Understanding how ageing impacts on vascular regeneration through the endothelial senescence associated secretory phenotype

通过内皮衰老相关的分泌表型了解衰老如何影响血管再生

• 批准号: BB/T000805/1
• 负责人: Reinhold Medina
• 金额: $ 54.64万
• 依托单位: Queen's University Belfast
• 依托单位国家: 英国
• 项目类别: Research Grant
• 财政年份: 2020
• 资助国家: 英国
• 起止时间: 2020 至 无数据
• 项目状态: 已结题
• 来源: https://gtr.ukri.org/projects?ref=BB%2FT000805%2F1
• 关键词: Understanding; how; ageing; impacts; vascular

Ageing is the greatest risk factor for poor health and chronic diseases. While life expectancy continues to rise, health span is not improving at the same pace, and therefore there is a real need to increase the quality of life in the elderly population. Ageing impacts on every tissue in our body, and our lab is particularly interested in ageing of blood vessels. The idea of ageing in the vasculature is not new as there is an English saying from the 1600s stating, "A man is only as old as his arteries"; however, recent technological advances in science have opened new opportunities to understand the ageing of blood vessels at the molecular level.This study will employ state-of-the-art technology to investigate ageing in stem cells from blood vessels. These cells known as vascular stem cells or endothelial progenitor cells are responsible for repairing and maintaining a healthy vasculature. There is a theory of ageing suggesting that there is a loss of stem cells with age, while others propose that stem cells become dysfunctional or senescent. Here, we will elucidate how stem cells in blood vessels change during the ageing process.The ageing process in cells is called cellular senescence, and there is evidence to indicate that senescent cells adopt an inflammatory phenotype. The secretion of these inflammatory proteins is called SASP and reinforces the senescence programme. While this idea was demonstrated in human skin fibroblasts, it is not known if this applies to other tissues and cells. Here, we will investigate if inflammation and SASP drives cellular senescence in endothelial progenitors. Importantly, we aim to inhibit this SASP as a strategy to enhance vascular health.A multidisciplinary team comprising of stem cell biologists, vascular biologists, and inflammation biologists designed this project. Working together, we will investigate vascular ageing and endothelial senescence in vascular stem cells using state-of-the-art technologies. We will provide the first detailed molecular characterisation of SASP in endothelial progenitors. Furthermore, we will identify components of the SASP that could be modulated to promote vascular health. In addition, we will use a unique animal model to test the role of inflammation driving vascular ageing and vascular stem cell exhaustion. In summary, outcomes of this project will provide critical information in relation to how vascular ageing is driven by cellular senescence and inflammation in vascular stem cells.

老龄化是健康状况不佳和慢性病的最大风险因素。虽然预期寿命继续延长，但健康状况却没有以同样的速度改善，因此，真实的需要提高老年人口的生活质量。衰老影响着我们身体的每一个组织，我们的实验室对血管的衰老特别感兴趣。血管老化的概念并不新鲜，早在十七世纪，英国便有一句谚语：“人的年龄与他的动脉一样大”。不过，随着科学技术的发展，我们有机会从分子层面了解血管的老化。是项研究将利用先进的科技，研究血管干细胞的老化过程。这些细胞被称为血管干细胞或内皮祖细胞，负责修复和维持健康的血管系统。有一种衰老理论认为，随着年龄的增长，干细胞会丢失，而其他人则认为干细胞会变得功能失调或衰老。在这里，我们将阐明血管中的干细胞如何在衰老过程中发生变化。细胞的衰老过程称为细胞衰老，有证据表明衰老细胞采用炎症表型。这些炎症蛋白的分泌被称为SASP，并加强衰老程序。虽然这一想法在人类皮肤成纤维细胞中得到了证实，但尚不清楚这是否适用于其他组织和细胞。在这里，我们将研究炎症和SASP是否驱动内皮祖细胞的细胞衰老。重要的是，我们的目标是抑制这种SASP作为一种策略，以提高血管健康。一个多学科的团队，包括干细胞生物学家，血管生物学家和炎症生物学家设计了这个项目。我们将共同努力，利用最先进的技术研究血管干细胞中的血管老化和内皮衰老。我们将首次提供SASP在内皮祖细胞中的详细分子特征。此外，我们将确定SASP的组成部分，可以调节，以促进血管健康。此外，我们将使用一种独特的动物模型来测试炎症驱动血管老化和血管干细胞耗竭的作用。总之，该项目的结果将提供有关血管衰老如何由血管干细胞中的细胞衰老和炎症驱动的关键信息。

项目成果

Advances in cell therapies using stem cells/progenitors as a novel approach for neurovascular repair of the diabetic retina.

• DOI: 10.1186/s13287-022-03073-x
• 发表时间: 2022-07-30
• 期刊: Stem cell research & therapy
• 影响因子: 7.5

The Long Pentraxin PTX3 as a New Biomarker and Pharmacological Target in Age-Related Macular Degeneration and Diabetic Retinopathy.

• DOI: 10.3389/fphar.2021.811344
• 发表时间: 2021
• 期刊: Frontiers in pharmacology
• 影响因子: 5.6
• 作者: Stravalaci M;Ferrara M;Pathak V;Davi F;Bottazzi B;Mantovani A;Medina RJ;Romano MR;Inforzato A
• 通讯作者: Inforzato A

Retinal pigment epithelium extracellular vesicles are potent inducers of age-related macular degeneration disease phenotype in the outer retina.

• DOI: 10.1002/jev2.12295
• 发表时间: 2022-12
• 期刊: Journal of extracellular vesicles
• 影响因子: 16

Long term high glucose exposure induces premature senescence in retinal endothelial cells.

• DOI: 10.3389/fphys.2022.929118
• 发表时间: 2022
• 期刊: Frontiers in physiology
• 影响因子: 4

Current concepts on endothelial stem cells definition, location, and markers.

• DOI: 10.1002/sctm.21-0022
• 发表时间: 2021-11
• 期刊: Stem cells translational medicine
• 影响因子: 6
• 作者: Chambers SEJ;Pathak V;Pedrini E;Soret L;Gendron N;Guerin CL;Stitt AW;Smadja DM;Medina RJ
• 通讯作者: Medina RJ