Intervertebral disc plasticity in response to mechanical and biological perturbations

肌肉骨骼组织不断暴露于各种类型的刺激，必须通过重塑来保持体内平衡。我的研究计划的长期目标是推进我们对脊柱如何响应机械和生物刺激的理解，以及这最终如何影响生物力学。拟议的实验旨在研究机械和特异性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。预计存在一种相互依赖的关系，其中任何一种兴奋剂都会扰乱脊柱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）。从大鼠椎间盘中提取的细胞将嵌入胶原蛋白支架中，然后将其暴露于机械和/或炎症刺激下。暴露后，将检查胶原蛋白支架机械性能的变化（因此是重构的证据）以及组织重构基因的表达。同样，在组织水平上，整个椎间盘将暴露在类似的刺激下，完整椎间盘的生物力学特性将被量化，以辨别对刺激的反应的重塑。最后，探索性实验旨在揭示在机械和炎症刺激下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。因此，这项研究将为改变椎间盘力学特性的重要途径和过程提供新的认识。目前，很少的研究集中在这些属性的组合上，这使得我们对椎间盘功能的理解变得新颖。这项工作的发现也有可能帮助我们理解椎间盘病变，这是加拿大普遍存在的问题，也是全世界残疾的重要来源。

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.