Application of SHP2 PROTAC to Mitigate Articular Cartilage Degeneration

应用 SHP2 PROTAC 减轻关节软骨退变

基本信息

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
项目类别：
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

项目摘要

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然而，其形成与 SOX9 表达升高有关。从机制上讲，SHP2 耗竭如何增加 SOX9 并促进软骨样细胞增殖。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。刺激这样的假设：SHP2通过翻译后生理学限制软骨中的SOX9水平因此，关节内 SHP2 缺失会增加 SOX9 蛋白丰度和转录。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。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。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成功完成拟议的工作将产生重大影响。软骨生物学和 OA 预防。