BLRD Senior Research Career Scientist Award Application

BLRD 高级研究职业科学家奖申请

• 批准号: 10512759
• 负责人: Aaron J. Janowsky
• 金额: --
• 依托单位: PORTLAND VA MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-10-01 至 2028-09-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10512759
• 关键词: Address; Admission activity; Adrenergic Receptor; Affect; Aging; Animal Model; Antipsychotic Agents; Award; Binding; Biological Assay; Cells; Central Nervous System; Cessation of life; Clinical; Clinical Treatment; Cocaine Abuse; Computer Models; Data; Development; Diagnosis; Disease; Dose; Drug Modelings; Drug Receptors; Drug abuse; Engineering; Etiology; FDA approved; Fentanyl; Friends; G-Protein-Coupled Receptors; General Population; Genetic; Genetic Polymorphism; Goals; Heroin; Hospitals; Human; Image; In Vitro; Ion Channel; Laboratories; Mediating; Medical; Mental Depression; Mental Health; Mental disorders; Methamphetamine; Methods; MicroRNAs; Mission; Modification; Morphine; Naloxone; Neurotransmitters; Opioid; Outpatients; Overdose; Patient Care; Patients; Pharmaceutical Preparations; Pharmacology; Pharmacotherapy; Post-Traumatic Stress Disorders; Proteins; Protocols documentation; Psychotic Disorders; Publications; Publishing; Reagent; Recombinant Proteins; Recombinants; Recurrence; Reporting; Research; Schizophrenia; Scientist; Second Messenger Systems; Services; Signal Transduction; Sleep Apnea Syndromes; Substance Use Disorder; Symptoms; System; Therapeutic; Toxic effect; United States Department of Veterans Affairs; Ventilatory Depression; Veterans; Veterans Health Administration; Wakefulness; Work; addiction; analog; animal tissue; career; commercialization; comorbidity; compliance behavior; computational chemistry; experience; extracellular vesicles; fentanyl overdose; heroin overdose; human disease; human model; human subject; human tissue; improved; in vivo; individualized medicine; interest; methamphetamine abuse; microRNA delivery; military veteran; model development; molecular modeling; mu opioid receptors; neurochemistry; neuropsychiatric disorder; neurotransmitter release; neurotransmitter uptake; novel; novel therapeutics; opioid abuse; opioid mortality; opioid overdose; opioid use disorder; pharmacologic; programs; radioligand; receptor; response; screening; symptomatic improvement; synthetic opioid; vesicular monoamine transporter; vesicular release; vocal cord

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.

项目摘要/摘要： 2019年6月至2020年5月，美国约有8.1万人吸毒过量-- 有记录以来的最高比率。合成阿片类药物(即芬太尼及其类似物)是主要驱动力 死亡人数的增加，尽管纳洛酮可用于治疗阿片类药物引起的呼吸 抑郁症。西部十个州报告合成阿片类药物相关死亡人数增加了98%以上 (CDC)。最近的科学数据表明，在中国，患者中阿片类药物使用障碍的比率 退伍军人健康管理局(VHA)的比例是非VHA参与者的7倍。(Ahonle et Al.，FED Pract.2020年；PMID：33029067；PMC7535957)。通常和太频繁地，毒品 虐待是一个令人困惑的问题，它与创伤后应激障碍和其他 精神疾病，包括精神分裂症和抑郁症。精神科门诊患者是第二位 退伍军人事务部为精神病患者提供服务的最大群体 比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)，这些患者反复进入退伍军人医院， 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在 30亿美元，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……里面 此外，退伍军人管理局在抗精神病药物上的支出超过2.5亿美元，仅波特兰退伍军人管理局就花费了2.5亿美元 每年在抗精神病药物上花费超过250万美元。因此，药物滥用和精神分裂症 对退伍军人管理局病人护理任务的医疗和财务方面产生了压倒性的影响。 开发治疗和治疗方法可以深刻和积极地影响医疗和财务方面 退伍军人事务部的。 我们实验室的首要目标是1)发现和表征基因和 神经精神障碍和药物反应的神经化学前驱决定因素，以及2) 发现和开发基于病因学的神经精神障碍药物疗法， 包括上瘾。 使用表达重组蛋白的工程细胞，实验室已经开发出和 继续开发中等吞吐量的放射性配基结合和第二信使/信号 大约(目前)15个人G蛋白偶联受体或离子的转导系统分析 渠道及其多态。此外，我们还量化了放射性配基结合、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。类似的分析方法也被用来表征受体和转运体。 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 用于识别感兴趣蛋白质的细胞内定位以及它们在细胞内的定位 细胞，以帮助计算模型为新的药物疗法。目前，我们正在确认 疾病和药物对细胞外小泡(EVS)miRNA载量的影响 细胞摄取EVS，以及对照组和精神分裂症患者之间的差异。 因为缺乏让患者轻松、安全、有效地进行分娩的方法 直接到中枢神经系统的治疗，我们正在开发临床上有用的递送 EV/miRNAs系统。此外，我们还表征了体外的药理差异。 和体内合成阿片类药物(芬太尼及其类似物)和吗啡之间的关系，现在是 开发针对每种药物过量症状的药物疗法。