Circadian rhythms in the ageing spine: implications in intervertebral disc degeneration and stem-cell based regeneration

衰老脊柱的昼夜节律：对椎间盘退变和干细胞再生的影响

• 批准号: 2627645
• 金额: --
• 依托单位: University of Manchester
• 依托单位国家: 英国
• 项目类别: Studentship
• 财政年份: 2021
• 资助国家: 英国
• 起止时间: 2021 至 无数据
• 项目状态: 未结题
• 来源: https://gtr.ukri.org/projects?ref=studentship-2627645
• 关键词: Circadian; rhythms; ageing; spine; implications

Low back pain is amongst the most prevalent spinal diseases, causing severe pain and loss of mobility. Progressive degeneration of the intervertebral disc (IVD) tissue is a major cause, with ageing as a major risk factor. Stem cell-based therapies provide hope for tissue regeneration of the IVD and restoration of function. The Hoyland and Meng labs have r shown, for the first time, an autonomous circadian (24 hourly) rhythm in mouse IVD tissue explants and human IVD cells (Dudek et al., Annals Rheum Dis 2016). We have generated a conditional BMAL1 (a core clock factor) knockout mouse model that selectively disrupts circadian rhythm in the IVD, and a BMAL1-Venus knock-in mouse model using CRISPR-CAS technique (Yang et al., PLoS Gen 2020). These exciting novel discoveries and animal models place us in a unique position internationally and provide an unprecedented new opportunity to further our understanding of the pathogenesis of IVD degeneration and low back pain. We therefore hypothesize that disruption to the circadian clock (for example, during ageing) may be a critical risk factor in human disc degeneration. Consequently, enhancing circadian rhythms may slow down tissue degeneration and promote stem-cell based regenerative therapies. In this PhD project, we will utilize state of the art "-omics" techniques (RNAseq deep sequencing), bio-informatics, high-end imaging, biochemistry and monitoring of clock gene activities, to elucidate roles of circadian rhythm in human disc degeneration and cell-based therapy for treatment of disc degeneration. This project will provide fresh new insights into the function of a core circadian clock factor BMAL1 in IVD physiology and pathogenesis and establish a mechanistic link between ageing and IVD circadian rhythm disruption. More importantly, the project will directly demonstrate the relevance of circadian clocks in human degenerative discs and mesenchymal stem-cell differentiation protocols being currently developed for cell based regenerative strategies for the treatment of disc degeneration and low back pain.

腰痛是最常见的脊柱疾病之一，会导致严重的疼痛和活动能力丧失。椎间盘（IVD）组织的进行性退变是一个主要原因，衰老是一个主要的危险因素。干细胞治疗为IVD的组织再生和功能恢复提供了希望。Hoyland和孟实验室首次在小鼠IVD组织外植体和人类IVD细胞中显示了自主的昼夜节律（24小时）节律（Dudek等人，Annals Rheum Dis 2016）。我们已经建立了一个条件BMAL1（核心时钟因子）敲除小鼠模型，该模型选择性地破坏IVD中的昼夜节律，并使用CRISPR-CAS技术建立了BMAL1- venus敲入小鼠模型（Yang等人，PLoS Gen 2020）。这些令人兴奋的新发现和动物模型使我们在国际上处于独特的地位，并为进一步了解IVD变性和腰痛的发病机制提供了前所未有的新机会。因此，我们假设生物钟的破坏（例如，在衰老过程中）可能是人类椎间盘退变的关键风险因素。因此，增强昼夜节律可能会减缓组织退化并促进基于干细胞的再生治疗。在这个博士项目中，我们将利用最先进的“组学”技术（RNAseq深度测序）、生物信息学、高端成像、生物化学和时钟基因活动监测，阐明昼夜节律在人类椎间盘退变中的作用，以及细胞治疗椎间盘退变的方法。该项目将为核心生物钟因子BMAL1在IVD生理和发病机制中的功能提供新的见解，并建立衰老与IVD昼夜节律中断之间的机制联系。更重要的是，该项目将直接证明昼夜节律时钟在人类退行性椎间盘和间充质干细胞分化方案中的相关性，目前正在开发用于治疗椎间盘退变和腰痛的基于细胞的再生策略。