Development of Tethered Toxins for Neuroscience Research
用于神经科学研究的系留毒素的开发
基本信息
- 批准号:7009229
- 负责人:
- 金额:$ 15.27万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2004
- 资助国家:美国
- 起止时间:2004-02-01 至 2008-01-31
- 项目状态:已结题
- 来源:
- 关键词:
项目摘要
DESCRIPTION (provided by applicant):
The purpose of this grant is to generate a novel series of agents for genetic manipulation of receptors, ion channel, and signaling molecules in vivo. These agents (tethered toxins) are chimeric molecules derived from tethering of naturally occurring peptide neurotoxins to the cell surface via GPI anchors or transmembrane. These studies derive from the discovery of mammalian prototoxin genes (e.g. Lynx 1) which are the evolutionary antecedents of snake venom toxins, and which can function as modulators of nAChRs in their native GPI-anchored form. Preliminary results are that tethered bungarotoxins retain their activity on nAChRs, and that they are not cleaved from the cell surface to inhibit adjacent cells. The existence of many thousands of naturally occurring peptide neurotoxins (e.g. bungarotoxins, conotoxins, conantokins, etc.), their exquisite target specificities, and the ability to target expression of the agents in vivo using BAC transgenic mice, suggests that the development of a generic strategy for harnessing their potency for in vivo use will permit genetic control over a wide variety of neuronal functions. For example, cell specific genetic control of neural activity, neurotransmitter receptor function (e.g. ACh, NMDA, 5-HT3 receptors), and specific GPCR signal transduction cascades would become possible. The specific aims are to: 1) Construct additional tethered toxins, particularly tethered conotoxins, and test their activity in Xenopus oocytes; 2) Produce BAC transgenic mice expressing tethered toxins in specific CNS cell types in vivo. Assess the efficacy of tethered toxin action by evaluating phenotypes that would be expected based on results obtained in Specific Aim 1 and current knowledge of the roles of the targeted receptors and ion channels in vivo; 3) Develop inducible tethered toxins to improve the temporal resolution of this strategy for genetic manipulation of specific cells and signaling pathways. These studies will allow unprecedented precision in the genetic dissection of functions required for CNS development, function and dysfunction in vivo.
描述(由申请人提供):
本基金的目的是开发一系列新的药物,用于体内受体、离子通道和信号分子的遗传操作。这些试剂(栓系毒素)是通过GPI锚或跨膜将天然存在的肽神经毒素栓系到细胞表面而衍生的嵌合分子。这些研究源于哺乳动物原毒素基因(例如Lynx 1)的发现,这些基因是蛇毒毒素的进化前体,并且可以作为nAChR在其天然GPI锚定形式中的调节剂发挥作用。初步结果是,栓系的银环蛇毒素保留了它们对nAChR的活性,并且它们不会从细胞表面裂解以抑制相邻细胞。存在数千种天然存在的肽类神经毒素(例如银环蛇毒素、芋螺毒素、芋螺毒素等),它们精确的靶向特异性和使用BAC转基因小鼠体内靶向表达试剂的能力表明,开发利用其体内使用效力的通用策略将允许对多种神经元功能进行遗传控制。例如,神经活动、神经递质受体功能(例如ACh、NMDA、5-HT 3受体)和特异性GPCR信号转导级联的细胞特异性遗传控制将成为可能。具体目标是:1)构建额外的拴系毒素,特别是拴系芋螺毒素,并测试它们在爪蟾卵母细胞中的活性; 2)在体内产生在特定CNS细胞类型中表达拴系毒素的BAC转基因小鼠。通过评估基于特定目标1中获得的结果和靶向受体和离子通道在体内作用的现有知识预期的表型来评估拴系毒素作用的功效; 3)开发诱导型拴系毒素以提高该策略的时间分辨率,用于特定细胞和信号传导途径的遗传操作。这些研究将允许前所未有的精确度在体内CNS发育,功能和功能障碍所需的功能的遗传解剖。
项目成果
期刊论文数量(2)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
Methanolic Extracts of D. viscosa Specifically Affect the Cytoskeleton and Exert an Antiproliferative Effect on Human Colorectal Cancer Cell Lines, According to Their Proliferation Rate.
- DOI:10.3390/ijms241914920
- 发表时间:2023-10-05
- 期刊:
- 影响因子:5.6
- 作者:Anglana C;Rojas M;Girelli CR;Barozzi F;Quiroz-Troncoso J;Alegría-Aravena N;Montefusco A;Durante M;Fanizzi FP;Ramírez-Castillejo C;Di Sansebastiano GP
- 通讯作者:Di Sansebastiano GP
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NATHANIEL HEINTZ其他文献
NATHANIEL HEINTZ的其他文献
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{{ truncateString('NATHANIEL HEINTZ', 18)}}的其他基金
Molecular Definition of Brain Circuits Controlling Addiction
控制成瘾的大脑回路的分子定义
- 批准号:
9233959 - 财政年份:2013
- 资助金额:
$ 15.27万 - 项目类别:
Molecular Definition of Brain Circuits Controlling Addiction
控制成瘾的大脑回路的分子定义
- 批准号:
8551017 - 财政年份:2013
- 资助金额:
$ 15.27万 - 项目类别:
Molecular Definition of Brain Circuits Controlling Addiction
控制成瘾的大脑回路的分子定义
- 批准号:
8692543 - 财政年份:2013
- 资助金额:
$ 15.27万 - 项目类别:
USE OF BAC TRANSGENIC ANIMALS FOR ANALYSIS OF GENE EXPRESS & FUNCTION IN THE CN
使用 BAC 转基因动物进行基因表达分析
- 批准号:
8361497 - 财政年份:2011
- 资助金额:
$ 15.27万 - 项目类别:
SPECIFIC PROTEOME OF MAMMALIAN CORTEX INHIBITORY & EXCITATORY SYNAPSES
哺乳动物皮层抑制的特定蛋白质组
- 批准号:
8361533 - 财政年份:2011
- 资助金额:
$ 15.27万 - 项目类别:
Molecular Responses of Corticostriatal Pyramidal Cells to Antipsychotic Drugs
皮质纹状体锥体细胞对抗精神病药物的分子反应
- 批准号:
8150117 - 财政年份:2010
- 资助金额:
$ 15.27万 - 项目类别:
SPECIFIC PROTEOME OF MAMMALIAN CORTEX INHIBITORY & EXCITATORY SYNAPSES
哺乳动物皮层抑制的特定蛋白质组
- 批准号:
8169160 - 财政年份:2010
- 资助金额:
$ 15.27万 - 项目类别:
USE OF BAC TRANSGENIC ANIMALS FOR ANALYSIS OF GENE EXPRESS & FUNCTION IN THE CN
使用 BAC 转基因动物进行基因表达分析
- 批准号:
8169112 - 财政年份:2010
- 资助金额:
$ 15.27万 - 项目类别:
Translational and epigenetic profiling of cell types associated with addiction
与成瘾相关的细胞类型的翻译和表观遗传分析
- 批准号:
7938631 - 财政年份:2009
- 资助金额:
$ 15.27万 - 项目类别:
Translational and epigenetic profiling of cell types associated with addiction
与成瘾相关的细胞类型的翻译和表观遗传分析
- 批准号:
7856128 - 财政年份:2009
- 资助金额:
$ 15.27万 - 项目类别:
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