P53/PHD3/HIF-1α轴激活神经元自噬保护老年脊髓缺氧损伤的分子机制研究

脊髓损伤后肢体功能障碍影响患者身心健康，增加社会负担。我们研究发现:(1)老年脊髓损伤患者术后神经功能改善较青年差;(2)椎板密闭和脊髓动脉缺血两种模型中，老年较青年大鼠神经功能恢复差，神经元减少更多;(3)老年大鼠脊髓损伤神经元中，P53和PHD3表达更高，HIF-1α表达更低，自噬相关蛋白表达更低;(4)抑制PHD3可上调HIF-1α;抑制P53活性可降低PHD3，促进HIF-1α及自噬相关蛋白表达。因此，我们假说“老年脊髓神经元中P53激活引起细胞衰老，促进PHD3表达，降解HIF-1α从而抑制神经元自噬，是老年脊髓缺氧损伤预后差的重要机制”。我们将(1)阐明P53促进神经元衰老继发PHD3上调，抑制HIF-1α及其下游自噬的机制及效应;(2)观察P53/PHD3/HIF-1α/自噬轴与神经恢复的关系;(3)明确调控该轴在促进老年脊髓缺氧损伤中的价值，为老年脊髓损伤后治疗提供新思路。

Spinal cord injury can damage function of the body and limbs, which seriously affects the physical and mental health of the patients, and brings a huge social and economic burden. Our previous studies have found that: 1) the improvement rate of postoperative neural functional score of patients with spinal cord injury over 60 years old was lower than that of people under 60 years old. 2) In two models of hypoxia injury in the spinal cord, the neurological function of the spinal cord was poorer and the number of neuron atrophy in spinal cord was more in the aged rats than young rats. 3) The expression of HIF-1α (hypoxia inducible factor-1α) was lower, and the expression of autophagy related protein Beclin-1 and LC3 was lower in the neurons of the injured spinal cord of the aged rats than young rats. On the contrary, the expression of PHD3 was higher in the aged rats. 4) Inhibition of PHD3 could increase the expression of HIF-1α. Inhibition of P53 activity could reduce the expression of PHD3 and promote the expression of HIF-1α, Beclin-1 and LC3II/I. In conclusion, we hypothesized that P53 activation in aged spinal cord neurons could induce senescence of cell, and then promote expression of PHD3, degrade HIF-1α and inhibit autophagy, which was an important molecular mechanism of poor prognosis after spinal cord hypoxic injury in the aged. Therefore, this study will include the following steps: 1) to clarify the molecular mechanism of P53 in spinal cord neurons promoting senescence of cell and up regulation of PHD3, and then inhibiting HIF-1α and its downstream of autophagy. 2) to study the relation between P53/PHD3/HIF-1α /autophagy axis and neural functional recovery; 3) to prove the value of regulation of P53/PHD3/HIF-1α/autophagy axis in promoting the recovery of the spinal cord in the aged. We hope our study could provide a new target for the clinical treatment for spinal cord injury in the aged.