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

基本信息

批准号：
8643097
负责人：
Michael Jablonski
金额：
$ 0.19万
依托单位：
THOMAS JEFFERSON UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2013
资助国家：
美国
起止时间：
2013-04-01 至 2014-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8643097
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

项目摘要

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）：在美国任何特定时间都有 30,000 例 ALS 病例。目前 ALS 无法治愈，治疗选择也很少。大约 95% 的病例病因不明，但其余病例有明确的遗传起源。研究遗传病例可以深入了解这种疾病，这适用于散发性病例和家族性病例。继续研究基于 ALS 相关基因突变的动物模型和散发性 ALS 的体外模型将继续增加对该疾病的了解。中枢神经系统治疗的疗效受到中枢神经系统通路有限的影响，这可能导致耐药性。使用不同化合物的临床前试验未能治愈 ALS 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种可能解释。血脑屏障和血脊髓屏障（BBB/BSCB）的紧密连接在物理上限制了药物的神经渗透；此外，已知 ATP 结合盒 (ABC) 药物外流转运蛋白的主动药物挤出会影响多种药物的生物利用度和功效。最近，我们的实验室报告了疾病驱动的 SOD1-G93A 小鼠脊髓 P-gp 表达水平的增加。此外，我在实验室生成的新数据表明，除了 P-gp 之外，另一种 ABC 转运蛋白 BCRP 在 ALS 小鼠的疾病进展过程中表达和功能也有所增加。最近发布的初步数据提供了 ALS 中 ABC 药物外流转运蛋白改变的综合分析。将确定整个 ALS 进展过程中 BBB/BSCB 渗透性的功能评估，因为这种现象以及转运蛋白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，将研究导致 ALS 中药物转运蛋白和血脑屏障改变的分子机制。该提案的目标将有助于了解 ABC 药物外排转运蛋白和 BBB/BSCB 在开发有效的 ALS 药物疗法方面所造成的障碍。