Alterations in Blood-Brain/Blood-Spinal Cord Barrier Properties in Amyotrophic

肌萎缩症患者血脑/血脊髓屏障特性的改变

• 批准号: 8520835
• 负责人: Michael Jablonski
• 金额: $ 4.22万
• 依托单位: THOMAS JEFFERSON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-04-01 至 2015-09-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8520835
• 关键词: ABCB1 gene; ABCC1 gene; ABCG2 gene; ATP-Binding Cassette Transporters; Affect; Amyotrophic Lateral Sclerosis; Animal Model; Astrocytes; Axonal Transport; Binding; Biological Availability; Blood; Blood - brain barrier anatomy; Blood capillaries; Brain; Brain Stem; Caliber; Cells; Central Nervous System Diseases; Chronic; Clinical; Conflict (Psychology); Data; Disease; Disease Progression; Down-Regulation; Drug Efflux; Endothelial Cells; Etiology; Failure; Family member; Functional disorder; Gene Mutation; Genetic; Goals; Harvest; Human; Impairment; Knowledge; Laboratories; Link; Measures; Mediating; Microglia; Mitochondria; Molecular; Motor Cortex; Motor Neurons; Multidrug Resistance-Associated Proteins; Mus; Neuraxis; Neurodegenerative Disorders; Onset of illness; Oxidative Stress; P-Glycoprotein; Pathway interactions; Patients; Penetration; Permeability; Pharmaceutical Preparations; Pharmacodynamics; Pharmacotherapy; Process; Property; Protein Family; Proteins; Publishing; Reporting; Research; Spinal Cord; Symptoms; Testing; Therapeutic; Tight Junctions; Time; Treatment Efficacy; United States; Work; Xenobiotics; base; capillary; in vitro Model; insight; luminal membrane; malignant breast neoplasm; member; motor neuron degeneration; mouse model; mutant; neuroinflammation; novel; pre-clinical; preclinical study; protein aggregate; public health relevance; relating to nervous system

DESCRIPTION (provided by applicant): There are 30,000 cases of ALS at any given time in the United States. Presently there is no cure for ALS and few treatment options. Approximately 95% of cases have unknown etiology, but the remainder have a clear genetic origin. Studying the genetic cases has allowed great insight into the disease, which is applicable to both sporadic and familial cases. Continued work with animal models based on ALS-linked gene mutations and in vitro models of sporadic ALS will continue to increase knowledge of the disorder. The efficacy of CNS therapeutics is affected by limited CNS access, which can result in pharmacoresistance. Preclinical trials with different compounds have failed to cure the mouse model of ALS or even stop the progression of the disease and pharmacoresistance is one possible explanation for these failures. Tight junctions of the blood-brain and blood-spinal cord barriers (BBB/BSCB) physically restrict neural penetration of drugs; in addition, active drug extrusion by ATP-binding cassette (ABC) drug efflux transporters are known to affect the bioavailability and efficacy of multiple drugs. Recently, our laboratory reported a disease-driven increase in P-gp expression levels the spinal cords of SOD1-G93A mice. Furthermore, new data that I generated in the laboratory indicate that BCRP, another ABC transporter, increases in expression and function throughout disease progression in ALS mice, in addition to P-gp. This preliminary data, which was recently published, provides a comprehensive analysis of ABC drug efflux transporter alterations in ALS. A functional assessment of BBB/BSCB permeability throughout progression of ALS will be determined, since this phenomenon along with changes in transporter expression and function would alter the bioavailability of ALS- treating compounds. Finally, identification of the molecular mechanisms leading to drug transporter and blood- brain barrier alterations in ALS will be studied. The goals of this proposal will aid in understanding the obstacle provided by the ABC drug efflux transporters and the BBB/BSCB in developing effective pharmacotherapies for ALS.

描述(由申请人提供)：在美国，任何时候都有30,000例肌萎缩侧索硬化症病例。目前，肌萎缩侧索硬化症还没有治愈方法，治疗方案也很少。大约95%的病例病因不明，但其余病例有明确的遗传来源。对遗传病例的研究使人们对这种疾病有了很好的了解，这既适用于散发病例，也适用于家族病例。基于肌萎缩侧索硬化症相关基因突变的动物模型和散发性肌萎缩侧索硬化症的体外模型的持续工作将继续增加对这种疾病的了解。中枢神经系统治疗药物的疗效受到中枢神经系统通路受限的影响，这可能导致药物耐药。不同化合物的临床前试验未能治愈ALS的小鼠模型，甚至未能阻止疾病的进展，而耐药性是这些失败的一个可能的解释。血-脑和血-脊髓屏障(BBB/BSCB)的紧密连接在物理上限制了药物的神经渗透；此外，由ATP结合盒(ABC)药物外排转运体主动排出的药物会影响多种药物的生物利用度和疗效。最近，我们的实验室报道了疾病导致SOD1-G93A小鼠脊髓P-gp表达水平的增加。此外，我在实验室产生的新数据表明，除了P-gp外，另一种ABC转运蛋白BCRP在ALS小鼠的疾病发展过程中也增加了表达和功能。最近发表的这一初步数据提供了对肌萎缩侧索硬化症患者ABC药物外排转运体改变的全面分析。将确定在ALS进展过程中对BBB/BSCB通透性的功能评估，因为这种现象以及转运体表达和功能的变化将改变ALS治疗化合物的生物利用度。最后，将对导致ALS药物转运蛋白和血脑屏障改变的分子机制进行研究。这项提案的目标将有助于理解ABC药物外排转运体和BBB/BSCB在开发有效的ALS药物疗法方面所提供的障碍。