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）

• 批准号: 2885583
• 金额: --
• 依托单位: UNIVERSITY OF EXETER
• 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: https://gtr.ukri.org/projects?ref=studentship-2885583
• 关键词: Mechanochemical; interplay; between; Extracellular; Matrix; Mechanochemical; interplay; between; Extracellular; Matrix

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，诊断后仅3 - 5年的中位生存期 - 预后比许多癌症差。正常的肺部被疤痕组织不可逆转地取代，这会使呼吸逐渐变得更加困难。据估计，英国约有32,000人患有IPF，估计有6,000例每年发生6,000例新病例 - 造成所有英国死亡的1％> 1％。肺细胞行为受组织特异性的大分子分子结构的影响，称为细胞外矩阵（ECM），这给组织提供了物理支持，并且对健康的器官功能至关重要。但是，ECM的过度积累和肺结构的重塑是IPF的病理特征。纤维化ECM的生物力学特性的变化，例如增加的组织刚度，可能会影响细胞可用的促纤维化生长因子的数量，其行为以及如何确定表型。例如，ECM底物刚度大于8 kPa可能会导致成纤维细胞收缩力，细胞骨架变化，ECM分泌以及成纤维细胞与肌纤维细胞的分化 - IPF中的中心效应细胞。但是，ECM元素与导致大多数个体发生纤维化发生的过程之间的特定相互作用仍然很了解。 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肺活检以确认诊断。组织学在实验样本的病理生理研究中也是必不可少的，可以研究微观结构。一个不断发展的无标签光学技术领域的多学科领域为避免传统组织学的艰辛步骤提供了固有的好处，并增加了体内使用的可能性（例如，通过支气管镜检查）克服了这些限制。对于多模式平台而言，无标签的技术特别有希望，因为它们不需要人造对比剂，可能会干扰其他综合测量方法。使用多光子显微镜（MPM）对完整的未染色组织的研究依赖于非线性信号的内源性信号，这是在生物素和Bioomedicenice sengine and BioomediceNice and Bioomedicenice conportial compoction cons的依赖。特别地，可以在与细胞和细胞外2光激发荧光（2PEF）内源信号的汇总胶原蛋白的固有第二个谐波产生（SHG）（SHG）中观察到，从而使研究人员能够探索ECM ECM分子分子结构。极化敏感的SHG显微镜可以在微观尺度上图像结构和组成，并以分子尺度报告组织的量度。拉曼光谱（RS）是另一种无标签的光谱法，它通过使用具有离散的旋转或振动能链路的分子对光子的非弹性散射来深入研究材料的生化。 ECM的精确机械化学特性如何影响IPF中的细胞行为。还不清楚疾病成纤维细胞的表型是否可以直接修饰ECM以传播病理学。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的作用，重点是机械转导信号。因此，该项目的目的是在使用组织样品和型号的IPF中研究IPF的IPF中的IPF，并调查细胞外基质和肺成型成核细胞之间的双向机械化学关系。