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Leveraging Functional Selectivity in the Neurotensin Receptor 1-Mediated Treatment of Addiction

利用神经降压素受体 1 介导的成瘾治疗中的功能选择性

基本信息

批准号：
10395890
负责人：
Lauren M Slosky
金额：
$ 12.19万
依托单位：
DUKE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-06-15 至 2021-10-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10395890
关键词：
Abstinence Addictive Behavior Address Agonist Animal Model Animals Area Attenuated Behavior Behavioral Biological Brain Brain Diseases Characteristics Chemicals Chronic Clinical Cocaine Complement Complex Development Disease Dopamine Dopamine Antagonists Dopamine D2 Receptor Drug Modelings Drug usage Emission-Computed Tomography Epidemic Etiology Evaluation Exhibits G Protein-Coupled Receptor Signaling G-Protein-Coupled Receptors GTP-Binding Protein alpha Subunits, Gs GTP-Binding Proteins Genetic Genetic Engineering Genetically Engineered Mouse Goals Homeostasis Hypotension Image Imaging technology In Vitro Knock-out Laboratories Laboratory Study Lead Ligands Link Mediating Medical Mentors Methamphetamine Molecular Biology Morphine Mus Neurologic Neurotensin Receptors Neurotransmitters Normalcy Opiate Addiction Opioid Outcome Pathway interactions Patient-Focused Outcomes Peptides Pharmaceutical Preparations Pharmacology Pharmacotherapy Physiological Positioning Attribute Positron-Emission Tomography Property Psychostimulant dependence Public Health Recovery Relapse Research Running Self Administration Signal Transduction Signaling Protein Substance Use Disorder System Testing Therapeutic Time Training Universities X-Ray Computed Tomography addiction base beta-arrestin brain metabolism drug addict genetic manipulation improved outcome infancy interdisciplinary approach lead series mesolimbic system natural hypothermia neurochemistry neuroimaging novel novel therapeutics pre-clinical preservation psychostimulant remifentanil restoration side effect skills small molecule therapeutic target therapy outcome tool treatment strategy

项目摘要

Abstract: Opioid and psychostimulant addictions are large and growing public health concerns that are inadequately managed with available therapeutics. The objective of this proposal directly addresses this unmet clinical need, as it includes the evaluation of a novel anti-addiction therapeutic strategy. A shared feature of addictive drugs is their ability to induce inappropriate activation of the mesolimbic dopamine system. Restoration of dopamine signaling homeostasis may be achieved by targeting the G protein-coupled receptor (GPCR) neurotensin receptor 1 (NTR1). NTR1 modulates dopamine signaling via action at putative NTR1/dopamine receptor D2 (D2R) complexes. The efficacy of peptide NTR1 agonists in animal models of addiction have made clinically useful, small molecule NTR1 ligands highly desirable. NTR1, like other GPCRs, signals through both G protein- and β-arrestin-mediated pathways. Recently, we have developed and characterized a novel class of small molecule NTR1 ligands, typified by compound SBI-553, which activate β-arrestin without stimulating G protein signaling. This type of functional selectivity/biased siganling presents an opportunity to produce more directed physiological action and reduce unwanted side effects. My promising initial findings suggest that SBI- 553 attenuates drug-associated behaviors in mice without the hypotension and hypothermia characteristic of unbiased NTR1 agonism. The objectives of this application are to elucidate the mechanism by which β- arrestin biased NTR1 ligands attenuate drug-associated behaviors and validate their therapeutic potential by integrating murine self-administration and functional neuroimaging. My central hypothesis is that selective β- arrestin activation at NTR1 attenuates addiction-like behaviors and associated changes in regional brain metabolism through antagonism of D2R function. This hypothesis will be tested by pursuing three specific aims, using SBI-553 as a tool compound. I will first (1) K99) define the behavioral effects of β-arrestin biased NTR1 ligands by conducting self-administration studies in genetically engineered mice. I will then (2) K99) determine the physiological effects of β-arrestin biased NTR1 ligands using state-of-the-art small animal positron emission tomography/computed tomography (PET/CT). Finally, I will use my new training in murine self-administration and PET/CT to independently (3) R00) evaluate the contribution of D2R to the effects of β-arrestin biased NTR1 ligands. Pursuit of these aims requires interdisciplinary training in animal models of addiction and neuroimaging to complement my previous studies in molecular biology. Therefore, I have assembled expert collaborators into an interdisciplinary mentoring committee, chaired by Drs. Marc Caron (Mentor) and Lawrence Barak (Co-Mentor). The Caron laboratory at Duke University is uniquely well-positioned to answer questions regarding biased GPCR signaling in addiction. Together, we have crafted an individualized training plan that will provide me with the scientific and professional skills necessary to run a productive, independent laboratory and study addiction as a brain disease, including its neurological etiology and behavioral manifestations.

摘要：阿片类药物和精神兴奋剂成瘾是一个巨大且日益严重的公共卫生问题，可用的治疗方法治疗不充分。该提案的目标直接解决这一未满足的问题临床需求，因为它包括对新型抗成瘾治疗策略的评估。一个共同的特点是药物成瘾的原因在于它们能够诱导中脑边缘多巴胺系统的不当激活。恢复多巴胺信号稳态的调节可以通过靶向 G 蛋白偶联受体 (GPCR) 来实现神经降压素受体 1 (NTR1)。 NTR1 通过假定的 NTR1/多巴胺作用来调节多巴胺信号传导受体 D2 (D2R) 复合物。肽 NTR1 激动剂在成瘾动物模型中的功效已取得进展临床上非常需要有用的小分子 NTR1 配体。 NTR1 与其他 GPCR 一样，通过两者发出信号 G 蛋白和 β-抑制蛋白介导的途径。最近，我们开发并表征了一类新颖的小分子NTR1配体，以化合物SBI-553为代表，可激活β-arrestin而不刺激G 蛋白质信号传导。这种类型的功能选择性/有偏信号提供了生产更多信号的机会定向生理作用并减少不必要的副作用。我的初步研究结果很有希望，表明 SBI- 第553章无偏 NTR1 激动作用。本申请的目的是阐明 β- 抑制蛋白偏向的 NTR1 配体可减弱药物相关行为并通过以下方式验证其治疗潜力整合小鼠自我管理和功能神经影像。我的中心假设是选择性β- NTR1 上的抑制蛋白激活可减弱成瘾样行为和区域大脑的相关变化通过拮抗 D2R 功能进行代谢。这一假设将通过追求三个具体目标来检验，使用 SBI-553 作为工具化合物。我将首先 (1) K99) 定义 β-arrestin 偏向 NTR1 的行为效应通过在基因工程小鼠中进行自我给药研究来研究配体。然后我将 (2) K99) 确定使用最先进的小动物正电子发射研究 β-arrestin 偏向 NTR1 配体的生理效应断层扫描/计算机断层扫描 (PET/CT)。最后，我将使用我的新训练来进行小鼠自我管理和 PET/CT 独立 (3) R00) 评估 D2R 对 β-arrestin 偏向 NTR1 的影响的贡献配体。追求这些目标需要对成瘾动物模型进行跨学科培训神经影像学来补充我之前在分子生物学方面的研究。因此，我召集了专家合作者加入一个跨学科指导委员会，由博士担任主席。马克·卡伦（导师）和劳伦斯巴拉克（共同导师）。杜克大学卡隆实验室具有独特的优势来回答问题关于成瘾中 GPCR 信号的偏差。我们共同制定了个性化的培训计划将为我提供运营高效、独立实验室所需的科学和专业技能研究成瘾作为一种脑部疾病，包括其神经学病因和行为表现。