Application of SHP2 PROTAC to Mitigate Articular Cartilage Degeneration

项目概要： 多年来，软骨样细胞中的体细胞SHP 2缺失导致软骨肿瘤 形成与SOX 9表达升高相关。然而，它仍然不完全理解 SHP 2耗竭如何机械地增加SOX 9并促进软骨样细胞增殖。工作 本提案中概述的内容是基于我们的新发现，即软骨细胞中SHP 2的基因缺失 增加与SOX 9磷酸化和类小泛素化相关的SOX 9丰度。这些发现一起 刺激SHP 2通过翻译后作用生理性限制软骨中SOX 9水平的假设 修改.因此，关节内SHP 2缺失增加了SOX 9蛋白丰度和转录水平。 活性，促进软骨细胞凋亡，保护AC免受损伤诱发的退变。为了验证这一 新的假设，我们提出了两个具体的目的。在目标1中，我们将确定关节内 使用第一种SHP2 PROTAC药物SHP2D26的SHP2降解可减轻损伤诱发的关节软骨 退化在目标#2中，我们将询问SHP 2消耗的分子机制。 通过关注SHP 2对SOX 9翻译后修饰的调节来增强SOX 9丰度。这 一项创新性的研究将首次描述SHP 2调节软骨的机制 通过SOX 9进行分析，并提供有关SHP2D26在以下方面的翻译应用的工具信息： 对抗软骨退化顺利完成拟议的工作将产生重大影响 软骨生物学和OA预防的研究

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.