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: