Direct visualization of longitudinal effects of drug therapy on white matter in diffuse injured brain

药物治疗对弥漫性损伤脑白质的纵向影响的直接可视化

基本信息

批准号：
9064239
负责人：
Teresa Ann Murray
金额：
$ 13.92万
依托单位：
LOUISIANA TECH UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2015
资助国家：
美国
起止时间：
2015-08-01 至 2018-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9064239
关键词：
4D Imaging Address Animals Antibiotics Area Axon Basic Science Behavior Behavioral Blood flow Brain Brain Injuries Caliber Cell Count Cell physiology Cells Clinic Clinical Trials Combination Drug Therapy Combined Modality Therapy Data Data Set Diffuse Diffusion Magnetic Resonance Imaging Dose Event FDA approved Formulation Future Glass Health Histology Hour Human Hypoxia Image Imagery Imaging technology Implant Infiltration Inflammation Injury Interphase Cell Ischemia Knowledge Lateral Lead Length Life Measures Methods Microcirculation Microglia Microscope Microscopy Military Personnel Minocycline Modality Mus Needles Optics Outcome Pharmaceutical Preparations Pharmacotherapy Positioning Attribute Preclinical Testing Process Proteins Resolution Rodent Model Sports Staging System Techniques Testing Therapeutic Time Transgenic Mice Translations Traumatic Brain Injury Varicosity axon injury axonal degeneration brain cell clinically relevant cohort density effective therapy imaging modality imaging system in vivo in vivo imaging insight interest lens molecular marker monocyte non-invasive imaging novel pre-clinical pre-clinical research preclinical trial prevent repaired response temporal measurement tool water diffusion white matter

项目摘要

DESCRIPTION (provided by applicant): This project will provide high-content data that will be used for both basic and preclinical research. BASIC RESEARCH ASPECT: We will use a novel method of high-resolution, subcortical, in vivo imaging to fill critical gaps in knowledge about th dynamics of diffuse traumatic brain injury at a cellular level in subcortical white matter in live mice over a 60-day period post-injury. This knowledge will give us new insights into understanding the progressive degeneration that happens after TBI and for optimizing therapeutic windows for future combination drug therapy. We will obtain these images in live mice using a permanently implanted microlens positioned over a subcortical white matter tract and periodically image through this lens using a multiphoton microscope. We will reveal previously unseen spatio-temporal dynamics of axon degeneration, microglia infiltration and activation, and microvascular changes with cellular resolution in this region. PRECLINICAL ASPECT: We will also use 3 key outcomes from our observations to evaluate the efficacy of a drug which is now in preclinical trials. This drug, minocycline, is an FDA-approved antibiotic that has reduced axonal loss and microglial activation when given in a single dose within a few hours of experimental traumatic brain injury in mice. We hypothesize that a dose given 3 days post-injury will have the same therapeutic benefits of significantly (1) reducing axonal loss and (2) reducing microglial activation. We further hypothesize that minocycline will result in significant improvement in microcirculation rates. Widening the therapeutic window for this promising drug will better position it for translation to the clinic.

描述（由申请人提供）：该项目将提供将用于基础研究和临床前研究的高内心数据。基础研究方面：我们将使用一种新型的高分辨率，皮质下，体内成像的方法来填补有关活在60天内的活小鼠的细胞皮层白质的弥漫性创伤性脑损伤动态的关键差距。这些知识将使我们有了新的见解，了解在TBI之后发生的渐进变性，并为将来的结合药物治疗优化治疗窗口。我们将使用位于皮质下白质区域上的永久植入的微片在活小鼠中获得这些图像，并使用多光子显微镜通过该镜头定期形象。我们将揭示以前看不见的轴突变性，小胶质细胞浸润和激活以及该区域细胞分辨率的微血管变化的时空动力学。临床前方面：我们还将使用观察结果中的3个关键结果来评估现在正在临床前试验中的药物的功效。该药物是一种由FDA批准的抗生素，当在小鼠实验性创伤性脑损伤的几个小时内给予轴突丧失和小胶质细胞激活。我们假设受伤后3天给定的剂量将具有显着的治疗益处（1）减少轴突损失和（2）减少小胶质细胞激活。我们进一步假设米诺环素将导致微循环速率显着提高。扩大这种有前途的药物的治疗窗口将更好地将其定位为转化为诊所。