Metabolic Mechanisms of Recovery in Mild TBI

项目摘要 在过去的十年中，脑震荡或轻度TBI的发生率一直在稳步上升。 脑震荡的一个可能后果-脑震荡后综合征-可以持续数周至数月， 导致患者生活不满意和社会经济负担。与开发新 轻度TBI的啮齿动物模型，我们现在可以研究介导损伤和/或保护的分子机制 一次创伤性脑损伤我们以前的工作确定了鸟嘌呤脱氨酶细胞溶质PSD-95的显着变化 在轻度和中度TBI后，研究了相互作用物（cypin），反过来，发现了小分子cypin激活剂， 在轻度和中度TBI模型中，体外神经保护和体内神经认知恢复。蜂窝 蛋氨酸的浓度，一个关键的代谢效应，调节神经认知，增加后不久 我们的初步数据表明，cypin是恢复甲硫氨酸水平的关键分子， TBI后的基线。我们认为，激活嘌呤代谢的cypin减弱蛋氨酸 通过两种机制：1）通过改变甲硫氨酸产生所需的细胞代谢和2）通过 与腺苷高半胱氨酸酶样1（AHCYL1）结合，抑制腺苷高半胱氨酸酶， 减少蛋氨酸前体高半胱氨酸的产生。这些机制可以被利用 用于治疗应用。我们提出的工作确定是否激活cypin可以针对后， 轻度TBI促进小鼠功能恢复。概括地说，我们提出的实验将确定新的分子 为治疗TBI患者和降低TBI对社会的长期发病率提供了目标。

Project Summary The occurrence of concussion, or mild TBI, has been steadily increasing in incidence over the past decade. One possible consequence of concussion - post-concussion syndrome - can persist for weeks to months and result in life dissatisfaction for the patient and economic burden for society. With the development of new rodent models for mild TBI, we can now study the molecular mechanisms that mediate injury and/or protection from a single TBI. Our previous work identified significant changes in the guanine deaminase cytosolic PSD-95 interactor (cypin) after mild and moderate TBI, and in turn, discovered small molecule cypin activators that are neuroprotective in vitro and restore neurocognition in vivo in both mild and moderate TBI models. Cellular concentrations of methionine, a key metabolic effector that regulates neurocognition, increases shortly after mild TBI, and our preliminary data point to cypin as a pivotal molecule for restoring methionine levels to baseline after TBI. We are proposing that activation of purine metabolism by cypin attenuates methionine levels via two mechanisms: 1) by altering cellular metabolism needed for methionine production and 2) by binding to adenosylhomocysteinase like 1 (AHCYL1), acting to inhibit adenosylhomocysteinase, which decreases the production of the methionine precursor, homocysteine. These mechanisms can be harnessed for therapeutic application. Our proposed work determines whether the activation of cypin can be targeted after mild TBI to promote functional recovery in mice. Broadly, our proposed experiments will identify new molecular targets for treating TBI patients and reducing the long-term morbidity of TBI on society.