Glucosamine and Novel Anolgs for Cartilage Regeneration

描述(由申请人提供)：该项目的总体目标是设计和实施新的软骨修复和治疗骨关节炎(OA)的策略，利用组织工程和由葡萄糖(GlcN)启发的生物信号。小分子刺激组织生长将为经常依赖复杂和不稳定的生长因子蛋白作为生物信号的组织工程领域提供重要的工具。最初的资助期的初步数据和发表的研究确立了一个疗效窗口，在这个窗口中，GlcN可以刺激软骨细胞、干细胞和患病的骨关节细胞形成更多的软骨，Yarema实验室开发的新的糖类似物显示了更有效的效果。从机制的角度来看，我们发现某些新的类似物抑制了核因子-B，这是一种在软骨疾病(如骨关节炎)中很重要的分子。最后，体外结果被转化为体内试验，在一种啮齿动物模型中，将GlcN注射到关节间隙，与生理盐水对照组注射相比，改善了软骨结构。这些发现为药物化学方法定义新的小分子奠定了基础，这些小分子可以精确而有效地干预骨关节炎和软骨修复的组织工程。在这次竞争性更新中，我们建议研究由Yarema实验室设计的新型糖类似物在三维生物材料支架中刺激正常和骨关节炎软骨细胞组织生长的能力。对于表现出对软骨组织生长有显著刺激作用的糖，将评估其作用机制。这种糖类似物对正常和/或病变细胞具有最大的刺激作用，然后将应用于OA的啮齿动物模型。为了实现这些目标，这一更新应用程序将再次结合组织工程师和糖生物学家的专业知识，同时增加活跃在氨基葡萄糖临床试验中的风湿病医生的新意见，以推动和转化这种在软骨修复中应用糖的新方法。总体而言，将追求以下特定目标：特定目标1.评估和比较新型GlcN糖类似物对水凝胶培养的正常细胞和骨关节炎细胞的生物学反应和软骨组织发育。具体目的2.明确GlcN及其类似物在组织发育中的作用机制。具体目的3.将GlcN/GlcN类似物翻译成骨关节炎的啮齿动物模型。 公共卫生相关性：骨性关节炎是一个重大的公共卫生挑战，数百万美国人因其对关节的衰弱作用而遭受痛苦。我们建议开发新的方法来治疗骨性关节炎和促进新的软骨形成，使用基于糖氨基葡萄糖的新的糖类似物。

DESCRIPTION (provided by applicant): The overall goal of this project is to design and implement novel strategies for cartilage repair and treatment of osteoarthritis (OA), leveraging tissue engineering and biological signals inspired by the sugar glucosamine (GlcN). Small molecule stimulation of tissue growth would provide a significant tool for the field of tissue engineering that frequently depends on complex and unstable growth factor proteins as biological signals. Preliminary data and published research from the initial funding period established a window of efficacy where chondrocytes, stem cells, and diseased osteoarthritic cells could be stimulated by GlcN to form more cartilage, with new sugar analogs developed by the Yarema Lab demonstrated an even more potent effect. From the mechanistic perspective, we discovered that certain novel analogs suppressed NF-: B, a molecule important in cartilage disease such as osteoarthritis. Finally, in vitro results were translated to pilot in vivo testing in a rodent model of OA with GlcN injected into joint space improving cartilage structure compared to saline control injections. These findings lay the groundwork for a medicinal chemistry approach to defining new small molecules for precise and effective intervention in tissue engineering for OA and cartilage repair. In this competitive renewal, we propose to investigate the ability of novel sugar analogs, designed by the Yarema Lab, to stimulate tissue growth of normal and osteoarthritic chondrocytes in three dimensional biomaterial scaffolds. For sugars demonstrating a significant stimulation of cartilage tissue growth, the mechanism of action will be evaluated. The sugar analog that demonstrates the greatest stimulation of normal and/or diseased cells will then be applied to a rodent animal model of OA. To accomplish these goals, this renewal application will again combine the expertise of a tissue engineer and a glycobiologist while adding new input from a rheumatologist active in clinical trials for glucosamine, to drive forward and translate this new approach for applying sugars in cartilage repair. Overall, the following specific aims will be pursued: Specific Aim 1. Evaluate and compare the biological response and cartilage tissue development induced by novel GlcN sugar analogs on normal and osteoarthritis cells cultured in hydrogels. Specific Aim 2. Determine the mechanism of GlcN and novel GlcN analogs on tissue development. Specific Aim 3. Translation of GlcN/GlcN analogs to a rodent model of osteoarthritis. PUBLIC HEALTH RELEVANCE: Osteoarthritis is a significant public health challenge with millions of Americans suffering from its debilitating effects on joints. We propose to develop new methods to treat OA and promote new cartilage formation using novel sugar analogs based on the sugar glucosamine.