Targeting Immunometabolism: a novel role for itaconate in the treatment of HIV-associated neurocognitive disorder and cocaine use disorder

靶向免疫代谢：衣康酸在治疗 HIV 相关神经认知障碍和可卡因使用障碍中的新作用

• 批准号: 10700556
• 负责人: Rosemarie M Booze
• 金额: $ 21.91万
• 依托单位: UNIVERSITY OF SOUTH CAROLINA AT COLUMBIA
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-05-01 至 2025-04-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10700556
• 关键词: Aconitic Acid; Animal Model; Anti-Inflammatory Agents; Arthritis; Attenuated; Blood - brain barrier anatomy; Brain; Carboxy-Lyases; Cell Death; Cells; Cessation of life; Clinical; Cocaine; Cocaine use disorder; Data; Development; Disease; Esters; Fumarates; Functional disorder; Funding; Genes; HIV; HIV Infections; HIV-associated neurocognitive disorder; Immune; Immune response; Impaired cognition; Individual; Infection; Inflammasome; Inflammation; Inflammatory; Lipopolysaccharides; Macrophage; Metabolic; Microglia; Modeling; Mus; National Institute of Drug Abuse; Neurocognitive; Neurons; Pathway interactions; Patients; Penetration; Peripheral; Persons; Pharmaceutical Preparations; Post-Translational Protein Processing; Production; Proteins; Proteomics; Psoriasis; Regulation; Research; Rodent; Role; Severities; Shock; Study models; Suicide; Testing; Therapeutic; Toxic effect; Treatment Efficacy; Tricarboxylic Acids; Up-Regulation; Work; World Health Organization; activating transcription factor 3; attenuation; blood-brain barrier penetration; brain tissue; clinically relevant; cocaine exposure; cytokine; drug of abuse; immunoregulation; innovation; mouse model; neuroinflammation; novel; novel strategies; novel therapeutics; overexpression; programs; public health relevance; response; suicidal; therapeutically effective; transcription factor; transcriptome; transcriptomic profiling; transcriptomics; translational therapeutics

HIV Associated Neurocognitive Disorder (HAND) is one of the most common and clinically important complications of HIV infection. There is an urgent need for effective therapeutic strategies for HAND exacerbated by Cocaine Use Disorder (CUD). Through an extensive analysis of the HIV-induced transcriptome, we determined that HIV and cocaine profoundly induce overexpression of the microglia-specific gene aconitate decarboxylase 1 (acod1). Acod1 converts the tricarboxylic acid (TCA) intermediate cis-aconitate to itaconate during inflammation. Itaconate activates anti-inflammatory transcription factors thereby protecting macrophages from infection-triggered cell death. Although the attenuation of inflammation by itaconate has been characterized in peripheral macrophages, the role of immunometabolism, including itaconate production, has not been studied in HIV and cocaine-exposed microglia. This innovative proposal will characterize novel targets of itaconate action in the brain. The hypothesis of this proposal is that itaconate balances neuroinflammation by activating anti-inflammatory pathways in HIV-infected microglia cells, consequently cell death is attenuated allowing microglial HIV reservoirs to be maintained. Further, we hypothesize that inhibition of itaconate synthesis and downstream pathways in HIV-infected microglia has the potential to selectively eliminate HIV reservoirs in the brain tissues – i.e., an innovative “Non-activating Shock and Kill” cure approach. In contrast, we will also explore the strong anti-inflammatory potential of the cell- and blood-brain barrier (BBB)-penetrating modified derivatives of itaconate -- dimethyl Itaconate (DMI) and 4-octyl-itaconate. Our preliminary results show that 4-octyl-itaconate protects primary neurons from HIV-tat and cocaine toxicity. Thus sustained activation of itaconate pathways by BBB-penetrable itaconate derivatives may be an alternative approach for the treatment of HAND worsened by CUD. This innovative proposal employs a novel approach centered on immunomeabolism that has not been considered in targeting HIV-infected microglia. Esters of other metabolites, including fumarate, are already approved for inflammatory diseases such as psoriasis and arthritis, increasing the clinical relevance of these exciting studies.

HIV 相关神经认知障碍 (HAND) 是最常见且临床上最重要的疾病之一 HIV 感染的并发症迫切需要针对 HAND 恶化的有效治疗策略。 通过对 HIV 诱导的转录组的广泛分析，我们发现可卡因使用障碍 (CUD)。 确定 HIV 和可卡因深刻诱导小胶质细胞特异性基因乌头酸的过度表达 脱羧酶 1 (acod1) 将三羧酸 (TCA) 中间体顺乌头酸转化为衣康酸。 衣康酸激活抗炎转录，从而在炎症期间保护巨噬细胞。 尽管衣康酸减轻炎症的作用已得到证实。 在外周巨噬细胞中，免疫代谢的作用，包括衣康酸的产生，尚未被研究 这项创新提案将描述衣康酸作用的新目标。 该提议的假设是衣康酸通过激活来平衡神经炎症。 HIV感染的小胶质细胞中的抗炎途径，导致的细胞死亡减弱 此外，我们允许衣康酸的抑制。 HIV感染的小胶质细胞中的合成和下游途径有可能选择性地消除HIV 脑组织中的储存库——即一种创新的“非激活休克和杀伤”治疗方法相反，我们。 还将探索细胞和血脑屏障 (BBB) 穿透性的强大抗炎潜力 我们的初步结果显示衣康酸的改性衍生物——衣康酸二甲酯（DMI）和4-辛基衣康酸。 衣康酸 4-辛酯可保护初级神经元免受 HIV-tat 和可卡因毒性的影响，从而持续激活 BBB可穿透的衣康酸衍生物的衣康酸途径可能是一种替代方法 这项创新提案采用了一种以 CUD 为中心的新颖方法。 尚未考虑针对感染艾滋病毒的小胶质细胞的免疫代谢，其他代谢物的酯。 包括富马酸盐，已被批准用于治疗牛皮癣和关节炎等炎症性疾病， 这些令人兴奋的研究的临床意义。