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）：药物渗透有限是中枢神经系统疾病治疗中经常遇到的障碍。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、多药耐药蛋白或 MRP、乳腺癌耐药蛋白或 BCRP，又名 ABCG2）血脑屏障（BBB）和血脑脊液（BCSF）屏障。 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，在那里它们充当物质神经渗透的二级屏障。外排转运蛋白还排出分解代谢物和毒素，以防止它们在细胞中有害积累，构成细胞适应疾病介导和环境应激的主要机制。关于 ABC 转运蛋白在肌萎缩侧索硬化症 (ALS)（一种运动系统神经退行性疾病）中的定位和调节知之甚少。我们的初步数据显示，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，这表明药物在中枢神经系统中渗透的障碍因疾病而增加，必须克服该障碍才能开发有效的 ALS 药物疗法。鉴于其多特异性，尽管重要的问题仍未得到解答，但外排转运蛋白作为中枢神经系统疾病的关键参与者的认识是毫无疑问的。例如：ALS 如何影响外排转运蛋白的定位和功能？哪些 ALS 特异性信号通路导致 P-gp 上调？ ALS 介导的 P-gp 和/或其他 ABC 转运蛋白上调是否会改变我们治疗该疾病的小鼠模型以及最终 ALS 患者的方式？为了填补这一知识空白，我们建议：（1）研究 P-gp 和其他相关 ABC 药物转运蛋白在 ALS 中的活性、表达和分布概况； (2) 研究非神经元细胞中的外排转运蛋白活性是否导致ALS体外和体内模型中的运动神经元变性； (3)探讨消除ABC转运蛋白功能对ALS治疗的影响。