Mechanochemical interplay between Extracellular Matrix and cellular responses in Idiopathic Pulmonary Fibrosis (Ref: 4659)
特发性肺纤维化中细胞外基质和细胞反应之间的机械化学相互作用(参考文献:4659)
基本信息
- 批准号:2885583
- 负责人:
- 金额:--
- 依托单位:
- 依托单位国家:英国
- 项目类别:Studentship
- 财政年份:2023
- 资助国家:英国
- 起止时间:2023 至 无数据
- 项目状态:未结题
- 来源:
- 关键词:
项目摘要
Idiopathic pulmonary fibrosis (IPF) is a chronic lung disease with a median survival of only 3-5 years after diagnosis - a prognosis worse than many cancers. Normal lung is irreversibly replaced by scar tissue, which makes breathing progressively more difficult. Around 32,000 people in the UK are estimated to have IPF, with 6,000 new cases estimated to occur annually - and it is responsible for >1% of all UK deaths.Lung cell behaviour is influenced by a tissue-specific macromolecular structure called the extracellular matrix (ECM), which gives tissues physical support and is crucial to healthy organ function. However, an excessive accumulation of ECM and remodelling of the lung architecture is a pathological characteristics of IPF. Changes to the biomechanical properties of the fibrotic ECM, such as increased tissue stiffness, may affect the quantity of pro-fibrotic growth factors available to cells, their behaviours, and how phenotypes are determined. For instance, ECM substrate stiffness greater than 8 kPA may cause fibroblast contractility, cytoskeletal changes, ECM secretion, and differentiation of fibroblasts to myofibroblasts - the central effector cell in IPF. However, the specific interactions between the ECM elements and the processes that cause fibrosis to occur in the majority of individuals are still poorly understood. The word "matrisome" has been coined to characterise the constituents found in the tissue ECM, which include fibrillar proteins, glycoproteins, proteoglycans, and their associated modifying agents (such as metalloproteases and matricellular proteins).Current guidelines for diagnosing IPF are based on a high-resolution computed tomography (CT) findings and occasionally on the histological analysis of a lung biopsy for confirmation of diagnosis. Histology is also essential in pathophysiological investigations of experimental samples, allowing investigation of microstructure. A growing, multidisciplinary area of label-free optical technologies offers the inherent benefit of avoiding the laborious steps of traditional histology, with the added possibility of in-vivo use (e.g. via bronchoscopy), to overcome these limitations. Label-free technologies are especially promising for multimodal platforms since they do not need artificial contrast agents that might interfere with other integrated measurement methods.The study of intact, unstained tissue using multiphoton microscopy (MPM), which relies on endogenous sources of nonlinear signals, is gaining popularity in the fields of biomedicine and bioengineering. In particular, the intrinsic second harmonic generation (SHG) of fibrillar collagen can be observed in tandem with cellular and extracellular 2-Photon Excited Fluorescence (2PEF) endogenous signals, allowing researchers to explore the ECM macromolecular architecture. The polarisation sensitive SHG microscopy can image structure and composition at the microscopic scale, and report a measure of organisation at the molecular scale. Raman spectroscopy (RS) is another label-free spectroscopic method that permits in-depth investigation of the biochemical of materials by using the inelastic scattering of photons by molecules with discrete rotational or vibrational energy links. How the precise mechanochemical properties of the ECM can influence cellular behaviour in IPF is not well understood. It is also unclear whether the altered phenotype of disease fibroblasts can directly modify the ECM to propagate pathology. This research will add to our understanding of the ECM features that influence lung fibroblast behaviour and how this interaction works, with a focus on mechano-transduction signalling.The project Aim is therefore to investigate the bi-directional mechanochemical relationship between the extracellular matrix and lung fibroblasts in the context of IPF using tissue samples, organoids, multiphoton microscopy and Raman spectroscopy.
特发性肺纤维化(IPF)是一种慢性肺部疾病,诊断后的中位生存期仅为3-5年-预后比许多癌症更差。正常的肺部被疤痕组织不可逆转地取代,这使得呼吸逐渐变得更加困难。据估计,英国约有32,000人患有IPF,每年估计有6,000例新发病例,占英国所有死亡人数的1%以上。肺细胞行为受称为细胞外基质(ECM)的组织特异性大分子结构影响,ECM为组织提供物理支持,对健康器官功能至关重要。然而,ECM的过度积累和肺结构的重塑是IPF的病理特征。纤维化ECM的生物力学性质的变化,如组织硬度增加,可能会影响细胞可用的促纤维化生长因子的量、它们的行为以及表型的确定方式。例如,ECM底物硬度大于8 kPA可引起成纤维细胞收缩性、细胞骨架变化、ECM分泌和成纤维细胞分化为肌成纤维细胞-IPF中的中央效应细胞。然而,ECM元件和导致纤维化发生在大多数个体中的过程之间的特定相互作用仍然知之甚少。“基质体”一词是指在组织ECM中发现的成分,包括纤维蛋白、糖蛋白、蛋白聚糖及其相关的修饰剂(如金属蛋白酶和基质细胞蛋白)。目前诊断IPF的指南是基于高分辨率计算机断层扫描(CT)结果,偶尔也基于肺活检的组织学分析以确认诊断。组织学在实验样品的病理生理学研究中也是必不可少的,可以研究微观结构。无标记光学技术的一个不断发展的多学科领域提供了避免传统组织学的繁琐步骤的固有好处,并增加了体内使用的可能性(例如通过支气管镜检查),以克服这些限制。无标记技术是特别有前途的多模态平台,因为他们不需要人工造影剂,可能会干扰其他综合measurementmethods.The研究的完整的,未染色的组织使用多光子显微镜(MPM),它依赖于内源性来源的非线性信号,是越来越受欢迎的生物医学和生物工程领域。特别是,可以观察到纤维状胶原蛋白的固有二次谐波产生(SHG)与细胞和细胞外2-光子激发荧光(2 PEF)内源性信号,使研究人员能够探索ECM大分子结构。偏振敏感的SHG显微镜可以在微观尺度上对结构和组成进行成像,并在分子尺度上报告组织的测量。拉曼光谱(RS)是另一种无标记的光谱方法,其允许通过使用具有离散旋转或振动能量链接的分子对光子的非弹性散射来深入研究材料的生物化学。ECM的精确机械化学性质如何影响IPF中的细胞行为尚不清楚。还不清楚疾病成纤维细胞的改变的表型是否可以直接修饰ECM以传播病理。这项研究将增加我们对影响肺成纤维细胞行为的ECM特征以及这种相互作用如何起作用的理解,重点是机械转导信号传导。因此,该项目的目的是使用组织样本,类器官,多光子显微镜和拉曼光谱研究IPF背景下细胞外基质和肺成纤维细胞之间的双向机械化学关系。
项目成果
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其他文献
吉治仁志 他: "トランスジェニックマウスによるTIMP-1の線維化促進機序"最新医学. 55. 1781-1787 (2000)
Hitoshi Yoshiji 等:“转基因小鼠中 TIMP-1 的促纤维化机制”现代医学 55. 1781-1787 (2000)。
- DOI:
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LiDAR Implementations for Autonomous Vehicle Applications
- DOI:
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2021 - 期刊:
- 影响因子:0
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吉治仁志 他: "イラスト医学&サイエンスシリーズ血管の分子医学"羊土社(渋谷正史編). 125 (2000)
Hitoshi Yoshiji 等人:“血管医学与科学系列分子医学图解”Yodosha(涉谷正志编辑)125(2000)。
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Effect of manidipine hydrochloride,a calcium antagonist,on isoproterenol-induced left ventricular hypertrophy: "Yoshiyama,M.,Takeuchi,K.,Kim,S.,Hanatani,A.,Omura,T.,Toda,I.,Akioka,K.,Teragaki,M.,Iwao,H.and Yoshikawa,J." Jpn Circ J. 62(1). 47-52 (1998)
钙拮抗剂盐酸马尼地平对异丙肾上腺素引起的左心室肥厚的影响:“Yoshiyama,M.,Takeuchi,K.,Kim,S.,Hanatani,A.,Omura,T.,Toda,I.,Akioka,
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