Collagen mutations in bone matrix dysfunction

骨基质功能障碍中的胶原蛋白突变

• 批准号: nhmrc : 114119
• 负责人: Prof John Bateman
• 金额: $ 36.62万
• 依托单位国家: 澳大利亚
• 项目类别: NHMRC Project Grants
• 财政年份: 2000
• 资助国家: 澳大利亚
• 起止时间: 2000-01-01 至 2002-12-31
• 项目状态: 已结题
• 来源: https://researchdata.edu.au/collagen-mutations-bone-matrix-dysfunction/100631
• 关键词: Collagen; mutations; bone; matrix; dysfunction

This project is a biochemical investigation of collagen, which is the principle protein of bone, joints, blood vessels and skin. More than 200 mutations have been identified in the genes for type I collagen that result in Osteogenesis Imperfecta (OI), otherwise known as brittle-bone disease, in children and adults. However, very little is known about how these mutations cause bones to be brittle and why the disease varies so widely in severity. Our experiments are directed towards a better understanding of how bone cells respond to the mutant collagen and how these mutations actually result in brittle bones. We know that the majority of OI-causing mutations typically lead to a severe OI because the mutant collagen interferes with normal functioning of the matrix and effectively weakens it. We will examine how the mutant collagen disrupts normal cell function using bone and skin cell lines in which we have added a mutated collagen gene. The mutations we will introduce are the same ones that cause OI in patients. The experiments cannot be carried out with OI cell lines isolated from humans because it is very difficult to identify the mutant collagen in the matrix. Instead we have engineered a marker into the mutant collagen to allow the mutant collagen to be easily tracked. We will then examine how the presence of the mutant collagen affects matrix integrity, turnover and the formation of mutant matrix. In the second part of the study we will make a transgenic mouse that carries a specific collagen mutation. This will allow us to examine the fate of mutant collagen in a whole animal. As with the engineered cells described above, the mutant collagen will be altered to allow easy tracking. Collectively, these experiments will provide valuable information about how the presence mutant collagen disprupts integrity of the extracellular matrix of skin and bone.

该项目是对胶原蛋白的生化研究，胶原蛋白是骨骼、关节、血管和皮肤的主要蛋白质。 I 型胶原蛋白基因中已发现 200 多个突变，这些突变会导致儿童和成人成骨不全症 (OI)，也称为脆骨病。然而，人们对这些突变如何导致骨骼变脆以及为什么这种疾病的严重程度差异如此之大知之甚少。我们的实验旨在更好地了解骨细胞如何对突变胶原蛋白做出反应以及这些突变实际上如何导致脆骨。我们知道，大多数导致成骨不全的突变通常会导致严重的成骨不全，因为突变的胶原蛋白会干扰基质的正常功能并有效地削弱它。我们将使用添加了突变胶原蛋白基因的骨骼和皮肤细胞系来研究突变胶原蛋白如何破坏正常细胞功能。我们将引入的突变与导致患者成骨不全的突变相同。该实验不能用从人类分离的 OI 细胞系进行，因为很难识别基质中的突变胶原。相反，我们在突变胶原蛋白中设计了一个标记，以便可以轻松追踪突变胶原蛋白。然后我们将研究突变胶原蛋白的存在如何影响基质完整性、周转和突变基质的形成。在研究的第二部分中，我们将制作一只携带特定胶原蛋白突变的转基因小鼠。这将使我们能够检查突变胶原蛋白在整个动物中的命运。与上述工程细胞一样，突变胶原蛋白将被改变以方便追踪。总的来说，这些实验将提供有关突变胶原蛋白如何破坏皮肤和骨骼细胞外基质完整性的有价值的信息。