Subproject Investigator: Philippe J. Diaz

子项目研究员：Philippe J. Diaz

基本信息

批准号：
10004087
负责人：
Philippe J Diaz
金额：
$ 21.36万
依托单位：
UNIVERSITY OF MONTANA
依托单位国家：
美国
项目类别：
财政年份：
2011
资助国家：
美国
起止时间：
2011-09-01 至 2023-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10004087
关键词：
Adult Affect American Animal Model Animals Azoles Binding Biochemical Biological Biological Markers Brain Brain Injuries CYP26B1 gene Cell Culture Techniques Cell Death Cells Chemicals Computers Cytochrome P450 Data Development Docking Drug Design Drug Kinetics Enzyme Inhibitor Drugs Enzymes Evaluation Exhibits Family Feedback Hippocampus (Brain)Homology Modeling Human Impaired cognition In Vitro Individual Inflammatory Injury Lead Learning Libraries Ligands Mechanics Mediating Memory Memory impairment Microglia Modeling Modification Mus Nerve Regeneration Neuronal Injury Neuronal Plasticity Neurons Outcome Pharmaceutical Preparations Play Process Production Protein Isoforms Rat-1 Rattus Recovery Regulation Research Personnel Resistance Role Series Signal Transduction Signaling Molecule Structure TBI treatment Therapeutic Time Toxic effect Trauma Traumatic Brain Injury Traumatic Brain Injury recovery Tretinoin Vitamin A X-Ray Crystallography base behavior test cytokine design glial activation improved in silico in vivo inhibitor/antagonist innovation mild traumatic brain injury nanomolar nervous system disorder neurogenesis neuroinflammation neuron loss neuropathology novel novel therapeutic intervention novel therapeutics retinoic acid 4-hydroxylase stem cells therapeutic target virtual virtual library

项目摘要

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.

项目摘要创伤性脑损伤（TBI）是一种严重的残疾神经系统疾病，影响超过170万每年美国人。可用的治疗仅旨在稳定使用TBI和因此，需要制定新的治疗策略。全反式视黄酸（ATRA）是重要的内源信号分子。最近的数据表明，ATRA在保持神经元可塑性，学习和记忆，增加创伤引起的神经发生并减少人类或动物中的神经胶质激活，并支持我们的假设，即增加大脑的ATRA将改善恢复TBI受害者。但是，ATRA的药代动力学不良，并且会引起其自身的清除。长期治疗期间的活动丧失。 RA的清除主要由细胞色素介导 P450家族26酶（CYP26）。 CYP26家族具有三种同工型：CYP26A1，CYP26B1和CYP26C1。 CYP26B1似乎是主要的脑同工型。我们假设选择性抑制CYP26B1 在大脑中会增加神经元的ATRA浓度，并治疗记忆障碍和与TBI相关的神经炎症，为TBI受害者提供了治疗优势。我们设计了一个导致鉴定出新的选择性纳摩尔CYP26B1抑制剂的方法。这样的小说预计化合物将针对CYP26B1同工型特定，避免了非目标P450抑制与先前描述的基于唑的CYP26抑制剂有关。该提议的目的是优化我们新颖的CYP26B1选择性抑制剂，以增加大脑中的ATRA浓度并治疗与TBI相关的记忆障碍和神经炎症。使用我们先前发现的铅结构，我们建议首先生成一系列具有改善CYP26B1抑制效力的新化合物使用X射线晶体学和计算机引导的化学修饰的选择性。在第二部分提案，我们将证明CYP26B1抑制作用会改善记忆不足和减少TBI大鼠模型中的神经炎症和神经胶质激活。关联我们提出了一种创新的新治疗策略，以使用CYP26B1治疗创伤性脑损伤（TBI）会增加神经视黄酸浓度的抑制剂。我们详细详细介绍了通过优化我们先前发现的CYP26B1抑制剂，以评估TBI动物模型。如果成功，这项研究可以为治疗TBI提供一种新型的治疗方法。