Technologies for an in-vitro carbon copy of lung disease

肺部疾病的体外复制技术

• 批准号: EP/W004453/1
• 负责人: Pietro Cicuta
• 金额: $ 38.58万
• 依托单位: University of Cambridge
• 依托单位国家: 英国
• 项目类别: Research Grant
• 财政年份: 2021
• 资助国家: 英国
• 起止时间: 2021 至 无数据
• 项目状态: 已结题
• 来源: https://gtr.ukri.org/projects?ref=EP%2FW004453%2F1
• 关键词: Technologies; vitro; carbon; copy; lung

Our proposed work focuses on the lung, addressing physical aspects of how it maintains a physiological balance of mucus production and clearance, which is the first barrier to any airborne infection. Chronic lung disease can lead to development of a common condition known as chronic obstructive pulmonary disease (COPD) and, as reported widely in 2020, can result from the severe inflammatory processes triggered as the body responds to viruses such as SARS-Cov-2. There are also a number of prevalent genetic conditions that affect the lung. Cystic Fibrosis (CF), for example, manifests fundamentally as problem of impaired muco-ciliary clearance with patients developing airway obstruction, chronic infection, and subsequent inflammatory lung damage. Ciliopathies are genetic conditions that affect the motile cilia organelles themselves. In all these diseases, there is interplay between the specific cause of disease, and the health and function of the lung organ more broadly, and there is extremely large and poorly understood patient-to-patient variability. Clinical practice could be vastly more effective if there was a way to promptly and reliably create a model system that represented the particular patient, with their state of disease, and on which to rapidly test therapies. This means using the patient's primary cells from lungs, their resident macrophages, and any other relevant infection/co-infection/microbiota. A high fidelity disease model can then be built, together with scaffolds that can represent the extracellular matrix of interest, and any vasculature and geometric/structural boundaries. It is clearly time for life-sciences to move on from studying pathogens, hosts, stem cells, etc. each in isolation from each other. What we propose here are a series of technological steps in the direction of being able to rapidly and reliably, and without intensive labour, create a carbon copy of a certain organ (we will focus on lung) at the moment of serious disease, for the purpose of optimising treatment. This dovetails very well with increasing common pipelines of sequencing, with high throughput facilities in some hospital able to sequence samples down to single cell resolution. Our carbon copy platforms will recreate the relevant organ phenotypes, and enable physiological and physical readouts as well as molecular. We pay particular attention to the sustainability (scale and cost) of the technologies that we will propose to develop.

我们提出的工作重点是肺部，解决其如何维持粘液产生和清除的生理平衡的物理方面，这是任何空气传播感染的第一道屏障。慢性肺病可导致一种称为慢性阻塞性肺病 (COPD) 的常见病症，正如 2020 年广泛报道的那样，慢性肺病可能是由于身体对 SARS-Cov-2 等病毒做出反应而引发的严重炎症过程所致。还有许多影响肺部的常见遗传病。例如，囊性纤维化 (CF) 从根本上表现为粘液纤毛清除受损的问题，患者会出现气道阻塞、慢性感染和随后的炎症性肺损伤。纤毛病是影响活动纤毛细胞器本身的遗传性疾病。在所有这些疾病中，疾病的具体病因与更广泛的肺器官的健康和功能之间存在相互作用，并且患者之间存在极大且难以理解的变异性。如果有一种方法能够迅速、可靠地创建一个代表特定患者及其疾病状态的模型系统，并在其上快速测试治疗方法，那么临床实践可能会更加有效。这意味着使用患者肺部的原代细胞、其常驻巨噬细胞以及任何其他相关的感染/共感染/微生物群。然后可以建立高保真疾病模型，以及可以代表感兴趣的细胞外基质以及任何脉管系统和几何/结构边界的支架。显然，生命科学现在应该摆脱对彼此孤立的病原体、宿主、干细胞等的研究。我们在这里提出的是一系列技术步骤，旨在能够在严重疾病发生时快速可靠地、无需大量劳动力地创建某个器官（我们将重点关注肺）的副本，以供达到优化治疗的目的。这与不断增加的通用测序流程非常吻合，一些医院的高通量设施能够对样品进行低至单细胞分辨率的测序。我们的复写平台将重建相关的器官表型，并实现生理和物理以及分子读数。我们特别关注我们将提议开发的技术的可持续性（规模和成本）。

项目成果

Measuring Biophysical Properties of Cilia Motility from Mammalian Tissues via Quantitative Video Analysis Methods.

通过定量视频分析方法测量哺乳动物组织纤毛运动的生物物理特性。

• DOI: 10.1007/978-1-0716-3507-0_16
• 发表时间: 2024
• 期刊: Methods in molecular biology (Clifton, N.J.)
• 作者: Causa E

Assessing motile cilia coverage and beat frequency in mammalian in vitro cell culture tissues.

• DOI: 10.1098/rsos.230185
• 发表时间: 2023-08
• 期刊: ROYAL SOCIETY OPEN SCIENCE
• 影响因子: 3.5
• 作者: Fradique, Ricardo;Causa, Erika;Delahousse, Clara;Kotar, Jurij;Pinte, Laetitia;Vallier, Ludovic;Vila-Gonzalez, Marta;Cicuta, Pietro
• 通讯作者: Cicuta, Pietro