Advanced Glycation End Products Effects on Bone Biomechanics

描述（由申请方提供）：将在小鼠模型中研究晚期糖基化终产物（AGE）对皮质骨生物力学特性的影响。已知AGE形成损害骨生物力学性质的交联。AGE随着年龄的增长而增加，并且也在某些疾病中发现，包括1型和2型糖尿病。该项目将采用一种独特的工具组合：生物力学测量、拉曼光谱和固态魔角旋转核磁共振光谱（MAS NMR），这些工具将提供有关骨矿物微晶晶体结构和骨机械加载时胶原二级结构中材料特性变化的详细信息。一个定制设计的转子，包括提供应用压缩载荷将用于弹性变形MAS NMR实验。外部载荷将用于研究屈服点以外材料特性的化学结构相关性。我们假设矿物质的变化将包括矿物质压缩和基质胶原蛋白链的变形，因为交联被变形，并且这些变化可以作为骨的NMR和拉曼光谱的变化来跟踪。核糖孵育将用于在鼠皮质骨中产生AGE非酶交联。孵育时间的变化将用于改变交联丰度，并将为进一步研究提供背景信息。有了这些背景资料，将进行一项关于年龄依赖性的研究。我们假设矿物质压缩和胶原蛋白变形将随着年龄的增长而增加。接下来，我们将研究AGE在NOD皮质骨（1型糖尿病小鼠模型）中的作用。我们希望看到类似于衰老研究中的变化，但它们将在更早的年龄开始开始。我们还将开发AGE水平和全骨特性之间的相关性，以及NMR和全骨特性产生的超微结构水平组成数据之间的相关性，为超微结构变化如何转化为全骨功能提供重要见解，并作为骨骼脆性的预测因子。最后，我们将开发MAS NMR提供的详细结构信息和拉曼光谱提供的较不详细的信息之间的相关性。这些相关性将用于增加从其他拉曼光谱研究中获得的信息，特别是骨骼疾病的非侵入性诊断。

DESCRIPTION (provided by applicant): The effect of advanced glycation end products (AGE's) on the biomechanical properties of cortical bone will be studied in murine models. It is known that AGE's form cross-links that compromise bone biomechanical properties. AGE's accumlate with age and are also found in certain disorders, including type 1 and type 2- diabetes. The project will employ a unique combination of tools: biomechanical measurements, Raman spectroscopy and solid state magic angle spinning nuclear magnetic resonance spectroscopy (MAS NMR) that will provide detailed information on material property changes in the crystal structure of bone mineral crystallites and in the collagen secondary structure as the bone is mechanically loaded. A custom-designed rotor that includes provision for applying compressive load will be used for elastic deformation MAS NMR experiments. External loading will be used to study chemical structure correlates of material properties beyond the yield point. We hypothesize that changes in the mineral will include mineral compression and distortion of the matrix collagen chain as cross-links are distorted and that these changes can be followed as changes in both NMR and Raman spectra of the bone. Ribose incubation will be used to generate AGE non-enzymatic cross-links in murine cortical bone. Variations in incubation time will be used to vary the cross-link abundance and will provide background information for further studies. With this background information, a study of age- dependence will be undertaken. We hypothesize that mineral compression and collagen distortion will increase with age. Next, we will study the AGE effects in NOD cortical bone, a mouse model for type 1 diabetes. We expect to see changes similar to those in the aging study, but that they will begin at earlier ages. We will also develop correlations between AGE levels and whole bone properties and between ultrastructural level composition data generated by NMR and whole bone properties, providing important insights into how ultrastructural changes translate into whole bone function and serve as predictors of skeletal fragility. Finally, we will develop correlations between the detailed structural information provided by MAS NMR and the less detailed information provided by Raman spectroscopy. These correlations will be used to increase the information gained from other Raman spectroscopic studies, especially non-invasive diagnostics for bone disorders.