Defining the transciptional and extracellular matrix landscapes of developing human tendons

定义发育中的人类肌腱的转录和细胞外基质景观

• 批准号: 2443418
• 金额: --
• 依托单位: University of Oxford
• 依托单位国家: 英国
• 项目类别: Studentship
• 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=studentship-2443418
• 关键词: Defining; transciptional; extracellular; matrix; landscapes

Tendon diseases affect millions of people worldwide, leading to a significant socioeconomic burden and a healthcare challenge. The spectrum of aetiologies from injuries to age-related degeneration means that people of all ages can become vulnerable to tendinopathies. While non-surgical interventions are available, they are limited in scope and tend to mostly focus on symptomatic relief and restoration of functionality. Many patients do not benefit from conservative treatment and elect to undergo surgery with widely varying but generally high failure rates. In order to reduce surgery failure rates, novel biomaterials are being developed with the potential to provide structural support as well as a biologically active niche conducive to tendon regeneration. However, selection of candidate biomaterial strategies has been severely hampered by a paucity of research into the cellular biology defining healthy and diseased, or developing and aging tendons. To address this problem, a multi-disciplinary 'Tendon Seed Network' has recently been established within the Human Cell Atlas (HCA) initiative to undertake single-cell sequencing on healthy adult tendons. My project aims to complement this initiative with an open source, detailed and unbiased dataset of the cellular populations within diseased and developing tendons to ultimately provide critical metrics for informing the design of biomaterials capable of guiding diseased tissue repair towards a normal phenotype. Specifically, I will first extend the HCA of healthy tendons by characterising diseased tendons at single-cell and metabolomic resolutions to identify disease-specific transcriptomic signatures. Next, I will generate a spatial single-cell resolution map of gene expression in embryonic and adolescent healthy human tendons and compare it with the adult map to gain insight into the cellular mechanisms controlling the differentiation of tendon cells. Finally, once the diseased and developing tendon blueprints are established, I will develop and screen a biomaterial library for material candidates that induce diseased tendon cells to express gene modules representative of healthy or developing tendons and indicative of healing. This work will greatly enhance our understanding of tendon disease and contribute to the development of more effective therapies.

肌腱疾病影响全球数百万人，导致重大的社会经济负担和医疗保健挑战。从损伤到与年龄相关的退行性疾病的各种病因意味着，所有年龄段的人都可能容易患上肌腱病。虽然非手术干预措施是可用的，但它们的范围有限，往往主要集中在症状缓解和功能恢复上。许多患者没有从保守治疗中受益，他们选择接受手术，虽然差异很大，但失败率普遍很高。为了减少手术失败率，人们正在开发新的生物材料，这些材料具有提供结构支持的潜力，以及有利于肌腱再生的生物活性利基。然而，由于缺乏对定义健康和疾病或发育和老化肌腱的细胞生物学的研究，候选生物材料策略的选择受到了严重阻碍。为了解决这个问题，最近在人类细胞图谱(HCA)倡议内建立了一个多学科的‘肌腱种子网络’，对健康的成年肌腱进行单细胞测序。我的项目旨在用一个开源的、详细的和不偏不倚的数据集来补充这一倡议，该数据集是关于疾病和正在发育的肌腱中的细胞种群的，最终提供关键的指标，为能够引导疾病组织修复走向正常表型的生物材料的设计提供信息。具体地说，我将首先扩展健康肌腱的HCA，通过在单细胞和代谢组分辨率下表征患病肌腱来识别疾病特异性转录信号。接下来，我将生成胚胎和青少年健康肌腱基因表达的空间单细胞分辨率图谱，并将其与成人图谱进行比较，以深入了解控制肌腱细胞分化的细胞机制。最后，一旦建立了患病和发育中的肌腱蓝图，我将开发和筛选一个生物材料库，以寻找诱导患病肌腱细胞表达代表健康或发育中的肌腱和表明愈合的基因模块的候选材料。这项工作将极大地提高我们对肌腱疾病的认识，并有助于开发更有效的治疗方法。