Intervertebral disc plasticity in response to mechanical and biological perturbations

肌肉骨骼组织不断地暴露于各种类型的刺激，必须通过重塑以维持稳态作出充分的反应。我研究计划的长期目标是加深我们对脊柱如何对机械和生物刺激做出反应以及这最终如何影响生物力学的理解。提出的实验旨在研究机械和特别是炎症刺激对脊柱细胞和整个椎间盘水平生物力学特性的影响。预期存在相互依赖的关系，其中任一类型的刺激物将扰乱脊柱中的生物力学和生物平衡，从而改变组织结构（通过重塑）和功能（机械完整性）。将从大鼠椎间盘提取的细胞包埋在胶原支架中，然后将其暴露于机械和/或炎症刺激。暴露后，将检查胶原支架机械性能的变化（以及重塑的证据）以及组织重塑基因的表达。类似地，在组织水平上，整个椎间盘将暴露于类似的刺激，并且将量化完整椎间盘的生物力学性质，以便辨别响应于刺激的重塑。最后，探索性实验的目的是揭示机械和炎症刺激引起椎间盘生物力学变化的机制途径;这将通过受体抑制或改变组织重塑基因的调节来操纵这些途径来完成。因此，这项研究将提供一个新的理解的重要途径和过程中涉及改变椎间盘的机械性能。目前，最少的研究集中在这些属性的组合，使拟议的工作在进一步了解椎间盘功能的新。这项工作的结果也有可能帮助我们了解椎间盘病变，这是加拿大人普遍存在的问题，也是世界范围内残疾的重要来源。

Musculoskeletal tissues are constantly exposed to various types of stimuli and must respond adequately through remodelling to maintain homeostasis. The long-term goal of my research program is to advance our understanding of how the spine responds to mechanical and biological stimuli and how this ultimately affects biomechanics. Proposed experiments aim to investigate the effect of both mechanical and specifically inflammatory stimuli on the biomechanical properties at both the cellular and whole intervertebral disc level in the spine. It is anticipated that an interdependent relationship exists where either type of stimulant will perturb both biomechanical and biological equilibrium in the spine, thereby altering tissue structure (through remodelling) and function (mechanical integrity). Cells extracted from rat intervertebral discs will be embedded in collagen scaffolds which will then be exposed to mechanical and/or inflammatory stimulation. Following exposure, changes to the mechanical properties of the collagen scaffold (and therefore evidence of remodelling) as well as expression of tissue remodelling genes will be examined. Similarly, at the tissue level, whole discs will be exposed to similar stimuli and biomechanical properties of the intact discs will be quantified in order to discern remodelling in response to the stimulation. Last, exploratory experiments are aimed at uncovering the mechanistic pathways responsible for changes in disc biomechanics in response to both mechanical and inflammatory stimulation; this will be done by manipulating these pathways via receptor inhibition or altered regulation of tissue remodelling genes. This research will therefore provide a new understanding of the important pathways and processes involved in altering the mechanical properties of the intervertebral disc. Currently, minimal research is focused on the combination of these attributes making the proposed work novel in furthering our understanding of intervertebral disc function. Findings from this body of work also have the potential to assist in our understanding of disc pathologies, a prevalent issue among Canadian and significant source of disability worldwide.