Application of SHP2 PROTAC to Mitigate Articular Cartilage Degeneration

应用 SHP2 PROTAC 减轻关节软骨退变

• 批准号: 10535540
• 负责人: Wentian Yang
• 金额: $ 21.37万
• 依托单位: RHODE ISLAND HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-09-01 至 2024-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10535540
• 关键词: Alginates; Anabolism; Biological Assay; Biology; Cartilage; Cartilage injury; Cell Lineage; Cell Proliferation; Cells; Chondrocytes; Chondrogenic Neoplasm; Data; Degenerative polyarthritis; Development; Enzymes; Equilibrium; Foundations; Gene Expression; Genetic; Genetic Transcription; Goals; Homeostasis; Immunoprecipitation; In Situ Hybridization; In Vitro; Injections; Injury; Investigation; Joints; Knee joint; Luciferases; Mass Spectrum Analysis; Medial meniscus structure; Modeling; Molecular; Mus; Natural regeneration; Operative Surgical Procedures; Outcome; PTPN11 gene; Pathology; Phosphorylation; Physiological; Post-Translational Protein Processing; Prevention; Protac; Protein Dephosphorylation; Protein Tyrosine Kinase; Protein Tyrosine Phosphatase; Proteins; Publishing; Regulation; Reporter; Role; SOX9 protein; Signal Transduction; Sumoylation Pathway; Testing; Therapeutic; Therapeutic Agents; Thick; Tissues; Western Blotting; Work; articular cartilage; base; cancer therapy; cartilage cell; cartilage degradation; cartilage metabolism; chimera drug; druggable target; experimental study; innovation; insight; kinase inhibitor; novel; prevent; primary outcome; promoter; repaired; response; secondary outcome; stem cells; targeted treatment; transcription factor; translational applications; translational potential

PROJECT SUMMARY: It has been known for years that somatic SHP2 deletion in chondroid cells causes cartilage tumor formation associated with elevated SOX9 expression. However, it remains incompletely understood mechanistically how SHP2 depletion increases SOX9 and promotes chondroid cell proliferation. The work outlined in this proposal builds on our novel discovery that the genetic deletion of SHP2 in cartilage cells increases SOX9 abundance associated with SOX9 phosphorylation and sumoylation. These findings together stimulate the hypothesis that SHP2 physiologically limits SOX9 level in cartilage via posttranslational modifications. Therefore, intraarticular SHP2 depletion increases SOX9 protein abundance and transcriptional activity, promoting chondrocyte anabolism and protecting AC from injury-evoked degeneration. To test this novel hypothesis, we proposed two specific Aims. In Aim #1 we will determine to what extent intraarticular SHP2 degradation, using the first SHP2 PROTAC drug SHP2D26, mitigates injury-evoked articular cartilage degeneration. In Aim #2, we will interrogate the molecular mechanism through which SHP2 depletion enhances SOX9 abundance by focusing on SHP2’s regulation of SOX9 posttranslational modifications. This innovative study will result in the first-ever description of the mechanisms by which SHP2 modulates cartilage anabolism through SOX9 and provide instrumental information on the translational application of SHP2D26 in countering cartilage degeneration. Successful completion of the work proposed will have a significant impact on cartilage biology and OA prevention.

项目概要： 多年来人们就知道软骨样细胞中体细胞 SHP2 缺失会导致软骨肿瘤 形成与 SOX9 表达升高相关。但仍不完全了解 从机制上讲，SHP2 耗竭如何增加 SOX9 并促进软骨样细胞增殖。工作 本提案中概述的内容建立在我们的新发现之上，即软骨细胞中 SHP2 的基因缺失 增加与 SOX9 磷酸化和 sumoylation 相关的 SOX9 丰度。这些发现一起 刺激这样的假设：SHP2 通过翻译后在生理上限制软骨中的 SOX9 水平 修改。因此，关节内 SHP2 缺失会增加 SOX9 蛋白丰度和转录水平 活性，促进软骨细胞合成代谢并保护 AC 免受损伤引起的退化。为了测试这个 新的假设，我们提出了两个具体目标。在目标#1中，我们将确定关节内的程度 SHP2降解，使用第一个SHP2 PROTAC药物SHP2D26，减轻损伤引起的关节软骨 退化。在目标 #2 中，我们将探究 SHP2 耗竭的分子机制 通过关注 SHP2 对 SOX9 翻译后修饰的调节来增强 SOX9 丰度。这 创新研究将首次描述 SHP2 调节软骨的机制 通过 SOX9 进行合成代谢，并提供有关 SHP2D26 在中的转化应用的工具信息 对抗软骨退化。拟议工作的成功完成将产生重大影响 软骨生物学和 OA 预防。