Chemical Structure Effects on Bone Response to Mechanical Load

化学结构对骨骼对机械负荷反应的影响

• 批准号: 8268927
• 负责人: MICHAEL DAVID MORRIS
• 金额: $ 32.8万
• 依托单位: UNIVERSITY OF MICHIGAN AT ANN ARBOR
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-08-01 至 2015-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8268927
• 关键词: Age; Aging; Amino Acids; Binding; Biomechanics; Biopsy; Bone Diseases; Bone Matrix; Bone Tissue; Calcium; Calcium Carbonate; Carbonates; Cell Nucleus; Cells; Chemical Structure; Chemicals; Collagen; Collagen Diseases; Competence; Complex; Cross-Sectional Studies; Deuterium; Deuterium Oxide; Development; Exercise; Failure; Fatigue; Fracture; Genetic; Glycine; Goals; Health; Hydrogen Bonding; Imaging Techniques; Ions; Location; Magic; Measurement; Measures; Mechanical Stress; Mechanics; Metabolic Diseases; Minerals; Modeling; Molecular Conformation; Movement; Mus; Mutation; NMR Spectroscopy; Nuclear Magnetic Resonance; Osteoporosis; Phenotype; Physiologic pulse; Population; Porosity; Positioning Attribute; Proline; Property; Proteins; Protocols documentation; Protons; Public Health; Quantitative Trait Loci; Research Personnel; Resolution; Role; Secondary Protein Structure; Series; Site; Specimen; Stress; Structure; Surface; Techniques; Testing; Time; Tissues; Uncertainty; Water; Water Movements; Work; age related; behavior change; bone; bone quality; carboapatite; crosslink; disorder control; inorganic phosphate; method development; mouse model; new therapeutic target; novel diagnostics; public health relevance; research study; response; solid state; solid state nuclear magnetic resonance; tibia; tool

DESCRIPTION (provided by applicant): We will apply solid-state magic angle spinning nuclear magnetic resonance spectroscopy (MAS-NMR) to measure changes in the chemical structure of bone tissue under mechanical load. MAS-NMR will allow us to examine ultrastructure contributions to bone quality that have, to date, been unobtainable using traditional imaging techniques or other biophysical techniques. The enabling advance is a special NMR cell that allows compressive loading and displacement measurements. High-resolution structural information will be correlated to strain of bone tissue from mature murine tibiae as the specimens are deformed under uniaxial compression. In Aim 1 we will assess distortion of the bone mineral lattice as changes in the mineral ion spacings and water mobility using a several different 1D and 2D solid-state NMR pulse sequences. We will also study load- induced changes in a series of synthesized carbonated apatites, which are model compounds for bone mineral to guide interpretation of our bone mineral results and to enable measurements with isotopically enriched nuclei, especially 43Ca. In these simplified model compounds we can accurately measure inter-ion distances, movement of mineral impurities, and reorganization of local symmetry and resolve uncertainties in the measurements of the more complex biomineral. In Aim 2 we will investigate the role of water in stabilizing both the mineral and matrix components via hydrogen bonding and enthalpic stabilization. Changes in collagen secondary structure will be measured through 13C resonances. We will use a unique protocol for controlled disordering of the collagen and mineral by partial and complete displacement of native matrix water with deuterium oxide, which forms weaker hydrogen bonds. NMR will probe water bridges and glycine-proline bonds, as well as mineral changes, with correlations to measured strain and applied load. In Aim 3 we will examine the loading response of mineral deformation, collagen conformation changes and hydrogen bonding in native and damaged bone tissue from mice of various ages in order to understand how age-related changes in the mineral and matrix compromise the mechanical competence of bone tissue. Controlled partial replacement of hydrogen ion with deuterium ion will be used to provide a range of collagen conformation changes. PUBLIC HEALTH RELEVANCE: Fragility fractures are a major health threat in aging populations and understanding the factors that contribute to bone failure is vitally important to the development of new interventional approaches. Through the development of methods for measuring NMR spectra of bone under compressive load, this project, for the first time, brings to this problem the power of solid-state nuclear magnetic resonance spectroscopy to understand the changes in bone structure when subjected to mechanical loading.

描述（由申请人提供）：我们将应用固态魔角旋转核磁共振光谱（MAS-NMR）来测量机械载荷下骨组织化学结构的变化。MAS-NMR将使我们能够检查超微结构对骨质量的贡献，到目前为止，使用传统的成像技术或其他生物物理技术是无法获得的。使先进的是一个特殊的核磁共振细胞，允许压缩载荷和位移测量。当标本在单轴压缩下变形时，高分辨率结构信息将与来自成熟小鼠胫骨的骨组织应变相关。在目标1中，我们将使用几种不同的1D和2D固态NMR脉冲序列评估骨矿物晶格的变形，作为矿物离子间距和水流动性的变化。我们还将研究一系列合成碳酸磷灰石中的负荷诱导变化，这些磷灰石是骨矿物质的模型化合物，以指导我们的骨矿物质结果的解释，并使同位素富集的核，特别是43 Ca的测量成为可能。在这些简化的模型化合物中，我们可以准确地测量离子间距离，矿物杂质的运动，以及局部对称性的重组，并解决更复杂的生物矿物测量中的不确定性。在目标2中，我们将研究水在通过氢键和疏水稳定来稳定矿物和基质组分中的作用。胶原蛋白二级结构的变化将通过13 C共振测量。我们将使用一种独特的方案，通过用氘氧化物部分和完全置换天然基质水来控制胶原蛋白和矿物质的无序，氘氧化物形成较弱的氢键。核磁共振将探测水桥和甘氨酸-脯氨酸键，以及矿物质的变化，与测量的应变和施加的载荷相关。在目标3中，我们将检查来自不同年龄的小鼠的天然和受损骨组织中的矿物质变形、胶原蛋白构象变化和氢键的负荷响应，以了解矿物质和基质中的年龄相关变化如何损害骨组织的机械能力。氢离子与氘离子的受控部分置换将用于提供一系列胶原蛋白构象变化。 公共卫生关系：脆性骨折是老龄化人群的主要健康威胁，了解导致骨衰竭的因素对开发新的介入方法至关重要。通过开发在压缩载荷下测量骨的NMR光谱的方法，该项目首次将固态核磁共振光谱的力量带入这一问题，以了解骨结构在受到机械载荷时的变化。