RR&D Research Career Scientist Award Application

项目总结/摘要 目前VA资助的被提名人的研究活动分为两大类： TBI的慢性效应和帕金森病非运动症状的研究。关于TBI， 目前在被提名人的实验室的研究集中在军事人员中最常见的TBI形式， 退伍军人和平民-重复性轻度TBI（rmTBI）。这种阴险的头部损伤形式有许多共病 与之相关的精神、认知、睡眠和行为异常， 并且没有有效的治疗方法。被提名者的实验室最近开发了一种新的动物 rmTBI的模型，开辟了新的途径，调查慢性后果的头部损伤。初始 工作已经确定，该模型可以用于对小鼠头部施加多次冲击， 导致颅骨骨折颅内出血或瘫痪然而，这种模式是独特的，因为它导致许多 在退伍军人和运动员中看到的长期结果包括抑郁症和焦虑症 情感障碍、睡眠障碍、认知下降和CTE样神经病理学。另一个独特 这一系列研究的主要内容是测试rmTBI的新疗法。迄今为止，所有TBI治疗的临床试验 失败，必须考虑100%失败率的原因与 使用TBI的动物模型，这些模型不能忠实地创造人类所暴露的冲击条件。我们 新的rmTBI模型填补了这一空白。在我们的新模型发布后不久， 制药公司测试他们的新HDAC 6抑制剂作为治疗rmTBI。正在进行的研究与此新的 化合物正在产生有希望的结果，新兴的测试也将确定其在缓解 经常伴随rmTBI的共病状况。 关于帕金森病（PD），它正在成为非运动症状（NMS），这是 神经退行性疾病降低了退伍军人的生活质量， 运动症状帕金森氏症的NMS可以包括上文针对rmTBI所引用的许多相同病症。到 迄今为止，PD的绝大多数临床前和临床研究都集中在多巴胺（DA）神经元 系统及其破坏如何导致疾病的病理学。大多数PD治疗也针对DA 系统与rmTBI的情况一样，PD的NMS没有有效的治疗方法。然而，虽然大大 尽管5-羟色胺（5-HT）和去甲肾上腺素（NE）系统在PD中被低估，但它们也被广泛改变。 被提名者的实验室已经创造了两种缺乏大脑5 HT的转基因小鼠品系。一个是 色氨酸羟化酶基因中的组成性无效突变和一种新菌株是他莫昔芬诱导的 敲除同一基因。使这些小鼠品系如此适用于研究 帕金森病的NMS是这样一个事实，即他们中的5 HT缺陷与现在已知的人类中发生的缺陷非常相似 PD-功能丧失，而无5 HT神经元变性。这些5 HT缺陷小鼠将用于产生 使用选择性靶向DA（MPTP）和NE（DPS-4）的神经毒素的联合单胺缺乏 神经元系统和这些改变对NMS出现的影响将被评估。这些 研究还将测试每种单胺单独或组合的天然前体，以恢复功能， 缓解NMS。 上述研究的总体目标是改善治疗并提高治疗效果。 患有rmTBI和PD的退伍军人的康复。这个目标非常重要，因为这两个 疾病影响了非常多的退伍军人，每一个经常与许多，额外的 共病障碍我们的总体目标将通过增加对该疾病的了解来实现 通过应用新的和创新的技术方法， 通过测试新的、合理的和安全的治疗方法。

Project Summary / Abstract The current VA-funded research activities of the nominee fall into two major categories: studies of the chronic effects of TBI and studies of the non-motor symptoms of Parkinson's disease. With regard to TBI, current studies in the nominee's lab are focusing on the most prevalent form of TBI seen in military personnel, Veterans and civilians- repetitive, mild TBI (rmTBI). This insidious form of head injury has many comorbid psychiatric, cognitive, sleep and behavioral abnormalities associated with it yet it remains poorly understood and effective treatments for it are not available. The lab of the nominee recently developed a new animal model of rmTBI that has opened new avenues of investigation into the chronic outcomes of head injury. Initial work has established that the model can be used to deliver numerous impacts to the head of a mouse without causing skull fracture, intracranial bleeding or paralysis. However, this model is unique in that it results in many of the long-term outcomes that are being seen in Veterans and athletes to include depression- and anxiety-like affective disorders, sleep disturbances, cognitive decline and a CTE-like neuropathology. Another unique element this line of research is the testing of a new therapy for rmTBI. To date, all clinical tests of TBI therapies have failed and the possibility must be considered that the reason for this 100% failure rate is related to the use of animal models of TBI that do not faithfully create impact conditions to which humans are exposed. Our new model of rmTBI fills this gap. Soon after publication of our new model, we were approached by Acetylon Pharmaceuticals to test their new HDAC6 inhibitor as a therapy for rmTBI. Studies underway with this new compound are producing promising results and emerging tests will also determine its effectiveness in relieving the comorbid conditions that often accompany rmTBI. With regard to Parkinson's disease (PD), it is becoming that the non-motor symptoms (NMS) of this neurodegenerative disease lower the quality of life for Veterans more so than the much better understood motor symptoms. The NMS of Parkinson's can include many of the same conditions cited above for rmTBI. To date, the vast majority of preclinical and clinical studies of PD have focused on the dopamine (DA) neuronal system and how its destruction can result in disease symptomology. Most therapies for PD also target the DA system. As is the case for rmTBI, there is no effective therapy for the NMS of PD. However, while vastly underappreciated, the serotonin (5HT) and norepinephrine (NE) systems are also extensively altered in PD. The lab of the nominee has created two genetically modified mouse strains that lack brain 5HT. One is a constitutive null mutation in the gene for tryptophan hydroxylase and a new strain is a tamoxifen-inducible knockout of the same gene. The key facet that makes these mouse strains so applicable to the study of the NMS of PD is the fact that the 5HT deficits in them are very similar to those now known to occur in humans with PD- loss of function without degeneration of 5HT neurons. These 5HT deficient mice will be used to create combined monoamine deficits using neurotoxins that selectively target the DA (MPTP) and the NE (DPS-4) neuronal systems and the effects of these alterations on the emergence of NMS will be assessed. These studies will also test the natural precursors of each monoamine alone or in combination to restore function and alleviate the NMS. The overarching goal of the above described research is to improve the treatment and enhance the rehabilitation of Veterans afflicted with rmTBI and PD. This goal is extremely important because these two disorders affect a very large number of Veterans and each is frequently associated with numerous, additional comorbid disorders. Our overarching goal will be achieved by increasing the understanding of the disease mechanisms of rmTBI and PD NMS via the application of new and innovative technical approaches and through the testing of novel, rational and safe therapeutic approaches.