Subproject Investigator: Philippe J. Diaz

项目摘要 创伤性脑损伤（TBI）是一种严重的致残性神经系统疾病，影响超过170万人 美国人每年可用的治疗方法仅旨在稳定患有TBI的个体， 因此，非常需要开发新的治疗策略。全反式维甲酸 是重要的内源性信号分子。最近的数据显示，atRA在 维持神经元可塑性、学习和记忆，增加创伤诱导的神经发生， 在人类或动物中的神经胶质激活，并支持我们的假设，即增加大脑中的atRA将改善 TBI受害者的康复然而，atRA具有较差的药代动力学，并且它诱导其自身的清除， 在长期治疗中失去活性。RA的清除主要由细胞色素介导 P450家族26酶（CYP 26）。CYP26家族有三种亚型：CYP26A1、CYP26B1和CYP26C1。 CYP26 B1似乎是主要的脑亚型。我们假设选择性抑制CYP26B1 将增加神经元atRA浓度，并将治疗记忆障碍， 神经炎症与TBI相关，为TBI受害者提供治疗优势。我们设计了一个 这种方法导致了一类新的选择性纳摩尔CYP26B1抑制剂的鉴定。此类新颖 一类化合物预期对CYP26B1亚型具有特异性，避免非靶向P450抑制 与先前描述的基于吡咯的CYP 26抑制剂相关。这项建议的目的是 优化我们的新型CYP26B1选择性抑制剂，以增加大脑中的atRA浓度， 记忆障碍和与TBI相关的神经炎症。利用我们之前发现的线索 结构，我们建议首先产生一系列具有改善的CYP26B1抑制效力的新化合物 和选择性使用X射线晶体学和计算机引导的化学修饰。第二部分 我们将证明CYP26 B1抑制导致记忆缺陷改善， 减少TBI大鼠模型中的神经炎症和神经胶质活化。 相关性 我们提出了一个创新的新的治疗策略，治疗创伤性脑损伤（TBI）与CYP26 B1 增加神经元视黄酸浓度的抑制剂。我们详细制定了一项计划，通过以下方式验证这一目标： 优化我们先前发现的CYP26B1抑制剂用于TBI动物模型的评估。如果成功， 本研究为TBI的治疗提供了一种新的治疗方法。

PROJECT SUMMARY Traumatic brain injury (TBI) is a severe disabling neurological disorder that affects more than 1.7 million Americans each year. Available treatments are only aimed at stabilizing an individual with TBI and consequently there is a great need for development of new therapeutic strategies. All-trans retinoic acid (atRA) is an important endogenous signaling molecule. Recent data show that atRA plays an important role in maintaining neuronal plasticity, learning and memory, increasing trauma-induced neurogenesis and decreasing glial activation in human or in animal, and support our hypothesis that increasing atRA in the brain will improve recovery of TBI victims. However, atRA has poor pharmacokinetics and it induces its own clearance resulting in loss of activity during long-term treatment. The clearance of RA is predominantly mediated by cytochrome P450 family 26 enzymes (CYP26). The CYP26 family has three isoforms: CYP26A1, CYP26B1 and CYP26C1. CYP26B1 appears to be the predominant brain isoform. We hypothesize that selective inhibition of CYP26B1 in the brain will increase neuronal atRA concentrations and will treat memory impairment and neuroinflammation associated with TBI, providing a therapeutic advantage for TBI victims. We designed an approach that led to the identification of a novel class of selective nanomolar CYP26B1 inhibitors. Such novel class of compounds is expected to be specific for CYP26B1 isoform avoiding non-target P450 inhibition associated with previously described azole-based CYP26 inhibitors. The objective of this proposal is to optimize our novel selective inhibitors of CYP26B1, to increase atRA concentration in the brain and treat memory impairment and neuroinflammation associated with TBI. Using our previously discovered lead structures, we propose to first generate a series of new compounds with improved CYP26B1 inhibition potency and selectivity using X-ray crystallography and computer-guided chemical modifications. In the second part of the proposal, we will demonstrate that CYP26B1 inhibition result in an improvement of memory deficit and reduce neuroinflammation and glial activation in a rat model of TBI. RELEVANCE We propose an innovative new therapeutic strategy to treat Traumatic brain injury (TBI) with CYP26B1 inhibitors that will increase neuronal retinoic acid concentration. We detail a plan to validate this target by optimizing our previously discovered CYP26B1 inhibitors for evaluation in animal models of TBI. If successful, this study could provide a novel therapeutic approach for the treatment of TBI.