Identification of mechano-sensitive pathways in intervertebral disc cells

椎间盘形成沿脊柱长度方向的软结缔组织关节，这是脊柱稳定、承载和运动所必需的。椎间盘的主要功能是在机械负荷时起减震器的作用。它由不同但相互依赖的组织组成，包括高度水化的中央髓核和提供抗拉应变能力的纤维外环，前者高度水化，提供膨胀以承受压缩负荷。虽然日常机械负荷为椎间盘细胞提供了必要的反馈以维持组织的完整性，但过度的负荷通过激活椎间盘细胞的级联不可逆变化而导致椎间盘退变，最终导致椎间盘无法履行其生理功能。因此，特定的间盘细胞对机械负荷的反应对于维持功能的间盘组织是必不可少的。不同类型的机械负荷(由正常运动和振动引起)对不同类型的椎间盘细胞类型的影响以及调节这些反应的细胞通路都知之甚少。 这些研究的目的是描述机械负荷对特定类型的椎间盘细胞的影响，并探索哪些信号通路介导了细胞反应。我们将使用一个基因工程小鼠模型，该模型使用荧光细胞标记来区分髓核细胞和纤维环细胞。在实验室中生长的细胞将受到循环应变(生理加载)或振动(模拟暴露于重型机械或振动平台)形式的机械加载，这些类型的细胞的响应将通过一系列实验进行量化。这些研究将使我们更好地从根本上了解不同类型的椎间盘细胞对机械负荷的反应，这些信息是理解椎间盘如何保持其结构完整性的关键。破译控制椎间盘机械生物学的途径将有助于开发组织工程策略，在体外重建椎间盘的形成。

Intervertebral discs form the soft connective tissue joints located along the length of the spine - required for spinal stabilization, load bearing, and movement. The major function of the intervertebral disc is to act as a shock absorber during mechanical loading. It is composed of distinct yet interdependent tissues including the central nucleus pulposus, which is highly hydrated and provides turgor to withstand compressive loading, and the outer annulus fibrosus which contains the nucleus pulposus and provides resistance to tensile strain. Although daily mechanical loading provides necessary feedback to cells of the disc to maintain the tissue’s integrity, excessive loading contributes to disc degeneration by activating a cascade of non-reversible changes in disc cells that ultimately lead to an inability of the disc to fulfill its physiological function. The responses of specific disc cells to mechanical loading are therefore essential to maintaining a functional disc tissue. The effects of different types of mechanical loading (resulting from normal movement vs. exposure to vibration) on the distinct cell types of the disc are poorly understood, as are the cellular pathways that regulate these responses. The objective of these studies is to characterize the effects of mechanical loading on specific cell types of the disc, and explore which signaling pathways mediate the cellular response. We will use a genetically engineered mouse model that uses fluorescent cell markers to distinguish nucleus pulposus cells from annulus fibrosus cells. Cells grown in the lab will be subjected to mechanical loading in the form of either cyclic strain (physiological loading) or vibration (to model exposure to heavy machinery or vibration platforms) and the response of these cell types will be quantified through a series of experiments. These studies will give us a better fundamental understanding of how different cell types of the intervertebral disc respond to mechanical loading, information that is key to understanding how the disc maintains its structural integrity. Deciphering the pathways that control intervertebral disc mechanobiology will facilitate the development of tissue engineering strategies to recreate disc formation in vitro.