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软骨修复和骨关节炎（OA）治疗的新策略，利用组织工程和受糖葡萄糖胺（GlcN）启发的生物信号。组织生长的小分子刺激将为组织工程领域提供重要的工具，该领域经常依赖于复杂且不稳定的生长因子蛋白作为生物信号。最初资助期间的初步数据和已发表的研究建立了一个功效窗口，其中软骨细胞，干细胞和患病的骨关节炎细胞可以被GlcN刺激以形成更多的软骨，Yarema实验室开发的新糖类似物显示出更有效的效果。从机制的角度来看，我们发现某些新的类似物抑制NF-：B，一种在软骨疾病如骨关节炎中重要的分子。最后，将体外结果转化为在OA的啮齿动物模型中的初步体内测试，与盐水对照注射相比，将GlcN注射到关节间隙中改善软骨结构。这些发现为药物化学方法奠定了基础，以定义新的小分子，用于精确有效地干预OA和软骨修复的组织工程。在这种竞争性的更新中，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的组织生长的能力。对于显示出显著刺激软骨组织生长的糖，将评价作用机制。然后将显示出对正常和/或患病细胞的最大刺激的糖类似物应用于OA的啮齿动物模型。为了实现这些目标，该更新应用将再次结合联合收割机的组织工程师和糖生物学家的专业知识，同时增加来自活跃在葡萄糖胺临床试验中的流变学家的新输入，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，将追求以下具体目标：具体目标1。评价和比较新型GlcN糖类似物对在水凝胶中培养的正常和骨关节炎细胞诱导的生物反应和软骨组织发育。具体目标2。确定GlcN和新型GlcN类似物对组织发育的机制。具体目标3。将GlcN/GlcN类似物翻译至骨关节炎的啮齿动物模型。 公共卫生相关性：骨关节炎是一个重大的公共卫生挑战，数百万美国人遭受其对关节的衰弱影响。我们建议开发新的方法来治疗OA和促进新的软骨形成，使用基于糖葡萄糖胺的新型糖类似物。

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.