Role of ABC efflux transporters in ALS

描述(申请人提供)：药物渗透性有限是中枢神经系统疾病治疗中经常遇到的障碍。导致这一现象的一个机制可能是三磷酸腺苷结合盒(ABC)药物外排转运体(即P-糖蛋白或P-gp、多药耐药蛋白或MRPs、乳腺癌耐药蛋白或BCRP)的表达。血脑屏障(BBB)和血脑脊液屏障(BCSF)。ABC转运蛋白也在较小程度上定位于中枢神经系统实质细胞，在那里它们充当神经穿透物质的第二屏障。外排转运蛋白还排出分解代谢物和毒素，以防止它们在细胞内有害积累，构成细胞对疾病和环境压力适应的主要机制。肌萎缩侧索硬化症(ALS)是一种运动神经退行性疾病，对ABC转运体的定位和调控知之甚少。我们的初步数据显示，在ALS SOD1-G93A小鼠模型的脊髓星形胶质细胞以及散发性和家族性ALS患者的脊髓标本匀浆中，P-gp表达增加。从治疗的角度来看，这表明疾病增加了药物在中枢神经系统的渗透障碍，必须克服这一障碍，才能开发出有效的ALS药物疗法。考虑到它们的多重特异性，外排转运体在中枢神经系统疾病中的关键作用的认识是毋庸置疑的，尽管重要的问题仍然没有得到回答。例如：肌萎缩侧索硬化症如何影响外排转运体的定位和功能？哪些ALS特异性信号通路负责P-gp的上调？ALS介导的P-gp和/或其他ABC转运蛋白的上调是否会改变我们治疗这种疾病的小鼠模型，并最终改变ALS患者的方式？为了填补这一认识空白，我们建议：(1)研究P-gp和其他相关ABC药物转运体在ALS中的活性、表达和分布；(2)研究非神经元细胞的外排转运体活性是否在ALS体外和体内模型中参与运动神经元变性；(3)研究消除ABC转运体功能对ALS治疗的影响。

DESCRIPTION (provided by applicant): Limited drug penetration is an obstacle that is often encountered in the treatment of CNS diseases. One mechanism that may contribute to this phenomenon is the expression of ATP-binding cassette (ABC) drug efflux transporters (i.e. P-glycoprotein or P-gp, Multi-drug resistance proteins or MRPs, breast cancer resistance protein or BCRP, a.k.a. ABCG2) at the blood brain barrier (BBB) and blood cerebrospinal fluid (BCSF) barrier. ABC transporters also localize to a lesser extent at the CNS parenchyma cells where they act as secondary barrier to neural penetration of substances. Efflux transporters also extrude catabolites and toxins to prevent their harmful accumulation in the cell, constituting the major mechanism of cell adaptation to disease-mediated and environmental stress. Little is known on ABC transporters localization and regulation in amyotrophic lateral sclerosis (ALS), a neurodegenerative disease of the motor system. Our preliminary data show increased P-gp expression in spinal cord astrocytes of the SOD1-G93A mouse model of ALS as well as in spinal cord specimen homogenates of sporadic and familial ALS patients. From a therapeutic perspective, this suggests that the obstacle to drug penetration in the CNS is increased by the disease and must be overcome to develop effective pharmacotherapies for ALS. Given their multi-specificity, the recognition of efflux transporters as critical players in CNS diseases is unquestioned although important questions remain unanswered. For example: How does ALS affect efflux transporters localization and function? Which ALS-specific signaling pathways are responsible for up-regulation in P-gp? Will ALS-mediated up-regulation in P-gp and/or other ABC transporters change how we therapeutically treat the mouse model of the disease, and ultimately ALS patients? To fill this gap in knowledge, we propose: (1) To investigate activity, expression and distribution profile of P- gp and other relevant ABC drug transporters in ALS; (2) To study whether efflux transporter activity in non- neuronal cells contributes to motor neuron degeneration in in-vitro and in-vivo models of ALS; (3) To investigate the impact of eliminating ABC transporter function on ALS therapeutics.