Role of ABC efflux transporters in ALS

ABC 外排转运蛋白在 ALS 中的作用

基本信息

批准号：
8411138
负责人：
Davide Trotti
金额：
$ 32.72万
依托单位：
THOMAS JEFFERSON UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2011
资助国家：
美国
起止时间：
2011-03-01 至 2016-01-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8411138
关键词：
ABCB1 gene ABCC1 gene ABCG2 gene ATP-Binding Cassette Transporters Affect Alzheimer&apos s Disease American Amyloid Amyotrophic Lateral Sclerosis Astrocytes Binding Blood Blood - brain barrier anatomy Brain Cells Central Nervous System Diseases Cerebrospinal Fluid Data Deposition Diagnosis Disease Disease Progression Drug Delivery Systems Drug Efflux Etiology Familial Amyotrophic Lateral Sclerosis Family Goals Heterogeneity Homeostasis In Vitro Knowledge Laboratories Lead Life Link Mediating Microglia Molecular Molecular Profiling Motor Motor Cortex Motor Neurons Multi-Drug Resistance Multidrug Resistance-Associated Proteins Muscle Cells Mutation Nature Neurodegenerative Disorders Neuroglia Neuromuscular Diseases Onset of illness P-Glycoprotein Pathogenesis Pathology Patients Pattern Penetration Pharmaceutical Preparations Pharmacotherapy Play Proteins Regulation Role Schwann Cells Signal Pathway Specificity Specimen Spinal Spinal Cord Stress System Therapeutic Time Toxin United States Up-Regulation Western Blotting blood cerebrospinal fluid barrier cytokine disease stressor drug candidate environmental stressor human ABCG2 protein improved in vivo Model killings luminal membrane member motor neuron degeneration mouse model prevent prospective public health relevance relating to nervous system success toxicant uptake web site

项目摘要

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.

描述（由申请人提供）：有限的药物渗透是CNS疾病治疗时经常遇到的障碍。可能导致这种现象的一种机制是ATP结合盒（ABC）药物外排转运蛋白的表达（即P-糖蛋白或P-GP，多药物抗性蛋白或MRP，乳腺癌耐药性蛋白或BCRP，又名ABCG2）在血脑屏障（BBB）和脑脊液（BCSF）屏障上。 ABC转运蛋白在CNS实质细胞中也较小程度地定位，它们充当了物质神经穿透性的次要障碍。外排转运蛋白还会挤出分解代谢物和毒素，以防止其有害积累在细胞中，构成细胞适应疾病介导的和环境压力的主要机制。在ABC转运蛋白的定位和肌萎缩性侧索硬化症（ALS）的调节（一种运动系统的神经退行性疾病）中，知之甚少。我们的初步数据表明，在ALS的SOD1-G93A小鼠模型以及零星和家族性ALS患者的脊髓标本匀浆中，P-gp的表达增加了。从治疗的角度来看，这表明该疾病中CNS中药物渗透的障碍是增加了ALS的有效药物疗法。鉴于它们的多种特异性，尽管重要的问题仍然没有解决，但对中枢神经系统疾病的关键参与者的认识是毫无疑问。例如：ALS如何影响外排转运蛋白的定位和功能？哪些ALS特异性信号通路负责P-gp中的上调？ ALS介导的P-gp和/或其他ABC转运蛋白的上调会改变我们治疗疾病的小鼠模型以及最终ALS患者的方式吗？为了填补知识的差距，我们建议：（1）研究ALS中P-GP和其他相关ABC药物转运蛋白的活动，表达和分布谱；（2）研究非神经元细胞中的外排转运蛋白活性是否有助于ALS的体外和体内模型中的运动神经元变性；（3）研究消除ABC转运蛋白功能对ALS治疗剂的影响。