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

胶原蛋白是人体中最丰富的蛋白质（约25%质量），并形成长纤维，为具有非常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，肺中的平滑扁平晶格）。这表明细胞在产生和组装这些长纤维中的精细控制，并且这种控制的失调支持许多病理学，包括纤维化，心脏病和许多与年龄相关的病症，如骨折倾向，皮肤松弛和骨关节炎。传统认为不同的细胞具有不同的功能-特别是成纤维细胞是胶原蛋白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有助于胶原蛋白的产生。这突出表明，尽管胶原蛋白具有明确的基本重要性，但我们仍然没有完全了解其组装和维护的过程，特别是不同类型的细胞如何在此过程中相互交流和合作。这是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专门的隔室（称为内体）掌握着细胞内胶原蛋白命运的关键，即它们是否会被制成纤维，简单地分泌出细胞，或降解。使用我开创的新质谱方法，我的目标是确定这种纤维形成的控制如何在分子水平上发生，因为如何在不同命运之间引导胶原蛋白的知识将允许纤维化的新治疗策略-一种以丰富的胶原纤维为特征的疾病，目前没有有效的治疗方法。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蛋白摄取的分子网络，这可能从不同的角度为靶向纤维化提供进一步的见解。这些知识也将是其他严重涉及免疫系统和基质的疾病的基础，包括伤口愈合和癌症转移。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，会产生更多的胶原纤维。我将询问这种关系，并确定混合物中每种细胞类型产生的胶原蛋白的比例，使用最先进的遗传修饰和高通量生化测定，为成纤维细胞和免疫细胞如何在胶原蛋白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根本的影响，以进一步我们的机械理解纤维化反应，在其最广泛的意义。

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.