Visinin-like protein-1 modulation of nicotinic receptors

Visinin 样蛋白-1 烟碱受体的调节

• 批准号: 10712709
• 负责人: Maegan M Weltzin
• 金额: $ 19.84万
• 依托单位: UNIVERSITY OF ALASKA FAIRBANKS
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-08-01 至 2027-07-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10712709
• 关键词: Accounting; Address; Adult; Affect; Agonist; Alaska; Alzheimer' s Disease; Attenuated; Behavior; Binding; Binding Sites; Biological Assay; Brain; Cell membrane; Cell surface; Cells; Central Nervous System; Cessation of life; Cholinergic Receptors; Chronic; Clinical; Confocal Microscopy; Data; Development; Dopamine; Drug Design; Electrophysiology (science); Environment; Epilepsy; Extramural Activities; Faculty; Foundations; Funding; Future; Generations; Goals; Homeostasis; Individual; Institution; Ion Channel Gating; Knowledge; Letters; Ligands; Mediating; Mentors; Mentorship; Mission; Molecular Chaperones; Mutate; National Institute of Drug Abuse; Neurons; Nicotine; Nicotine Use Disorder; Nicotinic Agonists; Nicotinic Receptors; Pathway interactions; Pharmacologic Substance; Pharmacology; Physiology; Plasma Enhancement; Play; Population; Positive Reinforcements; Prevention; Protein Isoforms; Proteins; Publications; Publishing; Regulation; Relapse; Research; Research Personnel; Research Support; Resources; Rewards; Role; Schizophrenia; Science; Scientific Advances and Accomplishments; Signal Transduction; Site; Students; Techniques; Time; Tobacco smoke; Tobacco use; Underrepresented Students; United States; Universities; Work; World Health Organization; aspirate; career; cholinergic; cigarette smoking; drug development; follow-up; hands on research; improved; neurobiological mechanism; nicotine cessation; nicotine reward; nicotine use; novel; novel strategies; novel therapeutics; preventable death; protein phosphatase inhibitor-2; receptor; receptor expression; receptor function; small molecule; smoking cessation; stoichiometry; success; timeline; tobacco products; tobacco user; visinin

ABSTRACT. Tobacco use is the world’s leading cause of preventable death, according to the World Health Organization. Within the US, cigarette smoking cases approximately one in five deaths, accounting for more than 480K deaths each year. Tobacco users who strive to quit usually relapse. In 2018, approximately 55% of adults in the US who smoked tobacco had made a quit attempt within the past year; only roughly 8% successfully quit for 6-12 months. Because of this, novel approaches are necessary to improve nicotine cessation success rates. Nicotine, a compound highly involved in nicotine use disorder (NUD), binds to neuronal nicotinic acetylcholine receptors (nAChRs) to activate brain reward and positive reinforcement circuits. Further, nicotine use results in cholinergic tone imbalance caused, in part, by dysregulation of the nAChR α4β2 subtype. The neuronal α4β2 subtype expresses in two isoforms with high and low sensitivity to nicotinic agonist (HS (α4β2)2β2 and LS (α4β2)2α4, respectively). Nicotine upregulates functional α4β2 nAChRs and enriches plasma membrane expression of the HS (α4β2)2β2 isoform. These changes result in hypersensitive brain reward (mesocorticolimbic) circuits while enhancing dopamine levels that reinforce rewarding behavior, contributing to NUD. Restoring the cholinergic tone to be less sensitive and comparable to pre-nicotine levels, is likely to be critical in the development of an efficacious approach to treating NUD. Little is known regarding chaperone protein regulation of α4β2 nAChR isoforms, a key proposal mission, and the ability of chaperone proteins to counteract nicotine-driven α4β2 isoform imbalance. To begin to answer some of these questions, we propose to define the basis of visinin-like protein-1 (VILIP-1) functional effects on receptor physiology, the interaction site, and VILIP-1-driven changes in α4β2 nAChR plasma membrane expression. Our preliminary data consistently show VILIP-1 attenuates α4β2 nAChR function and enhances plasma membrane expression. These underlying findings led us to our hypothesis that leveraging the interactions between VILIP-1 and α4β2 nAChRs by a small molecule may be a novel approach to treating NUD. Defining the VILIP-1/α4β2 nAChR interaction site, as proposed here, will remove critical barriers that stymie scientific and clinical NUD work, in addition to other conditions affected by α4β2 nAChR dysregulation. We will pursue the aims of this proposal by combining electrophysiology studies of receptor function with live cell confocal microscopy. Funding of this application will provide foundational support for PI Weltzin’s progress towards becoming an independent and established researcher by demonstrating project fundability and feasibility, assay advancement, preliminary data generation, and senior-author publications. Her mentorship team includes Drs. Miwa and Whiteaker, established nAChR experts. In addition, the proposal will provide hands-on research support for underrepresented students in biomedical science. Activities supported by this proposal will sustenance and enrich the research environment at the University of Alaska Fairbanks.

抽象的。据世界卫生说，烟草使用是世界可预防死亡的主要原因 组织。在美国，吸烟案件大约五分之一的死亡案件超过五分之五 每年480k死亡。努力退出的烟草用户通常退休。 2018年，大约有55％的成年人 在过去的一年中，在美国吸烟的美国已经戒烟了。大约只有8％的成功退出 6-12个月。因此，新颖的方法是提高尼古丁停止成功率所必需的。 尼古丁是一种高度参与尼古丁使用障碍（NUD）的化合物，与神经元烟碱乙酰胆碱结合 受体（NACHR）激活大脑奖励和阳性增强电路。此外，尼古丁的使用结果 NACHRα4β2亚型失调引起的胆碱能张力不平衡。神经元α4β2 亚型在对烟碱激动剂较高和低灵敏度的两个同工型中表达（HS（α4β2）2β2和LS （α4β2）2α4）。尼古丁上调功能性α4β2NACHR并富集质膜 HS（α4β2）2β2同工型的表达。这些变化导致大脑奖励过敏 （中皮层）电路，同时增强了多巴胺水平，从而增强了奖励行为，从而有助于 裸体。恢复胆碱能的张力较低敏感和与前凝蛋白水平相当，可能是 在开发有效治疗裸体方法的过程中至关重要。关于链人知之甚少 α4β2NACHR同工型的蛋白质调节，一个关键的建议任务以及伴侣蛋白的能力 抵消尼古丁驱动的α4β2同工型不平衡。为了开始回答其中一些问题，我们建议 定义Visin样蛋白-1（VILIP-1）功能对受体生理的功能的基础，相互作用位点， α4β2NACHR质膜表达的VILIP-1驱动变化。我们的初步数据一致 显示Vilip-1会减弱α4β2NACHR功能并增强质膜表达。这些基础 调查结果使我们提出了我们的假设，即通过小 分子可能是治疗裸体的一种新方法。定义vilip-1/α4β2NACHR相互作用位置，为 此处提出的，除其他 受α4β2NACHR失调影响的条件。我们将通过合并来追求该提议的目标 活细胞共聚焦显微镜受体功能的电生理研究。该申请的资金将 为Pi Weltzin的进步提供基本的支持，成为独立并建立 研究人员通过证明项目资金性和可行性，测定进步，初步数据生成， 和高级作者出版物。她的精神训练团队包括Drs。 Miwa和Whiteaker，已建立NACHR 专家。此外，该提案将为代表性不足的学生提供动手研究支持 生物医学科学。该提案支持的活动将维持和丰富研究环境 在阿拉斯加大学费尔班克斯大学。