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Cellular homeostasis and healthy ageing: protein folding, redox and metabolism

细胞稳态和健康衰老：蛋白质折叠、氧化还原和新陈代谢

基本信息

批准号：
2737209
负责人：
金额：
--
依托单位：
University of Leicester
依托单位国家：
英国
项目类别：
Studentship
财政年份：
2022
资助国家：
英国
起止时间：
2022 至无数据
项目状态：
未结题

来源：
https://gtr.ukri.org/projects?ref=studentship-2737209
关键词：
Cellular homeostasis healthy ageing protein

项目摘要

At a cellular level, healthy ageing depends upon the resilience of homoeostatic mechanisms. Pathways regulating clearance of misfolded proteins (proteostasis), redox responses, metabolic pathways and general injury responses appear important in this regard and may be linked. In tissue, collapse of these processes manifests as fibrosis or scarring. I plan to probe their relationships with each other. I propose to do this by using CRISPR editing of a promoter region to generate pairs of epithelial cell lines differing only in the degree of proteostatic challenge relating to expression of a single mucin protein, MUC5B. To fold properly this protein requires correct formation of three pairs of intramolecular disulphide bonds between six cysteine residues. This requires considerable engagement of the regulatory machinery of redox homoeostasis and protein folding within the endoplasmic reticulum (ER). Its overexpression in epithelial cells is associated with ER stress, and with dysfunctional injury and scarring responses in tissue. I will therefore use my cell models to correlate levels of homoeostatic challenge in protein folding, redox, and metabolic reprogramming. I further propose to assess the degree to which these responses relate to regulation of pro-fibrotic cross-talk between epithelial and mesenchymal cells by modulating ER stress, redox, and mitochondrial function.

在细胞水平上，健康的老龄化取决于体内平衡机制的恢复力。在这方面，调节错误折叠蛋白质的清除（蛋白质稳态）、氧化还原反应、代谢途径和一般损伤反应的途径似乎很重要，并且可能是相关的。在组织中，这些过程的崩溃表现为纤维化或瘢痕形成。我打算调查他们之间的关系。我建议通过使用CRISPR编辑启动子区域来产生成对的上皮细胞系，其差异仅在于与单个粘蛋白MUC5B表达相关的蛋白抑制挑战程度。为了正确折叠这种蛋白质，需要在六个半胱氨酸残基之间正确形成三对分子内二硫键。这需要相当大的参与调节机制的氧化还原稳态和蛋白质折叠内质网（ER）。其在上皮细胞中的过表达与ER应激以及组织中的功能障碍性损伤和瘢痕形成反应相关。因此，我将使用我的细胞模型来关联蛋白质折叠、氧化还原和代谢重编程中的同源平衡挑战水平。我进一步建议，以评估这些反应涉及到调节促纤维化的上皮细胞和间充质细胞之间的串扰的程度，通过调节ER应激，氧化还原和线粒体功能。