Synthetic Lubricin Mimetics for the Treatment of Osteoarthritis

用于治疗骨关节炎的合成润滑素模拟物

• 批准号: 9270501
• 负责人: DAVID A PUTNAM
• 金额: $ 36.69万
• 依托单位: CORNELL UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-07-01 至 2018-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9270501
• 关键词: Acids; Amino Acids; Anterior Cruciate Ligament; Architecture; Binding; Biocompatible Materials; Carbomer-940; Cartilage; Cartilage Matrix; Characteristics; Clinical; Collaborations; Custom; Data; Data Reporting; Degenerative polyarthritis; Disease; Disease Progression; Friction; Glycoproteins; Hyaluronic Acid; Inferior; Injury; Intra-Articular Injections; Kinetics; Knee; Libraries; Light; Lubricants; Lubrication; Mechanics; Methods; Modeling; Molecular; Molecular Weight; Orthopedics; Outcome; Peptides; Polyethylene Glycols; Polysaccharides; Prevention; Property; Proteoglycan; Publishing; Research; Series; Side; Sprague-Dawley Rats; Surgeon; Teleconferences; Testing; Translations; Vertebral column; Weight-Bearing state; Wit; articular cartilage; copolymer; density; design; experimental study; glycosylation; innovation; large scale production; lubricin; mimetics; mutant; palliative; pre-clinical; prevent; programs; public health relevance; scale up

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.

产品说明：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，以延迟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，是膝关节的天然流体动力学模式润滑剂（快速和轻的正常负荷）。Lubricin是一种蛋白聚糖，是膝关节中的天然边界模式润滑剂（缓慢和沉重的正常负荷）。 流体动力学和边界模式润滑对于充分润滑膝关节和延迟或预防OA进展都是必不可少的，但临床上还不可用。这是拟议研究的重点。假设是，膝关节的边界模式润滑可以由合成润滑素模拟物提供，并且关节内施用模拟物将预防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：量化合成润滑素模拟物的分子结构如何与软骨上的边界模式润滑相关。合成润滑素模拟物的库，特别是聚丙烯酸-接枝-聚乙二醇的刷状共聚物，将被合成并表征为在它们的主链分子量、侧链分子量和侧链密度方面具有系列改变。将量化每种刷共聚物的边界模式润滑特性。特定目标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其在边界模式条件下润滑软骨的能力相关。� 具体目标二：量化连接到合成润滑素模拟物的软骨基质结合肽如何影响软骨上的边界模式润滑。一系列软骨结合肽将被拴系到合成润滑素模拟物的主链末端，并将量化润滑特性。预期 具体目标2的结果是对软骨结合肽如何影响润滑素模拟结合动力学和结合常数以及这些集合参数如何影响边界模式润滑的定量理解。� 具体目标3：在Sprague-Dawley大鼠的前交叉韧带横断模型中，量化合成润滑素模拟物对OA进展的预防作用。将在严格的ACL横断模型中评价从特定目的1和2中鉴定的合成润滑素模拟物的能力。特定目标3的预期结果将是鉴定一种或多种具有延迟或预防OA发作潜力的临床有前景的润滑素模拟物。拟议研究的预期结果将是鉴定一种或多种临床上有前途的润滑素模拟物，其具有延迟或预防骨关节炎发作的临床潜力。