Organization of the early secretory pathway in vertebrates: the role of the Mia gene family.
脊椎动物早期分泌途径的组织:Mia 基因家族的作用。
基本信息
- 批准号:BB/V004352/1
- 负责人:
- 金额:$ 62.58万
- 依托单位:
- 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:未结题
- 来源:
- 关键词:
项目摘要
The internal organization of every cell in our bodies is inherently linked to their function. We study the way in which the individual compartments (organelles) within cells relate to one another in the context of protein secretion. This is fundamental for many aspects of life in particular the formation and maintenance of the extracellular matrix that surrounds cells in every tissue. This matrix is largely made up of collagen, the most abundant protein in our bodies. We have discovered that the way in which these organelles relate to one another requires specific proteins that were previously considered to have quite specific roles in collagen transport. We are now in a position to exploit the latest advances in genome engineering to define the role of a family of proteins (called the Mia family) in cell and tissue function. We can only develop this work so far in cells in culture and so also plan to develop our experiments using zebrafish models. This gives us huge advantages of being able to look at cells in context, as they interact and move within a living organism. Zebrafish are well established as a developmental model and many tools that are well suited to this project are already available. Fortunately for us, we have established a collaboration with Brian Link (Milwaukee, USA) who has recently developed some Mia gene family knockout fish.While our work is very much aimed at defining the fundamental cell biology of this system it is also of significant relevance to society. Collagen is the most abundant protein in the human body, forming a vital protein scaffold to support cells and maintain tissue integrity. It is a critical component of cartilage and bone. Understanding the biology of the collagen matrix is fundamental to human health. As we age, loss of skin elasticity, poor wound healing, and an increased susceptibility to osteoarthritis and bone fractures become prevalent and the underlying cause is usually a reduction in the quality of collagen in the affected tissues. There are no effective treatments for many of these diseases. Conversely, abnormal accumulation of collagen causes fibrosis, a type of scarring, which is associated with 45% of all deaths (including those from cancer and cardiovascular disease). Here, we propose a project to define the fundamental mechanisms of protein secretion by looking at a holistic level at the early secretory pathway. We will however maintain an overall vision of considering the assembly and secretion of the collagen-rich extracellular matrix from cells. Any future opportunities to modulate tissue maintenance, and turnover will require a detailed understanding of the mechanisms by which collagen is made. The process is unfortunately tremendously complex, and we have only just begun to understand which components are involved in the system and what they do. Much work to date has been necessarily limited to simple systems. Our work will provide new insight into how cells are organized, how the system functions in the normal state, what goes wrong in particular human genetic diseases that affects these specific components, and into how collagen is synthesised and packaged by cells. As such this work integrates very well with our other UKRI-BBSRC funded work leading to synergies and economies of scale.
我们身体中每个细胞的内部组织都与它们的功能有着内在的联系。我们在蛋白质分泌的背景下研究细胞内各个隔室(细胞器)相互联系的方式。这对生命的许多方面都是基本的,特别是围绕着每个组织中细胞的细胞外基质的形成和维持。这种基质主要由胶原蛋白组成,胶原蛋白是我们身体中含量最丰富的蛋白质。我们已经发现,这些细胞器相互联系的方式需要特定的蛋白质,这些蛋白质以前被认为在胶原蛋白运输中具有非常特殊的作用。我们现在能够利用基因组工程的最新进展来确定蛋白质家族(称为Mia家族)在细胞和组织功能中的作用。到目前为止,我们只能在培养细胞中开展这项工作,因此也计划利用斑马鱼模型来开展我们的实验。这给了我们巨大的优势,能够在背景下观察细胞,因为它们在活的有机体中相互作用和移动。斑马鱼作为一种发展模式已得到很好的确立,许多非常适合该项目的工具已经可用。幸运的是,我们已经与布莱恩·林克(美国密尔沃基)建立了合作关系,他最近开发了一些Mia基因家族剔除鱼。虽然我们的工作主要是为了定义这个系统的基本细胞生物学,但它也与社会有重要的相关性。胶原蛋白是人体内含量最丰富的蛋白质,是支持细胞和维持组织完整性的重要蛋白质支架。它是软骨和骨骼的重要组成部分。了解胶原蛋白基质的生物学特性对人类健康至关重要。随着年龄的增长,皮肤弹性丧失,伤口愈合不良,骨关节炎和骨折的易感性增加,其根本原因通常是受影响组织中胶原质量的降低。这些疾病中的许多都没有有效的治疗方法。相反,胶原蛋白的异常积累会导致纤维化,这是一种疤痕形成,与45%的死亡(包括癌症和心血管疾病)有关。在这里,我们提出了一个项目,通过观察早期分泌途径的整体水平来定义蛋白质分泌的基本机制。然而,我们将保持一个全面的愿景,考虑从细胞中组装和分泌富含胶原的细胞外基质。任何未来调节组织维护和周转的机会都需要详细了解胶原蛋白的形成机制。不幸的是,这个过程极其复杂,我们才刚刚开始了解系统中涉及哪些组件以及它们的功能。到目前为止,许多工作必然局限于简单的系统。我们的工作将提供新的见解,了解细胞是如何组织的,系统在正常状态下是如何运作的,在影响这些特定成分的人类遗传病中发生了什么问题,以及胶原是如何由细胞合成和包装的。因此,这项工作与UKRI-BBSRC资助的其他工作很好地结合在一起,从而产生协同效应和规模经济。
项目成果
期刊论文数量(0)
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Chrissy Hammond其他文献
09-P004 Two populations of endochondral osteoblasts with differential sensitivity to Hedgehog signaling
- DOI:
10.1016/j.mod.2009.06.334 - 发表时间:
2009-08-01 - 期刊:
- 影响因子:
- 作者:
Chrissy Hammond;Stefan Schulte-Merker - 通讯作者:
Stefan Schulte-Merker
Chrissy Hammond的其他文献
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{{ truncateString('Chrissy Hammond', 18)}}的其他基金
Maintenance, regeneration, and repair of skeletal systems: molecular regulation of autophagy in the joint
骨骼系统的维护、再生和修复:关节自噬的分子调节
- 批准号:
BB/Y002504/1 - 财政年份:2023
- 资助金额:
$ 62.58万 - 项目类别:
Research Grant
Biomechanical characterisation of joints in osteoarthritis mutant zebrafish; studying interactions between genotype and biomechanics in osteoarthritis
骨关节炎突变斑马鱼关节的生物力学特征;
- 批准号:
MR/L002566/1 - 财政年份:2014
- 资助金额:
$ 62.58万 - 项目类别:
Research Grant
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