Synthetic Lubricin Mimetics for the Treatment of Osteoarthritis

描述：拟议研究的目的是研究天然蛋白聚糖润滑剂，润滑素的合成模拟物，以延缓或预防膝关节负重关节软骨损伤后骨关节炎的进展。透明质酸是一种多糖，是膝关节的天然水动力模式润滑剂（快速和轻正常负荷）。润滑素是一种蛋白聚糖，是膝关节的天然边界模式润滑剂（缓慢而沉重的正常负荷）。流体动力和边界模式润滑都是必不可少的，但尚未临床可用，以充分润滑膝关节并延迟或防止OA进展。这是本研究的重点。假设是膝关节的边界模式润滑可以由合成润滑剂模拟物提供，并且模拟物的关节内管理将防止OA疾病进展。我们的假设将在以下具体目标的实验中进行评估：具体目标1：量化合成润滑油模拟物的分子结构如何与软骨的边界模式润滑相关。本文将合成一系列合成润滑油模拟物，特别是聚丙烯酸-接枝-聚乙二醇的刷状共聚物，并对其主链分子量、侧链分子量和侧链密度进行一系列改变。每个刷状共聚物的边界模式润滑特性将被量化。Specific Aim 1的预期结果是定量理解合成润滑油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。具体目标2：量化软骨基质结合肽系在合成润滑剂模拟物上如何影响软骨的边界模式润滑。一系列的软骨结合肽将被拴在合成的润滑模拟物的骨干末端，润滑特性将被量化。预期的

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.