to the synovial response and cartilage degradation characteristic of OA. We will test this hypothesis through the following specific aims: Specific Aim 1: To demonstrate that TLR-2 or TLR-4 ligands are produced in patients with early knee OA and mensical injury and stimulate IL-15 production. Specific Aim 2: To demonstrate a role for HA oligosaccharides and TLR-activation in IL-15 production by cells and tissues relevant to joint pathology. Specific Aim 3: To establish the action of IL-15 on cartilage, synovium and meniscal tissue. Specific Aim 4: To verify that IL-15 and TLR activation play central roles in OA pathogenensis in a murine model of OA. We hope that these investigations lead to better understanding of the stimulating factors and consequences of a specific inflammatory pathway in early OA, and ultimately to development of novel therapeutics to interfere with this pathway. As we currently have no interventions for early OA that impact disease progression, defining important pathways in early disease is essential.