Apolipoproteins and Amyloid Formation in Atheroma

动脉粥样硬化中的载脂蛋白和淀粉样蛋白形成

• 批准号: nhmrc : 350229
• 负责人: A/Pr Geoffrey Howlett
• 金额: $ 29.31万
• 依托单位: The University of Melbourne
• 依托单位国家: 澳大利亚
• 项目类别: NHMRC Project Grants
• 财政年份: 2005
• 资助国家: 澳大利亚
• 起止时间: 2005-01-01 至 2007-12-31
• 项目状态: 已结题
• 来源: https://researchdata.edu.au/apolipoproteins-amyloid-formation-atheroma/98385
• 关键词: Apolipoproteins; Amyloid; Formation; Atheroma

We propose to study the poorly understood, disease-associated process of amyloid formation, using a sensitive and reproducible model developed in our laboratory. Amyloid deposits are a feature of several neurodegenerative and metabolic disorders such as Alzheimer's and Parkinson's disease and are also common in atherosclerotic plaque or atheroma. They are composed of tangled networks of fibrillar proteins together with several non-fibrillar proteins and proteoglycans. Atherosclerotic plaques typically consist of fibrous proteins, lipids and foam cells derived from macrophages via receptor-mediated uptake of oxidized low density lipoproteins. Our model system is based on the formation of amyloid fibrils from apolipoprotein (apo) C-II which accumulates in atherosclerotic plaques where it co-localizes with serum amyloid P component, a marker of amyloid fibrils. ApoC-II is a component of plasma lipoproteins and an important activator of the enzyme lipoprotein lipase, which functions in the transport and distribution of triacylglycerols to tissues. We have shown that apoC-II (79 amino acids) readily forms amyloid fibrils under lipid-free conditions, adopting a cross-beta sheet structure that reacts with the amyloid stains thioflavin T and Congo Red. The formation and properties of apoC-II amyloid fibrils and the amyloid-like properties of oxidized lipoproteins are the subject of the present proposal. We will characterize the effects of lipids and oxidation on the rate of formation and the properties of apoC-II amyloid fibrils. We will also study the effects of oxidation on the amyloid-like properties of lipoproteins and their interactions with serum amyloid P component and cell surface receptors.

我们建议研究知之甚少，疾病相关的淀粉样蛋白形成过程，使用我们实验室开发的敏感和可重复的模型。淀粉样蛋白沉积是一些神经退行性和代谢性疾病的特征，如阿尔茨海默病和帕金森病，也常见于动脉粥样硬化斑块或动脉粥样硬化。它们是由纤维蛋白与几种非纤维蛋白和蛋白聚糖组成的缠结网络。动脉粥样硬化斑块通常由纤维蛋白、脂质和泡沫细胞组成，这些细胞来源于巨噬细胞，通过受体介导的氧化低密度脂蛋白的摄取。我们的模型系统基于载脂蛋白C-II形成淀粉样原纤维，载脂蛋白C-II积聚在动脉粥样硬化斑块中，与血清淀粉样蛋白P成分（淀粉样原纤维的标记物）共定位。ApoC-II是血浆脂蛋白的组成部分，也是脂蛋白脂肪酶的重要激活剂，在三酰基甘油向组织的运输和分布中起作用。我们已经证明apoC-II（79个氨基酸）在无脂条件下很容易形成淀粉样蛋白原纤维，采用交叉β片结构，与淀粉样蛋白染色剂硫黄素T和刚果红发生反应。apoC-II淀粉样原纤维的形成和性质以及氧化脂蛋白的淀粉样性质是本提案的主题。我们将描述脂质和氧化对apoC-II淀粉样原纤维形成速率和性质的影响。我们还将研究氧化对脂蛋白淀粉样特性的影响及其与血清淀粉样蛋白P组分和细胞表面受体的相互作用。