Targeting Inflammasome with stable endocannabinoid ligand AMG315. CRISPR/Cas9 and nanotechnology study in the context of HIV and cannabinoid
使用稳定的内源性大麻素配体 AMG315 靶向炎症体。
基本信息
- 批准号:10620752
- 负责人:
- 金额:$ 37.06万
- 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:2020-07-01 至 2025-05-31
- 项目状态:未结题
- 来源:
- 关键词:AffinityAnalgesicsAnimal ModelAnti-Inflammatory AgentsAttenuatedBehavioralBindingBiological ModelsBrainCNR1 geneCRISPR/Cas technologyCannabinoidsCellsChargeClustered Regularly Interspaced Short Palindromic RepeatsDNADevelopmentDiseaseDoxycyclineDrug Delivery SystemsDrug TargetingElectromagneticsElectrostaticsEncapsulatedEndocannabinoidsGenesGenetic TranscriptionGenomeGrantGuide RNAHIVHIV GenomeHIV InfectionsHIV SeropositivityHIV-1HIV-associated neurocognitive disorderImpairmentIn VitroInfectionInflammasomeInflammationLegal patentLigandsLiposomesMediatingMedicalMedical MarijuanaMetabolicMethodsMicrogliaMotor ActivityMusNanotechnologyNerve DegenerationNeurocognitiveNeurocognitive DeficitNeurologicNeuronal PlasticityNeuronsPatientsPeripheralPharmaceutical PreparationsPlantsPreventionProductionPropertyProteinsReceptor ActivationReportingRoleSurfaceSystemTechnologyTherapeuticTimeTransgenic MiceTreatment EfficacyViral Load resultanaloganandamideantiretroviral therapyastrogliosisblood-brain barrier crossingcannabinoid administrationclinical applicationcontrolled releasedrug of abuseendogenous cannabinoid systemimprovedin vivolatent infectionmagnetic fieldmarijuana usemouse modelmultidisciplinarynanocarriernanoformulationnanoparticlenanoparticle deliveryneuroAIDSneurobehavioralneurogenesisneuroinflammationneurotoxicitynovelpreventresearch studyresponsesynthetic cannabinoidtat Genestat Protein
项目摘要
Targeting Inflammasome with stable endocannabinoid ligand AMG315: CRISPR/Cas9 and
nanotechnology study in the context of HIV and cannabinoid.
PROJECT SUMMARY (ABSTRACT):
Although the use of cannabis for medical purposes has shown great promise for the treatment of certain
medical conditions, cannabinoid abuse exerts significant impairments in neurocognitive and behavioral
functions and these effects are exacerbated in patients with HIV infection. Studies suggest that even after
HIV-1 suppressing combined antiretroviral therapy (cART), HIV-1 Tat is being produced in the brain from
proviral DNA and implicated as a causative agent for latent infection and development of inflammasome
mediated neuroinflammation in HIV infected patients. CRISPR/Cas9 gene-editing technology has been
shown by us and others to be effective for excising the HIV genome integrated into the host genome. Our
preliminary studies using a
recently discovered and potent metabolically stable endocannabinoid analog
AMG315 demonstrate that this synthetic cannabinoid exerts anti-inflammatory properties by suppressing
NLRP3 inflammasome and HIV infection. Accordingly, we hypothesize that elimination of the HIV-1 Tat gene
in CNS cells using Tat specific CRISPR/Cas9 and suppression of inflammasome with CB1-specific stable
endocannabinoid analog AMG315 can eliminate active HIV infection/induce permanent latency and prevent
neurodegeneration, respectively.
However, AMG-315 and CRISPR are impenetrable to the brain in sufficient
quantities necessary to prevent HIV-infection, inflammasome activation, and subsequent neurodegeneration.
To overcome this, we will use our patented magneto-electric nanoparticles (MENP) technology and
liposomes to deliver CRISPR/Cas9 and AMG315, and for on-demand controlled-release. For the sustained
release and to protect CRISPR from lysosomal degradation, MENP-bound CRISPR and AMG315 will be
encapsulated in liposomes. Accordingly, in Specific Aim # 1, we will develop, characterize, and evaluate the
delivery of Tat-specific CRISPR Cas9/gRNA and AMG315 across the in vitro BBB using MENP-based drug
delivery approach to excise HIV-1 Tat gene, and attenuate cannabinoid and Tat-induced inflammasome,
respectively. In Specific Aim # 2, we will study the in vivo therapeutic efficacy of MENP nanoformulation
containing CRISPR, and AMG315 using doxycycline-inducible HIV-1 Tat transgenic mice (iTat) as an
HIV/neuroAIDS and cannabinoid administration animal model. In Specific Aim-3, we will validate the effects
of these nanoformulations on neuronal plasticity and neurocognitive functions in vivo. Successful completion
of this grant will have a translational significance in preventing HIV-1 Tat and cannabinoid-mediated
neurodegeneration in HIV infected cannabinoid-abusing patients. This multidisciplinary new break-through
concept targeting inflammasome in the brain with stable endocannabinoid ligand AMG315 and Tat specific
CRISPR/Cas9 using MENP-based technology is in response to RFA-DA-20-026 and will be useful for the
suppression of HIV replication, NLRP3 inflammasome activity and to treat cannabinoid-induced neuronal
impairments in HIV infected cannabinoid abusers.
用稳定的内源性大麻素配体AMG 315靶向炎症体:CRISPR/Cas9和
艾滋病毒和大麻素背景下的纳米技术研究。
项目总结(摘要):
虽然大麻用于医疗目的已经显示出治疗某些疾病的巨大希望,
在医疗条件下,大麻素滥用会对神经认知和行为产生显着损害
这些作用在HIV感染患者中加剧。研究表明,即使在
HIV-1抑制联合抗逆转录病毒疗法(cART),HIV-1达特是在大脑中产生的,
前病毒DNA,并作为潜伏感染和炎性小体发展的病原体
介导的神经炎症。CRISPR/Cas9基因编辑技术已被
我们和其他人证明,它能有效地切除整合到宿主基因组中的HIV基因组。我们
初步研究使用了
最近发现的有效的代谢稳定的内源性大麻素类似物
AMG 315证明,这种合成大麻素通过抑制
NLRP 3炎性小体与HIV感染因此,我们假设消除HIV-1达特基因
在CNS细胞中使用达特特异性CRISPR/Cas9和用CB 1特异性稳定的CRISPR/Cas9抑制炎性小体
内源性大麻素类似物AMG 315可以消除活动性HIV感染/诱导永久潜伏期,
神经退行性变。
然而,AMG-315和CRISPR对大脑是不可穿透的,
预防HIV感染、炎性小体激活和随后的神经变性所必需的量。
为了克服这一点,我们将使用我们的专利磁电纳米粒子(MENP)技术,
脂质体以递送CRISPR/Cas9和AMG 315,并用于按需控释。用于持续
为了释放CRISPR并保护CRISPR免受溶酶体降解,将与MENP结合的CRISPR和AMG 315结合。
包封在脂质体中。因此,在具体目标1中,我们将开发、表征和评估
使用基于MENP的药物递送Tat特异性CRISPR Cas9/gRNA和AMG 315穿过体外BBB
切除HIV-1达特基因并减弱大麻素和塔特诱导的炎性体的递送方法,
分别在具体目标#2中,我们将研究MENP纳米制剂的体内治疗功效。
含有CRISPR的小鼠和AMG 315,使用强力霉素诱导的HIV-1达特转基因小鼠(i达特)作为
HIV/neuroAIDS和大麻素给药动物模型。在具体目标-3中,我们将验证效果
这些纳米制剂对体内神经元可塑性和神经认知功能的影响。成功完成
这项拨款的一半将在预防HIV-1达特和大麻素介导的
HIV感染的大麻素滥用患者的神经变性。这一多学科的新突破
用稳定的内源性大麻素配体AMG 315和达特特异性靶向脑中炎性体的概念
使用基于MENP的技术的CRISPR/Cas9是对RFA-DA-20-026的响应,并且将对以下研究有用:
抑制HIV复制、NLRP 3炎性体活性和治疗大麻素诱导神经元
艾滋病毒感染的大麻素滥用者的损害。
项目成果
期刊论文数量(5)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
Multi-functional auto-fluorescent nanogels for theranostics.
- DOI:10.1007/s13365-023-01138-y
- 发表时间:2023-06
- 期刊:
- 影响因子:3.2
- 作者:Vashist, Arti;Raymond, Andrea D.;Chapagain, Prem;Vashist, Atul;Arias, Adriana Yndart;Kolishetti, Nagesh;Nair, Madhavan
- 通讯作者:Nair, Madhavan
Cannabidiol for neurodegenerative disorders: A comprehensive review.
- DOI:10.3389/fphar.2022.989717
- 发表时间:2022
- 期刊:
- 影响因子:5.6
- 作者:
- 通讯作者:
Drug Delivery to the Brain: Recent Advances and Unmet Challenges.
- DOI:10.3390/pharmaceutics15122658
- 发表时间:2023-11-23
- 期刊:
- 影响因子:5.4
- 作者:Bhunia S;Kolishetti N;Vashist A;Yndart Arias A;Brooks D;Nair M
- 通讯作者:Nair M
Recent Advances in Nanotherapeutics for Neurological Disorders.
- DOI:10.1021/acsabm.3c00254
- 发表时间:2023-07-17
- 期刊:
- 影响因子:4.7
- 作者:Vashist, Arti;Manickam, Pandiaraj;Raymond, Andrea D;Arias, Adriana Yndart;Kolishetti, Nagesh;Vashist, Atul;Arias, Emanuel;Nair, Madhavan
- 通讯作者:Nair, Madhavan
Anti-inflammatory effects of CBD in human microglial cell line infected with HIV-1.
- DOI:10.1038/s41598-023-32927-4
- 发表时间:2023-05-05
- 期刊:
- 影响因子:4.6
- 作者:Arias, Adriana Yndart;Kolishetti, Nagesh;Vashist, Arti;Madepalli, Lakshmana;Llaguno, Lorgeleys;Nair, Madhavan
- 通讯作者:Nair, Madhavan
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Alexandros Makriyannis其他文献
Alexandros Makriyannis的其他文献
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{{ truncateString('Alexandros Makriyannis', 18)}}的其他基金
Targeting Inflammasome with stable endocannabinoid ligand AMG315. CRISPR/Cas9 and nanotechnology study in the context of HIV and cannabinoid
使用稳定的内源性大麻素配体 AMG315 靶向炎症体。
- 批准号:
10085922 - 财政年份:2020
- 资助金额:
$ 37.06万 - 项目类别:
CB1 Neutral Antagonists for Alcohol Use Disorder
CB1 中性拮抗剂治疗酒精使用障碍
- 批准号:
10928929 - 财政年份:2020
- 资助金额:
$ 37.06万 - 项目类别:
CB1 Neutral Antagonists for Alcohol Use Disorder
CB1 中性拮抗剂治疗酒精使用障碍
- 批准号:
10679060 - 财政年份:2020
- 资助金额:
$ 37.06万 - 项目类别:
Targeting Inflammasome with stable endocannabinoid ligand AMG315. CRISPR/Cas9 and nanotechnology study in the context of HIV and cannabinoid
使用稳定的内源性大麻素配体 AMG315 靶向炎症体。
- 批准号:
10197872 - 财政年份:2020
- 资助金额:
$ 37.06万 - 项目类别:
Targeting Inflammasome with stable endocannabinoid ligand AMG315. CRISPR/Cas9 and nanotechnology study in the context of HIV and cannabinoid
使用稳定的内源性大麻素配体 AMG315 靶向炎症体。
- 批准号:
10404955 - 财政年份:2020
- 资助金额:
$ 37.06万 - 项目类别:
CB1 Neutral Antagonists for Alcohol Use Disorder
CB1 中性拮抗剂治疗酒精使用障碍
- 批准号:
10266861 - 财政年份:2020
- 资助金额:
$ 37.06万 - 项目类别:
Effect of a potent and metabolically stable endocannabinoid receptor agonist on inflammasome-induced neuroinflammation in a comorbid mouse model of Alzheimer's disease and HIV
一种有效且代谢稳定的内源性大麻素受体激动剂对阿尔茨海默病和艾滋病毒共病小鼠模型中炎症小体诱导的神经炎症的影响
- 批准号:
10285175 - 财政年份:2020
- 资助金额:
$ 37.06万 - 项目类别:
CB1 Neutral Antagonists for Alcohol Use Disorder
CB1 中性拮抗剂治疗酒精使用障碍
- 批准号:
10475285 - 财政年份:2020
- 资助金额:
$ 37.06万 - 项目类别:
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