Strain-Dependent Glucose Transport and Metabolism in Intervertebral Disc

描述(申请人提供)：腰痛(LBP)在美国是一个主要的社会经济问题。虽然LBP的确切原因尚不清楚，但脊柱的椎间盘退变(IVD)被认为是主要原因。IVD是人体内最大的无血管结构，使水和溶质在盘中的运输成为重要的营养机制。了解重要营养素(如葡萄糖)的运输和代谢特性对于了解参与椎间盘退变的病理生理学很重要。组织水平的机械力可以影响细胞水平的物理信号，组织重塑通过组织材料属性的变化改变物理信号的方式，也可能调节可能控制椎间盘退变开始和进展的细胞反应。因此，确定机械应变引起的组织特性的变化对于了解IVD细胞对力和其他刺激的生物反应是重要的，因此对于阐明与椎间盘退变和LBP有关的病因也是重要的。申请者的长期目标是(1)更好地了解LBP发展过程中涉及的病理生理学；(2)进一步阐明正常和退行性IVD的运输和代谢特性；以及(3)开发评估和治疗腰椎间盘退变和LBP的新策略。这项建议的主要目的是确定机械应变对非变性和退行性人类IVD组织中葡萄糖运输和代谢的影响。为了实现这一目标，该计划分为三个研究，采用理论和实验相结合的方法。在研究1中，将使用一维非稳态扩散实验和定制设计的扩散池来确定正常和退变的人类IVD组织中依赖应变的葡萄糖扩散系数(具体目标1)。在研究#2中，葡萄糖在正常和退变的人体IVD组织中的应变相关分配系数将通过测量在压缩和自由肿胀条件下与组织标本连续平衡的三个浴中的葡萄糖浓度来确定(具体目标#2)。在研究#3中，将通过监测洗浴介质中的葡萄糖浓度并使用有限元分析和Michaelis-Menten方程的理论曲线拟合来确定猪IVD细胞依赖于应变的葡萄糖消耗率(具体目标#3)。获得的数据将被合并到一个理论模型中，以分析机械应变下IVD的运输和代谢特性。这些研究的结果将提供对腰椎间盘退变和LBP的病因的洞察，并可能用于开发治疗LBP的新策略。

DESCRIPTION (provided by applicant): Low back pain (LBP) is a major socio-economic concern in the US. While the exact cause of LBP is not clear, degeneration of the intervertebral discs (IVD) of the spine is believed to be the main origin. The IVD is the largest avascular structure in the human body, making transport of water and solutes in the discs an important mechanism of nutrition. Knowledge of transport and metabolic properties of important nutrients (e.g. glucose) is important in understanding pathophysiology involved in disc degeneration. Mechanical forces at the tissue level can affect physical signals at the cellular level and the way tissue remodeling changes physical signals through changes in tissue material properties and may also regulate cellular responses that may govern the initiation and progression of disc degeneration. Thus, determining changes in tissue properties as a result of mechanical strain is important in understanding the biological responses of IVD cells to force and other stimuli, and is therefore important in elucidating the etiologic factors involved in disc degeneration and LBP. The applicant's long-term goals are to (1) better understand the pathophysiology involved in the development of LBP; (2) further elucidate transport and metabolic properties in normal and degenerated IVD; and (3) develop new strategies for assessing and treating disc degeneration and LBP. The main objective of this proposal is to determine the effects of mechanical strain on glucose transport and metabolism in non-degenerated and degenerated human IVD tissues. In order to achieve this objective, the proposed plan is divided into three studies combining theoretical and experimental approaches. In Study #1, the strain-dependent glucose diffusivity in normal and degenerated human IVD tissues will be determined (Specific Aim #1) using a 1D unsteady state diffusion experiment and a custom designed diffusion cell. In Study #2, the strain-dependent partition coefficient of glucose in normal and degenerated human IVD tissues will be determined (Specific Aim #2) by measuring glucose concentrations within three baths equilibrated sequentially with tissue specimens under compressed and free-swelling conditions. In Study #3, the strain-dependent glucose consumption rate of porcine IVD cells will be determined (Specific Aim #3) by monitoring of glucose concentrations in bathing medium and using FEM analysis and theoretical curve-fitting with the Michaelis-Menten equation. Data obtained will be incorporated into a theoretical model to analyze transport and metabolic properties in IVD under mechanical strain. The outcome of these studies will provide insight into the etiological causes of disc degeneration and LBP and may also be used in the development of new strategies for treatment of LBP.