A cutaneous gene therapy for cocaine abuse and alcohol co-abuse
针对可卡因滥用和酒精滥用的皮肤基因疗法
基本信息
- 批准号:10217078
- 负责人:
- 金额:$ 43.74万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2019
- 资助国家:美国
- 起止时间:2019-09-30 至 2024-07-31
- 项目状态:已结题
- 来源:
- 关键词:AcetylcholineAgonistAlcohol abuseAlcohol consumptionAlcoholsAttenuatedAutologous TransplantationBCHE geneBehaviorBehavioralBrain DiseasesButyrylcholinesteraseCRISPR/Cas technologyCellsClinicalCocaineCocaine AbuseCocaine UsersCounselingCuesCutaneousDevelopmentDoseDoxycyclineDrug AddictionDrug abuseEatingEngineered skinEngineeringEnzymesEthanolExhibitsExposure toFDA approvedFemaleGLP-I receptorGene DeliveryGenesGoalsHepatocyteHumanHuman EngineeringHydrolysisImmune responseImmunocompetentIntravenousMethodsMorbidity - disease rateMusMutagenesisNon-Insulin-Dependent Diabetes MellitusNude MiceOrganPatientsPeripheralPharmaceutical PreparationsPhysiologicalPlasmaPre-Clinical ModelPropertyRelapseResearchResidual stateRiskRodentSelf AdministrationSiteSkinSkin TransplantationSkin graftSubstrate SpecificitySudden DeathSurfaceSystemTestingTherapeuticTherapeutic AgentsTimeTissue EngineeringToxic effectTrainingTransplantationTreatment ProtocolsWorkalcohol relapsealcohol use disorderbehavioral responseblood glucose regulationburn therapyburn woundcell typecocaethyleneconditioned place preferencecostdrug of abuseepidermal stem cellexperiencegene therapyglucagon-like peptide 1help-seeking behaviorin vivoindividual variationinnovationmalemortalitynovelparenteral administrationpreventpreventable deathresponseskin woundstem cellstherapeutic gene
项目摘要
PROJECT SUMMARY
Cocaine and alcohol are commonly abused and frequently co-abused drugs. Available medications do not
meet the needs for treating ongoing cocaine and alcohol abuse, relapse and co-abuse. The modified human
butyrylcholinesterase (hBChE) exhibits great catalytic potency and substrate specificity for cocaine hydrolysis
and is effective in reducing the behavioral and toxic effects of cocaine in rodents. The glucagon-like peptide 1
(GLP1) receptor agonists can attenuate the reinforcing properties of cocaine and alcohol in rodents. Both
hBChE and GLP1 have very short half-lives in vivo, however, limiting their potential in treating cocaine abuse
and co-abuse with alcohol. Cultured epidermal autografts have been clinically used for treatment of massive
skin wounds for decades. Transplantation of skin grafts derived from engineered skin progenitor cells provides
a novel and ideal approach for long-term and efficient delivery of therapeutic agents in vivo. We have made
key technical advancement in developing a novel mouse-to-mouse skin transplantation method that allows the
stable introduction of engineered epidermal progenitor cells into immunocompetent host mice. We have also
used the CRISPR technology to target either an hBChE gene or a doxycycline (dox)-inducible modified GLP1
gene (DImGLP1) into epidermal progenitor cells. We then transplanted the engineered hBChE or DImGLP1
cells into mice either separately (GhBChE and GDImGLP1) or together (GBChEGLP1). GhBChE and
GDImGLP1 mice did not develop cocaine- and ethanol-induced conditioned place preference (CPP)
respectively. Grafting hBChE cells right after CPP expression attenuated cocaine-induced reinstatement of
CPP. GBChEGLP1 mice did not develop CPP and they exhibited a lower lethality rate induced by cocaine and
ethanol co-administration than those in control mice. The goal of this proposal is to take advantage of these
novel platforms to test an innovative cutaneous gene therapy for cocaine abuse and co-abuse with alcohol in
mice. We will also evaluate duration of hBChE and mGLP1 protection against cocaine and/or alcohol abuse,
potential immune responses and approaches to reduce them. We expect the proposed cutaneous gene
therapy to be long-lasting, highly specific and efficient with little individual variation. To be able to engineer
stable in vivo bio-delivery systems for therapeutic genes via epidermal progenitor cells is significant
because it holds potential for reducing ongoing cocaine abuse and co-abuse with alcohol and relapse
in users and addicts. The proposed work will have a high impact in that results will lay key
groundwork for the development of a highly personalized, long-lasting and affordable approach for
combating cocaine abuse and co-abuse with alcohol.
项目总结
可卡因和酒精是经常被滥用和经常共用的毒品。可用的药物不会
满足治疗持续的可卡因和酒精滥用、复发和共同滥用的需要。改造后的人类
丁酰胆碱酯酶(HBChE)对可卡因具有很强的催化活性和底物特异性
并能有效降低可卡因对啮齿动物的行为和毒性影响。胰升糖素样肽1
(GLP1)受体激动剂可以减弱可卡因和酒精对啮齿动物的增强作用。两者都有
然而,hBChE和GLP1在体内的半衰期非常短,限制了它们在治疗可卡因滥用方面的潜力
以及与酒精共同滥用。培养的自体表皮移植已在临床上用于治疗大面积皮肤溃疡。
几十年的皮肤创伤。来自工程皮肤祖细胞的皮肤移植提供了
一种新的和理想的方法,长期和有效地提供体内治疗药物。我们已经做出了
开发一种新的小鼠对小鼠皮肤移植方法的关键技术进展
稳定地将工程化的表皮祖细胞导入具有免疫活性的宿主小鼠。我们还有
使用CRISPR技术靶向hBChE基因或多西环素(DOX)诱导的修饰GLP1
将基因(DImGLP1)导入表皮祖细胞。然后我们移植了工程化的hBChE或DImGLP1
细胞分别(GhBChE和GDImGLP1)或一起(GBChEGLP1)进入小鼠。GhBChE和
GDImGLP1小鼠不形成可卡因和乙醇诱导的条件性位置偏爱(CPP)
分别进行了分析。CPP表达后立即移植hBChE细胞可减轻可卡因诱导的脑缺血再灌注损伤
CPP。GBChEGLP1小鼠不发生CPP,表现出较低的可卡因致死率和
乙醇联合给药的小鼠比对照组小鼠更强。这项提议的目标是利用这些优势
测试一种针对可卡因滥用和与酒精共滥用的创新皮肤基因疗法的新平台
老鼠。我们还将评估hBChE和mGLP1预防可卡因和/或酒精滥用的持续时间,
潜在的免疫反应和减少它们的方法。我们希望提出的皮肤基因
治疗要持久、高度特异和有效,个体差异很小。能够进行工程设计
通过表皮祖细胞稳定的体内治疗基因输送系统具有重要意义
因为它有可能减少持续的可卡因滥用以及与酒精的共同滥用和复发
在吸毒者和瘾君子身上。拟议工作将产生很大影响,因为结果将是关键
为开发高度个性化、持久和负担得起的方法奠定基础
打击可卡因滥用和与酒精共同滥用。
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 }}
Xiaoyang Wu其他文献
Xiaoyang Wu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('Xiaoyang Wu', 18)}}的其他基金
Development of a novel lymphocyte engineering approach for treatment of vitiligo
开发治疗白癜风的新型淋巴细胞工程方法
- 批准号:
10640098 - 财政年份:2022
- 资助金额:
$ 43.74万 - 项目类别:
A cutaneous gene therapy for cocaine abuse and alcohol co-abuse
针对可卡因滥用和酒精滥用的皮肤基因疗法
- 批准号:
10017029 - 财政年份:2019
- 资助金额:
$ 43.74万 - 项目类别:
A cutaneous gene therapy for cocaine abuse and alcohol co-abuse
针对可卡因滥用和酒精滥用的皮肤基因疗法
- 批准号:
9762266 - 财政年份:2019
- 资助金额:
$ 43.74万 - 项目类别:
A cutaneous gene therapy for cocaine abuse and alcohol co-abuse
针对可卡因滥用和酒精滥用的皮肤基因疗法
- 批准号:
10666502 - 财政年份:2019
- 资助金额:
$ 43.74万 - 项目类别:
A cutaneous gene therapy for cocaine abuse and alcohol co-abuse
针对可卡因滥用和酒精滥用的皮肤基因疗法
- 批准号:
10456838 - 财政年份:2019
- 资助金额:
$ 43.74万 - 项目类别:
Development of epidermal progenitor cell-based therapy for regenerative medicine
开发基于表皮祖细胞的再生医学疗法
- 批准号:
10091532 - 财政年份:2017
- 资助金额:
$ 43.74万 - 项目类别:
Development of epidermal progenitor cell-based therapy for regenerative medicine
开发基于表皮祖细胞的再生医学疗法
- 批准号:
9280088 - 财政年份:2017
- 资助金额:
$ 43.74万 - 项目类别:
Coordinated cytoskeletal dynamics in skin somatic stem cells - Resubmission 01
皮肤成体干细胞的协调细胞骨架动力学 - 重新提交 01
- 批准号:
9327655 - 财政年份:2013
- 资助金额:
$ 43.74万 - 项目类别:
Coordinated cytoskeletal dynamics in skin somatic stem cells - Resubmission 01
皮肤成体干细胞中协调的细胞骨架动力学 - 重新提交 01
- 批准号:
8735610 - 财政年份:2013
- 资助金额:
$ 43.74万 - 项目类别:
Coordinated cytoskeletal dynamics in skin somatic stem cells - Resubmission 01
皮肤成体干细胞的协调细胞骨架动力学 - 重新提交 01
- 批准号:
8625508 - 财政年份:2013
- 资助金额:
$ 43.74万 - 项目类别:
相似国自然基金
Agonist-GPR119-Gs复合物的结构生物学研究
- 批准号:32000851
- 批准年份:2020
- 资助金额:24.0 万元
- 项目类别:青年科学基金项目
相似海外基金
S1PR1 agonistによる脳血液関門制御を介した脳梗塞の新規治療法開発
S1PR1激动剂调节血脑屏障治疗脑梗塞新方法的开发
- 批准号:
24K12256 - 财政年份:2024
- 资助金额:
$ 43.74万 - 项目类别:
Grant-in-Aid for Scientific Research (C)
AHR agonistによるSLE皮疹の新たな治療薬の開発
使用 AHR 激动剂开发治疗 SLE 皮疹的新疗法
- 批准号:
24K19176 - 财政年份:2024
- 资助金额:
$ 43.74万 - 项目类别:
Grant-in-Aid for Early-Career Scientists
Evaluation of a specific LXR/PPAR agonist for treatment of Alzheimer's disease
特定 LXR/PPAR 激动剂治疗阿尔茨海默病的评估
- 批准号:
10578068 - 财政年份:2023
- 资助金额:
$ 43.74万 - 项目类别:
AUGMENTING THE QUALITY AND DURATION OF THE IMMUNE RESPONSE WITH A NOVEL TLR2 AGONIST-ALUMINUM COMBINATION ADJUVANT
使用新型 TLR2 激动剂-铝组合佐剂增强免疫反应的质量和持续时间
- 批准号:
10933287 - 财政年份:2023
- 资助金额:
$ 43.74万 - 项目类别:
Targeting breast cancer microenvironment with small molecule agonist of relaxin receptor
用松弛素受体小分子激动剂靶向乳腺癌微环境
- 批准号:
10650593 - 财政年份:2023
- 资助金额:
$ 43.74万 - 项目类别:
AMPKa agonist in attenuating CPT1A inhibition and alcoholic chronic pancreatitis
AMPKa 激动剂减轻 CPT1A 抑制和酒精性慢性胰腺炎
- 批准号:
10649275 - 财政年份:2023
- 资助金额:
$ 43.74万 - 项目类别:
A randomized double-blind placebo controlled Phase 1 SAD study in male and female healthy volunteers to assess safety, pharmacokinetics, and transient biomarker changes by the ABCA1 agonist CS6253
在男性和女性健康志愿者中进行的一项随机双盲安慰剂对照 1 期 SAD 研究,旨在评估 ABCA1 激动剂 CS6253 的安全性、药代动力学和短暂生物标志物变化
- 批准号:
10734158 - 财政年份:2023
- 资助金额:
$ 43.74万 - 项目类别:
Investigating mechanisms underpinning outcomes in people on opioid agonist treatment for OUD: Disentangling sleep and circadian rhythm influences on craving and emotion regulation
研究阿片类激动剂治疗 OUD 患者结果的机制:解开睡眠和昼夜节律对渴望和情绪调节的影响
- 批准号:
10784209 - 财政年份:2023
- 资助金额:
$ 43.74万 - 项目类别:
A novel nanobody-based agonist-redirected checkpoint (ARC) molecule, aPD1-Fc-OX40L, for cancer immunotherapy
一种基于纳米抗体的新型激动剂重定向检查点 (ARC) 分子 aPD1-Fc-OX40L,用于癌症免疫治疗
- 批准号:
10580259 - 财政年份:2023
- 资助金额:
$ 43.74万 - 项目类别:
Identification and characterization of a plant growth promoter from wild plants: is this a novel plant hormone agonist?
野生植物中植物生长促进剂的鉴定和表征:这是一种新型植物激素激动剂吗?
- 批准号:
23K05057 - 财政年份:2023
- 资助金额:
$ 43.74万 - 项目类别:
Grant-in-Aid for Scientific Research (C)