BLRD Senior Research Career Scientist Award Application

项目概要/摘要： 从2019年6月到2020年5月，美国约有81，000例药物过量- 有史以来最高纪录。合成阿片类药物（即，芬太尼及其类似物）是主要驱动力 尽管纳洛酮可用于治疗阿片类药物引起的呼吸道疾病， 萧条10个西部州报告说，与合成阿片类药物有关的死亡人数增加了98%以上。 （CDC）。最近的科学数据表明，“阿片类药物使用障碍的患者中， 退伍军人健康管理局（VHA）是非VHA注册者的7倍。”（Ahonle et 例如，Fed Pract.2020; PMID：33029067 PMCID：PMC7535957）。一般来说，过于频繁的药物 虐待是一个令人困惑的问题，与创伤后应激障碍和其他疾病并存。 精神疾病，包括精神分裂症和抑郁症。精神科门诊病人是第二位 由退伍军人事务部服务的最大的一群患有精神障碍的病人 例如精神分裂症是最常见的诊断之一。因为没有病因学- 基于（生物学）的治疗，这些患者经历复发性VA入院。医院， 并且治疗依从性和症状改善是可变的。在全国范围内，退伍军人管理局。花费超过 30亿美元和波特兰退伍军人管理局每年在心理健康项目上花费超过2500万美元。在 此外，V.A.在抗精神病药物和波特兰退伍军人管理局上花费了超过2.5亿美元。单独 每年花费超过250万美元用于抗精神病药物。因此，药物滥用和精神分裂症 对退伍军人管理局的医疗和财政方面产生了巨大的影响。病人护理使命。 开发治疗和治愈方法可以深刻而积极地影响医疗和财务方面 退伍军人管理局的 我们实验室的首要目标是1）发现和表征遗传和 神经精神疾病和药物反应的神经化学前决定因素，以及2） 发现和开发新的基于病因的神经精神疾病药物疗法， 包括成瘾。 利用表达重组蛋白的工程细胞，该实验室已经开发出 继续开发中等通量放射性配体结合和第二信使/信号 转导系统测定约（目前）15人G蛋白偶联受体或离子 通道及其多态性。此外，我们定量放射性配体结合，神经递质 重组人神经递质转运蛋白的摄取和神经递质释放， 囊泡单胺转运体类似的测定用于表征受体和转运蛋白 在人类疾病的动物模型和人体组织中。新开发的成像试剂是 用于鉴定感兴趣的蛋白质的细胞内定位，以及它们在细胞内的取向。 细胞来帮助新药物治疗的计算建模。目前，我们正在确定 疾病和药物引起的细胞外囊泡（EV）miRNA货物的变化，它们的影响 以及对照组和精神分裂症患者之间的差异。 因为缺乏让患者方便、安全、有效地分娩的方法， 治疗直接到中枢神经系统，我们正在开发临床上有用的交付 EV/miRNAs系统。此外，我们还描述了体外药理学差异， 和体内合成阿片类药物（芬太尼及其类似物）和吗啡之间，现在 开发药物治疗药物，以治疗每种药物的过量症状。

Project Summary/Abstract: There were about 81,000 drug overdoses in the U.S. from June 2019 to May 2020 – the highest rate ever recorded. Synthetic opioids (i.e., fentanyl and its analogues) are the primary driver of the increase in deaths, despite availability of naloxone for treatment of opioid-induced respiratory depression. Ten Western states reported an over 98% increase in synthetic opioid-involved deaths (CDC). Recent scientific data indicate, “The rate of opioid use disorder among patients in the Veterans Health Administration (VHA) is 7 times higher than that of non-VHA enrollees.” (Ahonle et al., Fed Pract. 2020; PMID: 33029067 PMCID: PMC7535957). Generally and too frequently, drug abuse is a confounding problem that is co-morbid with post-traumatic stress disorder and other mental illnesses, including schizophrenia and depression. Psychiatric outpatients are the second largest group of patients serviced by the Department of Veterans Affairs, with psychotic disorders such as schizophrenia being one of the most frequent diagnoses. Because there are no etiology- (biologically-) based treatments, these patients experience recurrent admissions to V.A. hospitals, and treatment compliance and symptom improvement are variable. Nationally, the V.A. spends over $3 billion and the Portland V.A. spends over $25 million annually on mental health programs. In addition, the V.A. spends over $250 million on antipsychotic medications and the Portland V.A. alone spends over $2.5 million annually on antipsychotic medications. Thus, drug abuse and schizophrenia have had an overwhelming impact on medical and financial aspects of the V.A. patient care mission. Developing treatments and cures could profoundly and positively impact medical and financial facets of the V.A. Our laboratory’s overarching goals are to 1) discover and characterize genetic and neurochemical pre-determinants for both neuropsychiatric disorders and drug response, and 2) discover and develop new etiology-based pharmacotherapies for neuropsychiatric disorders, including addictions. Using engineered cells expressing recombinant proteins, the laboratory has developed and continues to develop medium throughput radioligand binding and second messenger/signal transduction system assays for about (currently) 15 human G protein coupled receptors or ion channels and their polymorphisms. Additionally, we quantify radioligand binding, neurotransmitter uptake and neurotransmitter release by recombinant human neurotransmitter transporters and the vesicular monoamine transporter. Similar assays are used to characterize receptors and transporters in animal models of human disease and in human tissue. Newly developed imaging reagents are used to identify the intracellular localization of proteins of interest, as well as their orientation within cells to aid in computational modeling for new pharmacotherapies. Currently, we are identifying disease and drug-induced changes in the miRNA cargo of extracellular vesicles (EVs), their impact on cells taking up EVs, and differences between control subjects and subjects with schizophrenia. Because there is a paucity of methods for patients to easily, safely, and effectively deliver therapeutics directly to the central nervous system, we are developing clinically useful delivery systems for EV/miRNAs. Additionally, we have characterized pharmacological differences in vitro and in vivo between synthetic opioids (fentanyl and its analogues) and morphine, and are now developing pharmacotherapeutics for overdose symptoms specific to each.