Inter- and Intra-cellular effects of cannabinoids, HIV and ART in the CNS

大麻素、HIV 和 ART 对中枢神经系统的细胞间和细胞内影响

• 批准号: 10618933
• 负责人: Kelly L Jordan-Sciutto
• 金额: $ 69.59万
• 依托单位: UNIVERSITY OF PENNSYLVANIA
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-08-01 至 2026-05-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10618933
• 关键词: Anti-Inflammatory Agents; Anti-Retroviral Agents; Antiinflammatory Effect; Anxiety; Astrocytes; Attenuated; CNR1 gene; Cannabinoids; Cannabis; Cell Lineage; Cells; Central Nervous System; Central Nervous System Diseases; Chronic; Colitis; Colon; Complex; Dendritic Cells; Disease; Dissection; Drug Side Effects; Environment; Exhibits; Experimental Autoimmune Encephalomyelitis; Functional disorder; Gene Expression; Gene Expression Profile; HIV; HIV Infections; Heart; Human; Immunomodulators; Inflammasome; Inflammation; Inflammatory; Kidney; Kinetics; Life Expectancy; Liver; Macrophage; Medicine; Mental Depression; Microglia; Modeling; Morphology; Myelogenous; Myocardial Infarction; Neurologic Dysfunctions; Neuronal Dysfunction; Neurons; Oxidative Stress; Pain; Pathway interactions; Patients; Pattern; Persons; Production; Property; Reporting; Role; Signal Pathway; Signal Transduction; Stress; T-Lymphocyte; Tissues; Viral; antiretroviral therapy; anxiety reduction; biological adaptation to stress; body system; comorbidity; cytokine; experience; fetal; glial activation; immunoregulation; induced pluripotent stem cell; marijuana use; painful neuropathy; phytocannabinoid; pleasure; receptor; side effect

Abstract: Antiretroviral therapy (ART) has dramatically extended the lives of people living with HIV (PLWH); however, they continue to experience a plethora of co-morbid conditions including neuronal disorders and pain. Between 40 and 72% of PLWH use cannabis to mitigate anxiety, stress, ART side effects, pain, and/or for pleasure with over 55% of patients using cannabis at least daily. Interestingly, a recent study found that people who use cannabis heavily had reduced inflammatory signatures in PLWH on ART. These and a numerous other studies support the anti-inflammatory and immunomodulator effects of phytocannabinoids in a number of organ systems including heart, colon, kidney, liver and the gut; however, their medicinal use is confounded by the psychotropic activities. Efforts to separate the anti-inflammatory effects from the psychotropic effects have revealed differential activities of 3 endogenous receptors including cannabis receptor 1 (CB2) CB2 which exhibit differential tissue expression and agonism with endo- and phyto-cannabinoids. Several reports have shown that cannabinoids attenuate HIV infection and/or replication in T-cells, macrophages, dendritic cells and human fetal microglia cultured ex vivo. However, the effect of cannabinoids on HIV infection of microglia in the context of ART and the normal cellular environment of neighboring neurons and astrocytes in the CNS has not been examined. Several studies specifically implicate CB2 agonism which has been shown to have anti- inflammatory properties in the heart, gut, experimental autoimmune encephalitis and neuropathic pain via inflammasome activation. This has led us to hypothesize that Cannabinoid signaling influences HIV infection and chronic inflammation in the presence of ARV in the central nervous system by attenuating the inflammasome. In order to examine HIV infection in the context of cells of the CNS, we have developed a human induced pluripotent stem cell tri-culture model composed of iNeurons, iAstrocytes, and iMicroglia. This model recapitulates several key aspects of HIV infection in the CNS including increased cytokine production, oxidative stress response, inflammatory signaling, and integrated stress response. ARV treatment reduces HIV infection and inflammatory signaling pathways; however, a subset of pathways remain elevated despite viral suppression. We propose to further develop this model to determine the ability of cannabinoids to modulate HIV-induced inflammation and subsequent neuronal dysfunction via reducing inflammasome activation by: 1) Determining the effect of cannabinoids on chronic HIV infection and ART in the context of iMgl/iNrn/iAstr triculture. 2) Determining the effect of cannabinoids on cytokine levels, inflammatory gene expression profile, and microglial activation in iMgl/iNrn/iAstr triculture. 3) Determining the effect of cannabinoids on neurons and astrocytes in HIV infection and ART in iMgl/iNrn/iAstr triculture.

文摘:

项目成果

HIV-Associated Insults Modulate ADAM10 and Its Regulator Sirtuin1 in an NMDA Receptor-Dependent Manner.

• DOI: 10.3390/cells11192962
• 发表时间: 2022-09-22
• 期刊: CELLS
• 影响因子: 6
• 作者: Lloreda, Claudia Lopez;Chowdhury, Sarah;Ghura, Shivesh;Alvarez-Periel, Elena;Jordan-Sciutto, Kelly
• 通讯作者: Jordan-Sciutto, Kelly

Confound, Cause, or Cure: The Effect of Cannabinoids on HIV-Associated Neurological Sequelae.

• DOI: 10.3390/v13071242
• 发表时间: 2021-06-26
• 期刊: Viruses
• 作者: Starr A;Jordan-Sciutto KL;Mironets E
• 通讯作者: Mironets E