Synthetic Lubricin Mimetics for the Treatment of Osteoarthritis

描述：拟议研究的目的是研究天然蛋白多糖润滑剂润滑剂的合成模拟物，以延缓或防止膝关节承重关节软骨损伤后骨关节炎的进展。透明质酸是一种多糖，是膝盖中的天然流体动力模式润滑剂(快速和轻便的正常负荷)。润滑素是一种蛋白多糖，是膝关节中的自然边界模式润滑剂(缓慢和沉重的正常负荷)。流体动力和边界模式润滑都是必要的，但还不能用于临床，以充分润滑膝关节，延缓或防止OA的进展。这是本文拟研究的重点。假说是，膝关节的边界模式润滑可以通过模拟合成润滑剂来提供，关节内应用模拟润滑剂将防止OA疾病的进展。我们的假设将在以下特定目标的实验中得到验证：�特定目标1：量化合成润滑素模拟物的分子结构与软骨边界模式润滑之间的关系。将合成一系列合成润滑剂模拟物，特别是聚丙烯酸-接枝-聚乙二醇刷共聚物，并通过其主链相对分子质量、侧链相对分子质量和侧链密度的一系列变化进行表征。每种刷共聚物的边界模式润滑特性将被量化。具体目标1的预期结果是定量了解合成润滑素模拟物的分子结构如何与它们在边界模式条件下润滑软骨的能力相关。�的具体目标2：量化与合成润滑素模拟物捆绑的软骨基质结合肽如何影响软骨的边界模式润滑。将一系列软骨结合多肽连接到合成的润滑素模拟物的骨架末端，并对其润滑特性进行量化。预期中的 具体目标2的结果是定量了解软骨结合肽如何影响拟润滑素结合动力学和结合常数，以及这些集体参数如何影响边界模式润滑。�的具体目标3：量化合成润滑素模拟物在前交叉韧带横断模型中对OA进展的预防作用。根据特定目标1和2确定的合成润滑剂模拟物的能力将在严格的前交叉韧带横断模型中进行评估。特定目标3的预期结果将是识别一种或多种临床上有希望的润滑剂，具有延缓或预防OA发病的潜力。这项拟议研究的预期结果将是确定一种或多种临床上有前景的润滑剂模拟物，具有延缓或预防骨关节炎发生的临床潜力。

DESCRIPTION: The objective of the proposed research is to investigate synthetic mimetics of the natural proteoglycan lubricant, lubricin, to delay or prevent progression of osteoarthritis following injury to the weight bearing articular cartilage of the knee. Hyaluronic acid is a polysaccharide that is the natural hydrodynamic mode lubricant (fast and light normal load) in the knee. Lubricin is a proteoglycan that is the natural boundary mode lubricant (slow and heavy normal load) in the knee. Both hydrodynamic and boundary mode lubrication are essential, but not yet clinically available, to adequately lubricate the knee and to delay or prevent OA progression. This is the focus of the proposed research. The hypothesis is that boundary mode lubrication of the knee can be afforded by synthetic lubricin mimetics, and that intraarticular administration of the mimetics will prevent OA disease progression. Our hypothesis will be evaluated in the experiments of the following Specific Aims: � Specific Aim 1: To quantify how the molecular architecture of synthetic lubricin mimetics correlates to boundary mode lubrication on cartilage. A library of synthetic lubricin mimetics, specifically brush copolymers of polyacryli acid-graft-polyethylene glycol, will be synthesized and characterized with serial alterations in their backbone molecular weight, side chain molecular weight and side chain density. The boundary mode lubrication characteristics of each brush copolymer will be quantified. The anticipated outcome of Specific Aim 1 is a quantitative understanding of how the molecular architecture of the synthetic lubricin mimetics correlates to their ability to lubricate cartilage under boundary mode conditions. � Specific Aim 2: To quantify how cartilage matrix binding peptides tethered to the synthetic lubricin mimetics influence boundary mode lubrication on cartilage. A series of cartilage binding peptides will be tethered to the backbone terminus of the synthetic lubricin mimetics and the lubrication characteristics will be quantified. The anticipated outcome of Specific Aim 2 is a quantitative understanding of how the cartilage binding peptides influence lubricin-mimetic binding kinetics and binding constants, and how these collective parameters influence boundary mode lubrication. � Specific Aim 3: To quantify the prevention of OA progression of synthetic lubricin mimetics in an anterior cruciate ligament transection model in Sprague-Dawley rats. The ability of synthetic lubricin mimetics identified from Specific Aims 1 and 2 will be evaluated in a rigorous ACL transection model. The anticipated outcome of Specific Aim 3 will be the identification of one or more clinically promising lubricin mimetics wit the potential to delay or prevent the onset of OA. The anticipated outcome of the proposed research will be the identification of one or more clinically promising lubricin mimetics with the clinical potential to delay or prevent the onset of osteoarthritis.