RR&D Research Career Scientist Award Application

项目摘要/摘要 目前退伍军人管理局资助的被提名者的研究活动分为两大类： 脑外伤的慢性影响和帕金森病非运动症状的研究。关于TBI， 提名人实验室目前的研究重点是在军事人员中最常见的脑损伤形式， 退伍军人和平民--重复性、轻度脑外伤(RmTBI)。这种隐匿性的头部损伤有许多并发症。 与其相关的精神、认知、睡眠和行为异常，但仍知之甚少 而且目前还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动物 RmTBI模型为研究头部损伤的慢性后果开辟了新的途径。首字母 研究已经证实，该模型可以用来对鼠标头部进行多次冲击，而不需要 导致头骨骨折、颅内出血或瘫痪。然而，这种模式是独特的，因为它导致了许多 退伍军人和运动员的长期结果包括抑郁症和焦虑症 情感障碍、睡眠障碍、认知能力下降和类似CTE的神经病理。另一个独一无二的 这一系列研究是对一种治疗rmTBI的新疗法的测试。到目前为止，所有脑损伤疗法的临床试验 都失败了，必须考虑到这种100%失败率的原因与 使用不会忠实地造成人类暴露于其中的影响条件的脑损伤动物模型。我们的 新的rmTBI模型填补了这一空白。在我们的新型号问世后不久，有一家名为Acetron的公司与我们接洽 测试他们的新的HDAC6抑制剂作为治疗rmTBI的药物。正在对这一新技术进行研究 化合物正在产生有希望的结果，新出现的试验也将确定其缓解疾病的有效性 经常伴随着rmTBI的并存情况。 关于帕金森氏病(PD)，其非运动症状(NMS)正在成为 神经退行性疾病降低退伍军人的生活质量比人们更了解的更严重 运动症状。帕金森氏症的NMS可以包括上面提到的许多与rmTBI相同的情况。至 迄今为止，绝大多数帕金森病的临床前和临床研究都集中在多巴胺(DA)神经元 以及系统的破坏如何导致疾病症状。大多数帕金森病的治疗也针对DA 系统。与rmTBI的情况一样，帕金森病的NMS没有有效的治疗方法。然而，虽然极大地 在帕金森病患者中，5-羟色胺(5-羟色胺)和去甲肾上腺素(NE)系统也发生了广泛的改变。 被提名人的实验室创造了两个缺乏大脑5-羟色胺的转基因小鼠品系。一个是 色氨酸羟化酶基因的结构性零突变和一株新菌株是他莫昔芬诱导的 相同基因的敲除。使这些小鼠品系如此适用于研究的关键方面 帕金森病的NMS是这样一个事实，即它们中的5-羟色胺缺陷与现在已知的发生在人类身上的非常相似 伴有帕金森病，功能丧失，5HT神经元无变性。这些5-羟色胺缺乏的小鼠将被用来创造 使用选择性靶向多巴胺(MPTP)和去甲肾上腺素(DPS-4)的神经毒素结合单胺缺乏 将评估神经系统以及这些改变对NMS出现的影响。这些 研究还将单独或联合测试每种单胺的天然前体，以恢复功能和 缓解NMS。 上述研究的首要目标是改善治疗并增强 患有颅脑损伤和帕金森病的退伍军人的康复。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，每个退伍军人经常与无数、额外的 共病障碍。我们的首要目标将通过增加对这种疾病的了解来实现 通过应用新的和创新的技术方法和 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.