New paradigms in fibroblast-immune cells coordination in matrix homeostasis in health and disease

健康和疾病基质稳态中成纤维细胞-免疫细胞协调的新范例

• 批准号: MR/W016796/1
• 负责人: Joan Chang
• 金额: $ 160.66万
• 依托单位: University of Manchester
• 依托单位国家: 英国
• 项目类别: Fellowship
• 财政年份: 2022
• 资助国家: 英国
• 起止时间: 2022 至 无数据
• 项目状态: 未结题
• 来源: https://gtr.ukri.org/projects?ref=MR%2FW016796%2F1
• 关键词: New; paradigms; fibroblast; immune; cells

Collagen is the most abundant protein in the human body (~25% by mass), and is formed into long fibrils that provide structure to organs with very different functions and mechanical properties (e.g. giant parallel bundles in tendons, smooth flat lattices in lungs). This suggests a fine control of the cells in producing and assembling these long fibrils, and dysregulation of this control underpins many pathologies, including fibrosis, heart disease, and many age-related conditions such as proneness to fractures, skin looseness, and osteoarthritis. Convention dictates that different cells have different functions - notably fibroblasts are the key arbiters to collagen matrix formation, and immune cells are the removers; however, recently it has been discovered that immune cells directly contribute to the production of collagen. This highlights how despite collagen's clear fundamental importance, we still do not fully understand the process of its assembly and maintenance, in particular how different types of cells communicate and cooperate with one another in this process. This forms the basis and goals of my research. My recent work has shown that the circadian rhythm controls collagen production and secretion, and I have also discovered that a specialised compartment of the cells (known as the endosome) holds the key to the fate of collagen within the cells, i.e. whether they will be made into fibrils, simply secreted out of the cells, or degraded. Using new mass spectrometry approaches that I have pioneered, I aim to determine how this control of fibril formation happens at the molecular level, as knowledge of how to direct collagen between the different fates will allow for new therapeutic strategies for fibrosis - a disease characterised by an abundance of collagen fibrils that currently has no effective cure. Using the same mass spectrometry technique, I will further determine the molecular networks in immune cells that control collagen uptake, which may provide further insights to targeting fibrosis from a different angle. This knowledge will also be fundamental to other conditions heavily involving the immune system and matrix, including wound healing and cancer metastasis. I have also found that immune cells induce fibroblast circadian rhythms, and that fibroblasts and immune cells make more collagen fibrils when they are mixed together. I will interrogate this relationship and determine the proportion of collagen produced by each cell type in the mixtures, using state-of-the-art genetic modification and high throughput biochemical assays, providing important insights into how fibroblasts and immune cells communicate and coordinate in collagen deposition. As such, my work has important and fundamental implications to further our mechanistic understanding of fibrotic responses, in its broadest sense.

胶原蛋白是人体中含量最多的蛋白质（约占总量的25%），并形成长原纤维，为具有不同功能和机械特性的器官提供结构（例如肌腱中的巨大平行束，肺中的光滑扁平晶格）。这表明细胞在产生和组装这些长原纤维时受到良好的控制，而这种控制的失调是许多病理的基础，包括纤维化、心脏病和许多与年龄相关的疾病，如骨折、皮肤松弛和骨关节炎。传统观点认为，不同的细胞有不同的功能——尤其是成纤维细胞是胶原基质形成的关键仲裁者，而免疫细胞是清除者；然而，最近发现免疫细胞直接促进胶原蛋白的产生。这表明，尽管胶原蛋白具有明确的基础重要性，但我们仍然不完全了解其组装和维护的过程，特别是不同类型的细胞在此过程中如何相互沟通和合作。这构成了我研究的基础和目标。我最近的工作表明，昼夜节律控制着胶原蛋白的产生和分泌，我还发现细胞的一个特殊隔间（称为内核体）掌握着细胞内胶原蛋白命运的关键，即它们是否会被制成原纤维，简单地分泌出细胞，还是被降解。使用我开创的新的质谱分析方法，我的目标是确定纤维形成的控制是如何在分子水平上发生的，因为如何在不同命运之间指导胶原蛋白的知识将允许新的治疗纤维化的策略-一种以丰富的胶原原纤维为特征的疾病，目前尚无有效的治疗方法。使用相同的质谱技术，我将进一步确定免疫细胞中控制胶原摄取的分子网络，这可能从不同的角度为靶向纤维化提供进一步的见解。这一知识也将对其他严重涉及免疫系统和基质的疾病，包括伤口愈合和癌症转移，具有重要意义。我还发现，免疫细胞诱导成纤维细胞的昼夜节律，当成纤维细胞和免疫细胞混合在一起时，它们会产生更多的胶原原纤维。我将询问这种关系，并确定每种细胞类型在混合物中产生胶原蛋白的比例，使用最先进的基因修饰和高通量生化分析，为成纤维细胞和免疫细胞如何在胶原沉积中沟通和协调提供重要见解。因此，我的工作具有重要的和基本的意义，进一步我们的机制理解纤维化反应，在其最广泛的意义上。

项目成果

Modeling collagen fibril self-assembly from extracellular medium in embryonic tendon.

胚胎肌腱细胞外介质中胶原纤维自组装的建模。

• DOI: 10.1016/j.bpj.2023.07.001
• 发表时间: 2023
• 期刊: Biophysical journal
• 影响因子: 3.4
• 作者: Revell CK

The matrix in focus: new directions in extracellular matrix research from the 2021 ASMB hybrid meeting.

• DOI: 10.1242/bio.059156
• 发表时间: 2022-01-15
• 期刊: Biology open
• 影响因子: 2.4
• 作者: Nerger BA;Jones TM;Rose KWJ;Barqué A;Weinbaum JS;Petrie RJ;Chang J;Vanhoutte D;LaDuca K;Hubmacher D;Naba A
• 通讯作者: Naba A