Targeting mitostasis via activation of mitochondrial biogenesis after TBI

现代军事行动的经验表明，创伤性脑损伤（TBI）是标志性损伤 现代战争使我们的军队成为创伤性脑损伤的高危人群。在327，388名使用OEF/OIF的退伍军人中， 在2009年的VA服务中，6.7%被诊断为TBI，其中73%被诊断为创伤后 应激障碍（PTSD）。然而，到目前为止，还没有批准用于TBI的治疗，部分原因是由于不完整的 了解TBI的病理生物学基础。令人信服的实验数据表明，线粒体 功能障碍是脑损伤的神经病理学后遗症中的关键环节。这个前提来自于我们的 已发表的工作（和其他人）表明，线粒体稳态的丧失和 线粒体活性氧（ROS）产生发生在TBI之后。保护或恢复 通过治疗性靶向线粒体损伤的线粒体功能改善了神经元功能， 创伤性脑损伤在这里，我们提出了一种新的方法，激活线粒体生物合成（MB），一个必要的过程， 线粒体动力学，TBI后使用药物干预。通过MB，功能失调的线粒体 通过涉及过氧化物酶体增殖物激活受体γ辅激活因子1- α（PGC-1α）作为主调节因子。MB的激活可以是调节细胞凋亡的重要干预措施。 线粒体动力学和防止TBI后代谢中断。最近，两种药物福莫特罗和 我们和我们的合作者筛选了lasmiditan，发现其通过激活两个 β2-肾上腺素受体（β 2-AR）和5-羟色胺1F（5-HT 1F）。我们 假设在最佳药物剂量下MB活化将改善线粒体功能， 减轻创伤性脑损伤后的病理变化并恢复认知功能。为了验证这一假设，在《特定目标》中， 1，我们将通过以下方式检查TBI后受损皮层和海马中MB的时间和空间方面： MB的分子标志物分析。我们还将完善和建立剂量反应和治疗 福莫特罗和lasmiditan治疗的干预窗口，以优化TBI后的MB。在这个目标中，我们还将 测试以下假设：在最佳条件下，用MB激活剂治疗促进TBI后的认知恢复。 治疗方案。在具体目标2中，我们将评估能量稳态的细胞和组织特异性变化 在使用生物能量和代谢组学方法进行TBI和MB活化治疗后， 分离突触线粒体的方法。我们还将研究TBI的潜在代谢机制 使用体内和离体13 C标记的示踪，随后使用高级稳定同位素分辨的 代谢组学分析最后，在具体目标3中，我们将评估MB激活剂对诱导 TBI后MB。使用5-HT 1F/β2AR基因敲除小鼠，我们假设功能获益依赖于 特异性受体信号传导导致MB的活化。总的来说，我们假设优化治疗方案 TBI后这些MB激活剂的窗口和剂量反应将导致生物能量稳态的改善 以及脑外伤后的神经认知表现

Experience in contemporary military operations suggests that traumatic brain injury (TBI) is the signature injury of modern wars making our troops a high-risk population for TBI. Among the 327,388 OEF/OIF veterans using VA services in 2009, 6.7% were diagnosed with TBI of which 73% of those were diagnosed with posttraumatic stress disorder (PTSD). However, to date there is no approved treatment for TBI, in part due to an incomplete understanding of the pathobiology underlying TBI. Compelling experimental data demonstrate that mitochondrial dysfunction is a pivotal link in the neuropathological sequelae of brain injury. This premise comes from our published work (and that of others) demonstrating that loss of mitochondrial homeostasis and increased mitochondrial reactive oxygen species (ROS) production occurs following TBI. Protecting or restoring mitochondrial function by therapeutically targeting mitochondrial impairment improves neuronal function after TBI. Here, we propose a novel approach of activating mitochondrial biogenesis (MB), a necessary process in mitochondrial dynamics, after TBI using pharmacological intervention. Through MB, dysfunctional mitochondria are replaced via signaling networks involving peroxisome proliferator-activated receptor gamma coactivator 1- alpha (PGC-1α) as a master regulator. Activation of MB can be an important intervention to modulate mitochondrial dynamics and prevent metabolic disruption after TBI. Recently, two drugs formoterol and lasmiditan have been screened by us and our collaborators and found to induce PGC-1α via activation of two independent receptors, β2-adrenoreceptor (β2AR) and 5-hydroxytryptamine1F (5-HT1F) respectively. We hypothesize that MB activation at the optimized drug dosage will improve mitochondrial function, mitigate pathology and restore cognitive function following TBI. To test this hypothesis, in Specific Aim 1, we will examine the temporal and spatial aspects of MB after TBI in the injured cortex and hippocampus by analyzing molecular markers of MB. We will also refine and establish the dose-response and therapeutic window of intervention for formoterol and lasmiditan treatment to optimize MB after TBI. In this Aim, we will also test the hypothesis that treatment with MB activators promotes cognitive recovery following TBI at the optimal therapeutic regime. In Specific Aim 2, we will assess cell- and tissue-specific changes in energy homeostasis following TBI and MB activation therapy using bioenergetic and metabolomic approaches and a novel approach to isolate synaptic mitochondria. We will also examine the underlying metabolic mechanisms of TBI and MB activation using in vivo and ex vivo 13C-labeled tracing followed by advanced stable isotope-resolved metabolomic analysis. Lastly, in Specific Aim 3 we will assess the specificity of MB activators on induction of MB after TBI. Using 5-HT1F/β2AR KO mice, we hypothesize that functional benefit is dependent on the specific receptor signaling leading to activation of MB. Overall, we hypothesize that optimizing the therapeutic window and dose response of these MB activators after TBI will lead to improved bioenergetic homeostasis and neurocognitive performance after TBI.