Dissection of Addiction Relevant Signal Integration by Cyfip2 through Precise Genome Engineering
Cyfip2 通过精确基因组工程解析成瘾相关信号整合
基本信息
- 批准号:10450066
- 负责人:
- 金额:$ 38.28万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2020
- 资助国家:美国
- 起止时间:2020-07-15 至 2025-06-30
- 项目状态:未结题
- 来源:
- 关键词:ActinsAcuteAffectAlcoholsAllelesAmino Acid SubstitutionBehaviorBehavioralBindingBiochemicalBiochemistryBiological AssayBiophysicsBrain regionCRISPR/Cas technologyCell Surface ReceptorsCessation of lifeCloningCocaineCommunitiesComplementComplexConsultationsCritical PathwaysDataDideoxy Chain Termination DNA SequencingDisciplineDissectionEatingEconomicsEnvironmentEventFMR1FamilyFoodFragile X SyndromeFutureGenerationsGenesGeneticGenetic ModelsGenome engineeringGoalsGoldHealthInjuryIntravenousKnock-outKnowledgeLearningMass Spectrum AnalysisMeasuresMediatingMediator of activation proteinModelingMolecularMonomeric GTP-Binding ProteinsMusMutant Strains MiceMutationNicotinePalatePathway interactionsPhasePhenotypePlayProcessProteinsProteomicsPublishingQuantitative Trait LociResearchResearch PersonnelRewardsRoleSeriesSignal PathwaySignal TransductionSignaling ProteinSiteStructureSucroseTestingThe Jackson LaboratoryTherapeutic InterventionTranslationsVariantWorkaddictionbasebehavioral phenotypingchronic alcohol ingestioncocaine self-administrationconditioned place preferencecostdesigndrug of abuseeffective therapygenetic approachgenome editinggenome sequencingin vivoinsightmesolimbic systemmouse geneticsmouse modelmultidisciplinarymultidrug abusemutantneurobiological mechanismnew therapeutic targetnovelpolymerizationpostnatalpre-clinicalprecise genome editingpreferenceprotein protein interactionpublic health relevancereceptorrecruitrepairedresponsesocialtargeted treatmenttherapeutically effectivetoolwhole genome
项目摘要
PROJECT SUMMARY
Addiction is an enormous economic, personal, and social burden, costing over $600 billion per year in the U.S.
Understanding vulnerability to addiction, and developing effective therapies, requires identifying the genes and
pathways that mediate the addiction process. Our long-term goal is to develop novel genetic models for
addiction-relevant phenotypes, and use these models to characterize the genetic mechanisms of addiction. Here,
we propose to extend our previous work that led to the cloning of a QTL that regulates addiction and the
subsequent identification of Cyfip2 in mouse substrains as a regulator of cocaine acute and sensitized
responses. We and others have since shown that this mutation regulates food reward, nicotine preference, and
alcohol preference (preliminary data). In addition, we have shown that Cyfip2 regulates voluntary self-
administration of cocaine in the IVSA assay, the gold standard in the addiction field. Cyfip2 is a hub for signal
integration from multiple pathways, including the small GTPase RAC1, WIRS domain receptors, and Fragile X
family signaling. We hypothesize that this signal integration by Cyfip2 is critical for reward behaviors. In response
to PAR-19-278, we now propose to use precise genome engineering in mice to generate and functionally validate
5 variants in Cyfip2 (1-2 amino acid substitutions each) that specifically perturb each of these signal integration
events. These mutations are designed using published biochemical data and in consultation with our Co-
Investigator Dr. Chen, who is a leader in Cyfip biophysics and structure. In the R21 phase (Aim 1), we will
leverage the mouse genetics expertise of the Jackson Laboratory to generate by CRISPR/Cas9 a set of 5 Cyfip2
signaling mutants. Specific milestones for progression to the R33 phase are (i) viability of the mutants, since the
knockout of Cyfip2 is postnatal lethal, and (ii) the lack of functional off-target edits. We will then characterize
these mutants comprehensively for cocaine and natural reward behavior (R33, Aim 2). To gain insight into
mechanisms underlying these behaviors, we will determine the biochemical interactome of each mutant in mouse
brain regions using a comprehensive mass spectrometry-based study (R33, Aim 3). The successful completion
of this project will yield 5 preclinical mouse models of addiction transition for the scientific community, as well as
information about specific signaling pathways that are critical for transition to addiction and that can be targeted
for therapy.
项目摘要
成瘾是一种巨大的经济,个人和社会负担,在美国,每年耗资超过6000亿美元
了解成瘾和开发有效疗法的脆弱性需要识别基因和
介导成瘾过程的途径。我们的长期目标是开发新的遗传模型
与成瘾相关的表型,并使用这些模型来表征成瘾的遗传机制。这里,
我们建议扩展我们以前的工作,该工作导致了QTL的克隆,该QTL调节成瘾和
随后鉴定小鼠底座中的CYFIP2作为可卡因急性调节剂,并敏化
回答。从那以后,我们和其他人表明,这种突变调节食物奖励,尼古丁的偏好和
酒精偏好(初步数据)。此外,我们已经表明CYFIP2调节自愿自我
在IVSA测定中可卡因的给药,这是成瘾领域的黄金标准。 CYFIP2是信号的枢纽
来自多个途径的集成,包括小GTPase Rac1,WIR域受体和脆弱的X
家庭信号。我们假设CYFIP2的这种信号集成对于奖励行为至关重要。作为回应
至19-278年,我们现在建议在小鼠中使用精确的基因组工程来生成并在功能上验证
CYFIP2中的5种变体(每个氨基酸取代),这些变体特异性扰动这些信号积分
事件。这些突变是使用已发表的生化数据设计的,并与我们的共同咨询
研究人员Chen博士,他是Cyfip生物物理学和结构的领导者。在R21阶段(AIM 1),我们将
利用杰克逊实验室的鼠标遗传学专业知识由CRISPR/CAS9生成5 cyfip2
信号突变体。发展为R33相的特定里程碑是(i)突变体的生存能力,因为
CYFIP2的敲除是产后致命的,(ii)缺乏功能脱离目标编辑。然后我们将表征
这些突变体全面用于可卡因和自然奖励行为(R33,AIM 2)。洞悉
这些行为背后的机制,我们将确定小鼠中每个突变体的生化相互作用组
大脑区域使用基于质谱的全面研究(R33,AIM 3)。成功完成
这个项目将为科学界产生5种临床前鼠标成瘾过渡模型,以及
有关特定信号通路至关重要的特定信号通路的信息,可以针对性
用于治疗。
项目成果
期刊论文数量(0)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
数据更新时间:{{ journalArticles.updateTime }}
{{
item.title }}
{{ item.translation_title }}
- DOI:
{{ item.doi }} - 发表时间:
{{ item.publish_year }} - 期刊:
- 影响因子:{{ item.factor }}
- 作者:
{{ item.authors }} - 通讯作者:
{{ item.author }}
数据更新时间:{{ journalArticles.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ monograph.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ sciAawards.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ conferencePapers.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ patent.updateTime }}
VIVEK KUMAR其他文献
VIVEK KUMAR的其他文献
{{
item.title }}
{{ item.translation_title }}
- DOI:
{{ item.doi }} - 发表时间:
{{ item.publish_year }} - 期刊:
- 影响因子:{{ item.factor }}
- 作者:
{{ item.authors }} - 通讯作者:
{{ item.author }}
{{ truncateString('VIVEK KUMAR', 18)}}的其他基金
Machine learning based frailty index for the genetically diverse mice
基于机器学习的遗传多样性小鼠的衰弱指数
- 批准号:
10513177 - 财政年份:2022
- 资助金额:
$ 38.28万 - 项目类别:
Machine learning based frailty index for the genetically diverse mice
基于机器学习的遗传多样性小鼠的衰弱指数
- 批准号:
10688138 - 财政年份:2022
- 资助金额:
$ 38.28万 - 项目类别:
The Short Course on the Application of Machine Learning for Automated Quantification of Behavior
机器学习在行为自动量化中的应用短期课程
- 批准号:
10600079 - 财政年份:2022
- 资助金额:
$ 38.28万 - 项目类别:
Google Cloud Pipeline for mouse behavior and frailty assessment for the aging research community
Google Cloud Pipeline 用于衰老研究社区的小鼠行为和虚弱评估
- 批准号:
10827671 - 财政年份:2022
- 资助金额:
$ 38.28万 - 项目类别:
Establishment and Characterization of Novel Mutant Mouse Models for the Addiction Research Community
成瘾研究界新型突变小鼠模型的建立和表征
- 批准号:
10647879 - 财政年份:2021
- 资助金额:
$ 38.28万 - 项目类别:
Impacts of Sleep and Circadian Biology on Alzheimer's Disease and Aging: A Focus on Genetics and Genomics
睡眠和昼夜节律生物学对阿尔茨海默病和衰老的影响:关注遗传学和基因组学
- 批准号:
10606644 - 财政年份:2021
- 资助金额:
$ 38.28万 - 项目类别:
Impacts of Sleep and Circadian Biology on Alzheimer's Disease and Aging: A Focus on Genetics and Genomics
睡眠和昼夜节律生物学对阿尔茨海默病和衰老的影响:关注遗传学和基因组学
- 批准号:
10378650 - 财政年份:2021
- 资助金额:
$ 38.28万 - 项目类别:
Impacts of Sleep and Circadian Biology on Alzheimer's Disease and Aging: A Focus on Genetics and Genomics
睡眠和昼夜节律生物学对阿尔茨海默病和衰老的影响:关注遗传学和基因组学
- 批准号:
10237478 - 财政年份:2021
- 资助金额:
$ 38.28万 - 项目类别:
Dissection of Addiction Relevant Signal Integration by Cyfip2 through Precise Genome Engineering
Cyfip2 通过精确基因组工程解析成瘾相关信号整合
- 批准号:
10074946 - 财政年份:2020
- 资助金额:
$ 38.28万 - 项目类别:
Dissection of Addiction Relevant Signal Integration by Cyfip2 through Precise Genome Engineering
Cyfip2 通过精确基因组工程解析成瘾相关信号整合
- 批准号:
10424633 - 财政年份:2020
- 资助金额:
$ 38.28万 - 项目类别:
相似国自然基金
SGO2/MAD2互作调控肝祖细胞的细胞周期再进入影响急性肝衰竭肝再生的机制研究
- 批准号:82300697
- 批准年份:2023
- 资助金额:30 万元
- 项目类别:青年科学基金项目
SSRP1/Sp-1转录调控的MFGE8通过SIRT6影响铁死亡在脓毒症急性肾损伤中的机制研究
- 批准号:82302418
- 批准年份:2023
- 资助金额:30 万元
- 项目类别:青年科学基金项目
人群mtDNA空间异质性对急性高原反应发病的影响机制研究
- 批准号:42377466
- 批准年份:2023
- 资助金额:49 万元
- 项目类别:面上项目
蜗牛粘液糖胺聚糖影响中性粒细胞粘附和迁移在治疗急性呼吸窘迫综合征中的作用研究
- 批准号:82360025
- 批准年份:2023
- 资助金额:32 万元
- 项目类别:地区科学基金项目
高甘油三酯通过TLR4/caspase-8影响急性胰腺炎CD4+T细胞程序性死亡的机制研究
- 批准号:82360135
- 批准年份:2023
- 资助金额:32 万元
- 项目类别:地区科学基金项目
相似海外基金
Selective actin remodeling of sensory neurons for acute pain management
感觉神经元的选择性肌动蛋白重塑用于急性疼痛管理
- 批准号:
10603436 - 财政年份:2023
- 资助金额:
$ 38.28万 - 项目类别:
Understanding Chirality at Cell-Cell Junctions With Microscale Platforms
利用微型平台了解细胞与细胞连接处的手性
- 批准号:
10587627 - 财政年份:2023
- 资助金额:
$ 38.28万 - 项目类别:
Chlamydia type III effectors affecting the host actin-based cytoskeleton
III 型衣原体效应子影响宿主肌动蛋白细胞骨架
- 批准号:
10632935 - 财政年份:2023
- 资助金额:
$ 38.28万 - 项目类别:
Rhinovirus, airway smooth muscle, and mechanisms of irreversible airflow obstruction
鼻病毒、气道平滑肌和不可逆气流阻塞机制
- 批准号:
10735460 - 财政年份:2023
- 资助金额:
$ 38.28万 - 项目类别: