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

描述（由申请人提供）：本项目将提供高内容的数据，将用于基础和临床前研究。基础研究方面：我们将使用一种新的高分辨率，皮层下，在体内成像的方法，以填补知识的关键差距，在细胞水平上的弥漫性创伤性脑损伤的皮层下白色物质在活小鼠损伤后60天内的动态。这些知识将为我们提供新的见解，以了解TBI后发生的进行性变性，并优化未来联合药物治疗的治疗窗口。我们将在活体小鼠中获得这些图像，使用永久植入的微透镜定位在皮质下白色物质道上，并使用多光子显微镜通过该透镜定期成像。我们将揭示以前看不见的时空动态轴突变性，小胶质细胞浸润和激活，微血管变化与细胞分辨率在这个地区。临床前方面：我们还将使用我们观察到的3个关键结果来评估目前处于临床前试验中的药物的疗效。这种药物，米诺环素，是FDA批准的抗生素，在小鼠实验性创伤性脑损伤的几个小时内以单剂量给药时，可以减少轴突损失和小胶质细胞活化。我们假设，损伤后3天给予的剂量将具有显著（1）减少轴突损失和（2）减少小胶质细胞活化的相同治疗益处。我们进一步假设米诺环素将导致微循环率的显着改善。拓宽这种有前途的药物的治疗窗口将更好地将其转化为临床。

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.