BLRD Senior Research Career Scientist Award Application

BLRD 高级研究职业科学家奖申请

• 批准号: 10369448
• 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/10369448
• 关键词: Address; Admission activity; Adrenergic Receptor; Affect; Aging; Animal Model; Antipsychotic Agents; Award; Binding; Biological Assay; Cells; Centers for Disease Control and Prevention (U.S.); 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; 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; Neuraxis; 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; Time; Toxic effect; United States Department of Veterans Affairs; Ventilatory Depression; Veterans; Veterans Health Administration; Wakefulness; Work; addiction; analog; animal tissue; base; 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; 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; 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 81,000 起药物过量事件 合成阿片类药物（即芬太尼及其类似物）是有史以来最高的比率。 尽管有纳洛酮用于治疗阿片类药物引起的呼吸系统疾病，但死亡人数仍在增加 西方 10 个州报告称，与合成阿片类药物相关的死亡人数增加了 98% 以上。 （疾病预防控制中心）最近的科学数据表明，“美国患者中阿片类药物使用障碍的比例 退伍军人健康管理局 (VHA) 的比例比非 VHA 参与者高出 7 倍。” al.，Fed Pract 2020；PMID：33029067 PMCID：PMC7535957）。 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同时存在。 精神疾病，包括精神分裂症和抑郁症是第二位。 退伍军人事务部服务的最大的精神病患者群体 例如精神分裂症是最常见的诊断之一，因为没有病因- 基于（生物）的治疗，这些患者反复入院到弗吉尼亚州医院， 治疗依从性和症状改善情况在全国范围内各不相同，VA 的花费超过。 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。 此外，仅波特兰退伍军人管理局就在抗精神病药物上花费了超过 2.5 亿美元。 每年花费超过 250 万美元用于抗精神病药物，从而导致药物滥用和精神分裂症。 对退伍军人管理局患者护理任务的医疗和财务方面产生了压倒性的影响。 开发治疗方法可以对医疗和财务方面产生深远而积极的影响 弗吉尼亚州的 我们实验室的首要目标是 1) 发现并表征遗传和 神经精神疾病和药物反应的神经化学先决因素，以及 2) 发现和开发新的基于病因学的神经精神疾病药物疗法， 包括成瘾。 该实验室利用表达重组蛋白的工程细胞开发并 继续开发中等通量放射性配体结合和第二信使/信号 转导系统检测约（目前）15 种人类 G 蛋白偶联受体或离子 此外，我们还量化了放射性配体结合、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以及 类似的测定用于表征受体和转运蛋白。 新开发的成像试剂用于人类疾病的动物模型和人体组织。 用于识别感兴趣的蛋白质的细胞内定位，以及它们在细胞内的方向 目前，我们正在确定有助于新药物疗法计算建模的细胞。 疾病和药物引起的细胞外囊泡 (EV) miRNA 货物的变化及其影响 细胞摄取 EV 的变化，以及对照受试者和精神分裂症受试者之间的差异。 因为缺乏可供患者轻松、安全、有效分娩的方法 直接作用于中枢神经系统的疗法，我们正在开发临床上有用的递送 此外，我们还描述了 EV/miRNA 系统的体外药理学差异。 以及体内合成阿片类药物（芬太尼及其类似物）和吗啡之间的差异，现在 开发针对每种药物过量症状的药物治疗方法。