权益分类	功能权益	普通用户	{{item.name}}会员
{{category.name}}	{{benefitItem.name}}

Alpha-Conotoxin MII: A Selective Nicotinic Receptor Probe

Alpha-芋螺毒素 MII：选择性烟碱受体探针

基本信息

批准号：
8116617
负责人：
PAUL WHITEAKER
金额：
$ 35.53万
依托单位：
ST. JOSEPH'S HOSPITAL AND MEDICAL CENTER
依托单位国家：
美国
项目类别：
财政年份：
1999
资助国家：
美国
起止时间：
1999-02-01 至 2014-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8116617
关键词：
Address Adopted Affect Aminobutyric Acids Animals Behavioral Binding Biological Assay Biotin Chronic Complex Mixtures Conotoxin Conus genus Corpus striatum structure Development Dopamine Drosophila acetylcholine receptor alpha-subunit Engineering Equilibrium Exhibits Family Funding Goals Grant Health Human Hybrids Individual Knowledge Label Lesion Ligand Binding Ligands Location Maintenance Measures Mediating Modeling Molecular Mus Mutation Neurotransmitters Nicotine Nicotine Dependence Nicotinic Receptors Parkinson Disease Peptides Performance Play Population Progress Reports Property Radiolabeled Research Personnel Retinal Cone Role Series Snails Specificity System Toxin Variant alpha-Conotoxin alpha-conotoxin MII analog base design experience gain of function gamma-Aminobutyric Acid improved insight member neurotransmission novel programs radiotracer receptor research study response smoking cessation success tool

项目摘要

DESCRIPTION (provided by applicant): Nicotine produces behavioral effects through a diverse family of nicotinic acetylcholine receptors (nAChRs). Nicotine-evoked dopamine release is thought to play an important role in the establishment and maintenance of nicotine dependence, which undelies peoples' continued use of tobacoo products, despite their well-known dangers to health. alpha-conotoxin MII is a toxin isolated from the predatory cone-snail Conus magus, which distinguishes between subsets of nicotinic receptors. In the first funding periods of this grant, we used alpha-CtxMII to identify and analyse the nAChR populations that modulate nicotine-evoke dopamine release. We also began to study the effects of chronic nicotine exposure on these receptors, and how they are affected in models of Parkinson's Disease. In order to enhance the usefulness of alpha-CtxMII, we have also engineered variants which have incorporate new properties or increased its selectivity for particular nAChR populations. Experiments outlined in the current proposal will extend these studies further. 1) Chronic treatment and nicotinic subunit mutation will be used (alone, and in combination) to investigate how the nAChR populations characterized in the previous funding period interact with each other, and with the neurotransmitter systems that they modulate. 2) New alpha-CtxMII derivatives will be developed with two aims. First, to make alpha3beta2-nAChR subtype selective derivatives (we do not have such a compound at present, but this is a natually-expressed nAChR subtype that requires further study). Second, to produce alpha-CtxMII-based radiolabels that retain the original selectivity of [125l]alpha-CtxMII (which was developed in the previous funding periods), but with improved assay performance. This will improve out ability to measure and study these important nAChRs. 3) Synthesize and characterize derivatives of alpha-conotoxin ArIB, which has selectivity for alpha7-subtype nAChRs. We intend to develop a series of useful, highly-selective tools for the study of this naturally-occurring nAChR subtype. The proposed studies will provide further insights into the locations, numbers and functional roles of naturally-occurring nAChRs, and the interactions between them. It is likely that this increased understanding will, in turn, illuminate which nAChR subtypes are implicated in nicotine dependence, and thus assist in attempts to develop more-effective smoking cessation aids. These insights may also guide the design of nicotinic therapies for other conditions.

描述（由申请人提供）：尼古丁通过烟碱乙酰胆碱受体（nAChR）的不同家族产生行为效应。尼古丁引起的多巴胺释放被认为在尼古丁依赖的建立和维持中发挥着重要作用，这阻碍了人们继续使用烟草制品，尽管烟草制品对健康有众所周知的危害。 α-芋螺毒素 MII 是从捕食性圆锥蜗牛 Conus magus 中分离出来的一种毒素，可区分烟碱受体的子集。在本次资助的第一个资助期间，我们使用 alpha-CtxMII 来识别和分析调节尼古丁诱发多巴胺释放的 nAChR 群体。我们还开始研究长期接触尼古丁对这些受体的影响，以及它们在帕金森病模型中如何受到影响。为了增强 alpha-CtxMII 的实用性，我们还设计了变体，这些变体具有新的特性或增加了其对特定 nAChR 群体的选择性。当前提案中概述的实验将进一步扩展这些研究。 1) 将使用慢性治疗和烟碱亚基突变（单独或组合）来研究先前资助期间表征的 nAChR 群体如何相互作用，以及如何与它们调节的神经递质系统相互作用。 2) 新的α-CtxMII衍生物的开发有两个目的。首先，制作α3β2-nAChR亚型选择性衍生物（我们目前没有这样的化合物，但这是天然表达的nAChR亚型，需要进一步研究）。其次，生产基于 α-CtxMII 的放射性标记，保留 [125l]α-CtxMII 的原始选择性（在之前的资助期间开发），但具有改进的检测性能。这将提高测量和研究这些重要 nAChR 的能力。 3) 合成并表征α-芋螺毒素ArIB的衍生物，其对α7亚型nAChR具有选择性。我们打算开发一系列有用的、高选择性的工具来研究这种天然存在的 nAChR 亚型。拟议的研究将进一步深入了解天然存在的 nAChR 的位置、数量和功能作用以及它们之间的相互作用。反过来，这种加深的了解可能会阐明哪些 nAChR 亚型与尼古丁依赖有关，从而有助于尝试开发更有效的戒烟辅助剂。这些见解也可能指导其他病症的烟碱疗法的设计。

项目成果

期刊论文数量（36）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Genetic matters: thirty years of progress using mouse models in nicotinic research.

DOI：
10.1016/j.bcp.2013.05.021
发表时间：
2013-10-15
期刊：
Biochemical pharmacology
影响因子：
5.8
作者：
Marks MJ
通讯作者：
Marks MJ

The road to discovery of neuronal nicotinic cholinergic receptor subtypes.

DOI：
10.1007/978-3-540-69248-5_4
发表时间：
2009-01-01
期刊：
Handbook of experimental pharmacology
影响因子：
0
作者：
Collins, Allan C;Salminen, Outi;Grady, Sharon R
通讯作者：
Grady, Sharon R

A role for *4(non-*6)* nicotinic acetylcholine receptors in motor behavior.

*4(非-*6)*烟碱乙酰胆碱受体在运动行为中的作用。

DOI：
10.1016/j.neuropharm.2013.05.001
发表时间：
2013
期刊：
Neuropharmacology
影响因子：
4.7
作者：
Soll,LindseyG;Grady,SharonR;Salminen,Outi;Marks,MichaelJ;Tapper,AndrewR
通讯作者：
Tapper,AndrewR

α4β2 nicotinic acetylcholine receptors on dopaminergic neurons mediate nicotine reward and anxiety relief.

DOI：
10.1523/jneurosci.0937-11.2011
发表时间：
2011-07-27
期刊：
The Journal of neuroscience : the official journal of the Society for Neuroscience
影响因子：
0
作者：
McGranahan TM;Patzlaff NE;Grady SR;Heinemann SF;Booker TK
通讯作者：
Booker TK

Loss of alpha-conotoxinMII- and A85380-sensitive nicotinic receptors in Parkinson's disease striatum.

帕金森病纹状体中 α-芋螺毒素 MII 和 A85380 敏感烟碱受体的丧失。