基于SATB1/p21路径探讨养阴活血息风法防治帕金森病的抗多巴胺能神经元衰老机制

SATB1蛋白缺失导致p21依赖的多巴胺能神经元衰老，是帕金森病(PD)的重要发病机制。研究发现：作为临床有效防治PD的中医基本治法，养阴活血息风法能够上调中脑黒质SATB1、下调p21表达。尚需探讨：该法对PD的防治作用，是否通过SATB1/p21路径(SATB1依赖的p21表达抑制)抗多巴胺能神经元衰老而实现？拟在中医理论指导下，运用药理学、生物信息学、细胞分子生物学等方法，以抗细胞衰老药为探针(阳性药)，以养阴活血息风方为受试物，观察该方含药血清、空白血清对野生型、SATB1敲除/过表达、p21敲除/过表达、(SATB1敲除/过表达）/(p21敲除/过表达)的不同成熟多巴胺能神经元衰老表型的影响，并在整体水平上以SATB1敲低/过表达的小鼠模型进行抗多巴胺能神经元衰老药效验证。以期发现养阴活血息风法防治PD的生物学基础，为进一步防治PD提供一定依据，为开发抗PD中药新药奠定一定基础。

Cellular senescence of dopaminergic neurons is an important pathogenesis of Parkinson's disease (PD), and the substantia nigra special AT-rich sequence binding protein 1 (SATB1) can directly inhibit cellular senescence caused by p21 expression. It has been found that, as a basic method of traditional Chinese medicine to prevent and treat PD clinically, the method of nourishing-yin-activating-blood-extinguishing-wind (NAE), can up-regulate SATB1 and down-regulate p21 expression. Hence, we would like to find out whether the method of NAE could directly inhibit p21, or indirectly inhibit p21 through up-regulating SATB1 in PD prevention and treatment? Based on the previous work, and guided by the theory of traditional Chinese medicine, pharmacology, bioinformatics, and cell molecular biology will be applied, and the senolytics drugs will be selected as the probe, and the prescription of NAE will be used as the test substance. We will observe the cellular senescence effect of medicated serum containing the prescription of NAE and blank serum on different mature dopaminergic neuron phenotypes, such as wild type, SATB1 knockout /overexpression, p21 knockout /overexpression, (SATB1 knockout /overexpression)/ (p21 knockout /overexpression) and so on, then the effect of the prescription of NAE will be further tested on a mouse model of SATB1 knockdown/overexpression in vivo. We hope to verify that the underlying mechanism of PD to prevent and treat with method of NAE is through SATB1/p21 regulating dopaminergic neurons. This study would lay a foundation for further optimization of PD treatment protocols and development of new anti-PD Chinese drugs.