TRPV4在压应力重建退变髓核细胞力感应性中的作用及机制研究

Disc degenerative disease is a high-incidence spinal disease which originates from nucleus pulposus degeneration. The low extracellular matrix biosynthesis of the degenerated nucleus pulposus cells is the main internal cause of nucleus pulposus degeneration. However, there is no etiological treatment against disc degenerative disease currently. Low magnitude of compression could enhance matrix biosynthesis of nucleus pulposus cells and be an effective means to regulate matrix synthesis. However, the degenerated nucleus pulposus cells exhibited low mechanosensation, which was unable to respond to the anabolic effect caused by the low-magnitude compression. Preliminarily, we found mechanical-sensing channel TRPV4 was lowly expressed in degenerated nucleus pulposus cells. Overexpression of TRPV4 could enhanced its mechanosensation, suggesting that low expression of TRPV4 may be the key regulator to low mechanosensation of degenerated nucleus pulposus cells. Based on this, we propose a hypothesis that "TRPV4 downregulation is an important reason for the low mechanosensation of the degenerated nucleus pulposus cells. If up-regulating the expression of TRPV4 in the degenerated nucleus pulposus cells, their responsiveness to the low-magnitude compression could be restored and subsequently, their matrix biosynthesis could be enhanced via the RhoA related pathway". The project is intended to clarify the key role of TRPV4 in the low mechanosensation to the low-magnitude compression in the nucleus pulposus cells, explore the mechanism that TRPV4 restore the matrix biosynthesis of degenerated nucleus pulposus cells under the low-magnitude compression, and elucidate the meaning of TRPV4 as an intervening target of cellular mechanical signal to repair degenerated intervertebral discs. This study is significant for providing a theoretical and experimental basis for restoring mechanosensation and inducing the matrix biosynthesis of degenerated nucleus pulposus using TRPV4 as a target.

椎间盘退行性疾病是以髓核退变为核心的高发脊柱疾患，退变髓核细胞的胞外基质合成低下是髓核退变的内在原因，尚缺乏病因性治疗手段。低压应力可增强髓核细胞基质合成，是调控基质合成的有效手段。然而，退变髓核细胞的力感应性低下，无法响应低压应力的促合成作用。前期发现，力感应通道TRPV4在退变髓核细胞中低表达，过表达后可增强其力感应性，提示低表达的TRPV4可能是退变髓核细胞力感应性低下的关键。据此，本项目提出“TRPV4下调是退变髓核细胞力感应性低的重要原因，上调TRPV4可恢复其力感应性，通过RhoA通路，诱导其基质合成”假说，拟在明确TRPV4在恢复髓核细胞对低压应力感应性中的关键作用基础上，揭示低压应力下TRPV4诱导退变髓核细胞基质合成的机制，阐明TRPV4力信号干预靶点在退变椎间盘修复中的意义。本研究将为以TRPV4为靶点恢复退变髓核细胞力感应性、诱导胞外基质合成提供理论依据和实验基础。

椎间盘退行性疾病是以髓核退变为核心的高发脊柱疾患，退变髓核细胞的胞外基质合成低下是髓核退变的内在原因，尚缺乏病因性治疗手段。低压应力可增强髓核细胞基质合成，是调控基质合成的有效手段。然而，退变髓核细胞的力感应性低下，无法响应低压应力的促合成作用。本项目提出“TRPV4下调是退变髓核细胞力感应性低的重要原因，上调TRPV4可恢复其力感应性诱导其基质合成”的假说。通过研发具有良好生物活性和力学负载能力的水凝胶支架材料，构建了适用于髓核细胞三维培养和力学加载的新型研究平台。在此模型下开展力学生物学研究，发现TRPV4是低强度压应力促进髓核细胞基质生物合成的关键靶点，并阐明TRPV4-Ca2+-ERK1/2信号通路是低强度压应力调控髓核细胞大分子胞外基质生物合成的重要分子机制，进而发现退变髓核细胞对低强度压应力的响应能力低下的关键原因在于TRPV4的表达低下，通过上调退变髓核细胞的TRPV4可以有效增强其力学响应能力并促进胞外基质大分子合成。此外，还发现髓核祖细胞高表达活性TRPV4通道蛋白，可能是运用低强度应力修复椎间盘的目标细胞群体。综上所述，以TRPV4是髓核细胞力学响应能力的关键靶点，通过有效调控TRPV4表达具有实现椎间盘修复的潜能。本研究将为以TRPV4为靶点恢复退变髓核细胞力感应性、诱导胞外基质合成提供理论依据和实验基础，为建立椎间盘退行性疾病治疗防治策略提供了新思路。

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