Role of Desumoylase SENP6 in Joint Aging and Osteoarthritis Development

去糖化酶 SENP6 在关节衰老和骨关节炎发展中的作用

• 批准号: 10375570
• 负责人: Tao Yang
• 金额: $ 49.85万
• 依托单位: VAN ANDEL RESEARCH INSTITUTE
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-07-15 至 2024-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10375570
• 关键词: Adult; Affect; Age; Aging; Biology; Cartilage; Cell Aging; Cells; Cellular Stress; Chondrocytes; Chronic; DNA Damage; Data; Degenerative polyarthritis; Development; Disease; Endogenous Retroviruses; Environment; Enzymes; Epigenetic Process; Exhibits; Future; Gene Expression; Gene Expression Regulation; Genotoxic Stress; Goals; Health; Homeostasis; Inflammation; Inflammatory; Joints; Knowledge; Laboratories; Lead; Mediating; Mission; Modification; Mus; Pathogenesis; Pathway interactions; Peptide Hydrolases; Phenotype; Plant Roots; Predisposition; Prevention; Process; Production; Property; Proteins; Publishing; Reporting; Role; Signal Transduction; Site; Source; Stress; Sumoylation Pathway; Testing; Tissues; Translating; Tweens; Ubiquitination; United States National Institutes of Health; Variant; Work; Yang; age related; biological adaptation to stress; disability; epigenetic regulation; epigenome; genome wide association study; joint injury; mouse genetics; mouse model; novel; osteoprogenitor cell; palliative; premature; prevent; response; senescence; skeletal; stressor; transcriptome; treatment strategy; ubiquitin-protein ligase

PROJECT SUMMARY For decades, it has been known that the inflammatory and catabolic environment in the joints accelerates oste- oarthritis (OA) development. However, current OA therapies that inhibit this environment are not curative, as they do not target the underlying cause of such an environment. It was recently shown that senescent articular chondrocytes (ACs) are a major source of inflammatory and catabolic factors. Last year, it was reported that eliminating senescent ACs can alleviate the progression of age-related and post-traumatic OA in mice. While this suggests a potential treatment avenue, ideally, we would also identify the root causes (i.e. the pathways) that lead to AC senescence, and target those to prevent or slow the transition to senescence in the first place. Our long-term goal is to examine the mechanisms that lead to AC senescence, so that strategies can be devel- oped for prevention and/or treatment of OA. To that end, data from a genome-wide association study (arcO- GEN Consortium, 2012) showed a strong association of OA with SENP6, which is an enzyme (desumoylase) that reverses SUMO modifications on specific protein targets. We found this intriguing, because sumoylation is an enzymatic pathway that has been associated with both the stress response and the aging process, and is potentially druggable. My lab has reported the correlations among the SENP6 pathway, cell senescence, and stress response in skeletal progenitors. Also, we showed that this occurs partially via over-sumoylation of TRIM28, an epigenetic regulator associated with senescence. Moreover, our preliminary work found that SENP6 loss in cartilage accelerated AC senescence and OA in mice, providing a rationale for further examin- ing the role of SENP6. The hypothesis is that SENP6 reduces OA susceptibility by suppressing AC senes- cence induced by stress response and epigenetic alterations. To test this hypothesis, our first goal is to deter- mine the future viability of SENP6 as a possible target for treatment; we will examine the extent to which gain of SENP6 function reduces OA progression. Next, because our preliminary work suggested an interplay be- tween SENP6 stability and stress response, the second goal is to determine how stress induces SENP6 degra- dation and how the underlying mechanism affects AC senescence. Our third goal is to identify SENP6-orches- trated epigenetic alterations and their role in AC senescence. This is inspired by the facts that epigenetic alter- ations are a hallmark of aging and that our and other's findings suggest a potential role for the SENP6–TRIM28 axis in the epigenetic regulation of gene expression and inflammation. It is expected that this proposed work will have a broad impact by uncovering a new mechanism that connects the sumoylation pathways to stress response, epigenetic alterations, senescence, joint aging, and OA. These results will form a basis for develop- ing new OA treatments by inhibiting AC senescence through selective modulation of sumoylation-related path- ways, e.g., by increasing SENP6 level or activity.

项目摘要 几十年来，众所周知，关节中的炎症和分解代谢环境加速了骨气。 浮浮炎（OA）发育。但是，当前抑制这种环境的OA疗法无法治愈，因为 它们不针对这种环境的根本原因。最近表明感觉关节 软骨细胞（ACS）是炎症和分解代谢因素的主要来源。去年，有报道说 消除感觉AC可以减轻小鼠与年龄相关和创伤后OA的进展。尽管 这表明理想情况下，我们还将确定一个潜在的治疗途径（即途径） 这会导致AC感应，并靶向它们以防止或减慢过渡到感应的速度。 我们的长期目标是检查导致AC敏感的机制，以便可以发展策略。 OP用于预防和/或治疗OA。为此，来自全基因组关联研究的数据（arco- Gen Consortium，2012年）显示了OA与SENP6有很强的关联，这是一种酶（Desumoylase） 这逆转了对特定蛋白质靶标的SUMO修饰。我们发现这很有趣，因为Sumoylation是 与应力反应和衰老过程既相关的酶促途径又 潜在的吸毒。我的实验室报告了SENP6途径，细胞感应和 骨骼祖细胞中的压力反应。另外，我们表明，这部分通过过度肿胀发生 TRIM28，一种与感应相关的表观遗传调节剂。而且，我们的初步工作发现 软骨中的SENP6损失加速了AC的感应和OA的小鼠，为进一步检查提供了理由 - senp6的角色。假设是SENP6通过抑制AC传感器 - 由压力反应和表观遗传改变引起的裂变。为了检验这一假设，我们的第一个目标是确定 - 挖掘SENP6作为治疗的可能目标的未来生存能力；我们将研究获得的程度 SENP6功能的OA进展降低。接下来，因为我们的初步工作暗示了一个相互作用 推文SENP6稳定性和压力反应，第二个目标是确定压力如何诱导SENP6降解 dation以及潜在机制如何影响交流感应。我们的第三个目标是确定Senp6-orches- 表观遗传改变及其在交流传感中的作用。这是受表观遗传替代的事实的启发 ations是衰老的标志，我们和其他人的发现表明SENP6 – TRIM28的潜在作用 基因表达和炎症的表观遗传调节中的轴。预计这项建议的工作 通过发现将Sumoylation途径连接到压力的新机制，将产生广泛的影响 反应，表观遗传改变，感应，关节老化和OA。这些结果将构成发展的基础 - 通过选择性调节Sumoylation相关路径来抑制AC的感应，从而抑制AC的感觉 例如，通过提高SENP6水平或活动。