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。根据世界卫生组织的数据，吸烟是世界上可预防的死亡的主要原因 组织。在美国，吸烟案例约占死亡人数的五分之一，占死亡人数的比例超过 每年有48万人死亡。努力戒烟的吸烟者通常会复发。2018年，约55%的成年人 在美国，吸烟者在过去一年内曾尝试戒烟；只有大约8%的人成功戒烟 6-12个月。正因为如此，提高尼古丁戒断成功率的新方法是必要的。 尼古丁是一种与尼古丁使用障碍(Nud)高度相关的化合物，它与神经元烟碱型乙酰胆碱结合。 受体(NAChRs)激活大脑奖赏和正强化回路。此外，尼古丁的使用会导致 胆碱能张力失衡的部分原因是nAChRα4β2亚型的失调。神经元α-4-β-2 亚型表达两种亚型，对烟碱激动剂(HS(α4β2)2，β2和LS)具有高和低敏感性 (α4β2)2α4)。尼古丁上调功能性α4β2nAChRs并丰富质膜 HS(α4β2)2β2亚型的表达。这些变化导致了对大脑高度敏感的奖励 (中皮质边缘)回路，同时提高多巴胺水平，从而加强奖励行为，有助于 努德。将胆碱能张力恢复到不那么敏感，并与尼古丁之前的水平相当，可能是 在开发治疗NUD的有效方法方面至关重要。关于伴侣的信息知之甚少 α4β2nAChR异构体的蛋白质调节，一个关键的建议任务，以及伴侣蛋白对 中和尼古丁驱动的α4β2亚型失衡。为了开始回答其中一些问题，我们建议 明确粘蛋白样蛋白-1(VILIP-1)对受体生理的功能作用基础，相互作用部位， α-4、β-2nAChR质膜表达的改变。我们的初步数据一致 Show VILIP-1减弱α4β2nAChR功能，增强质膜表达。这些潜在的 研究结果引导我们的假设是，利用VILIP-1和α4β2 nAChRs之间的相互作用 分子可能是治疗NUD的一种新方法。将VILIP-1/α4β2 nAChR交互作用站点定义为 在这里提出的，将消除阻碍科学和临床NUD工作的关键障碍，以及其他 α-4、β-2nAChR失调对病情的影响。我们将通过以下方式实现这项提案的目标 活细胞共聚焦显微镜对受体功能的电生理学研究。这项申请的资金将 为PI Weltzin向独立和成熟的方向发展提供基础支持 研究人员通过论证项目的资助性和可行性、分析进展、初步数据生成、 和资深作者出版物。她的导师团队包括Miwa博士和Whiteaker博士，他们是nAChR的老牌医生 专家。此外，该提案将为代表人数不足的学生提供实践研究支持。 生物医学科学。这项提议支持的活动将支持和丰富研究环境 在阿拉斯加大学费尔班克斯分校。