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.

项目总结： 多年来已知软骨细胞中体细胞SHP2缺失会导致软骨肿瘤 与SOX9表达升高相关的形成。然而，它仍然没有完全被理解。 机制：SHP2缺失如何增加SOX9并促进软骨细胞增殖。这项工作 我们的新发现是在软骨细胞中SHP2基因缺失的基础上 增加与SOX9磷酸化和SUMO化相关的SOX9丰度。这些发现加在一起 支持SHP2通过翻译后生理作用限制软骨SOX9水平的假说 修改。因此，关节内SHP2的缺失增加了SOX9蛋白的丰度和转录 活性，促进软骨细胞合成代谢，保护AC免受损伤引起的退化。为了测试这一点 新的假设，我们提出了两个具体的目标。在目标1中，我们将确定关节内的程度 Shp2降解，使用第一种SHP2 PROTAC药物SHP2D26，减轻损伤引起的关节软骨 退化。在目标2中，我们将询问SHP2耗尽的分子机制 通过关注SHP2对SOX9翻译后修饰的S调节来提高SOX9的丰度。这 创新性研究将首次描述SHP2调节软骨的机制 通过SOX9的合成代谢，并提供了SHP2D26在 对抗软骨退变。拟议工作的圆满完成将产生重大影响 论软骨生物学与骨性关节炎预防。