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相关的神经认知障碍（Hand）是最常见且在临床上最重要的一种 HIV感染的并发症。迫切需要有效的治疗策略来加剧 通过可卡因使用障碍（CUD）。通过对HIV引起的转录组的广泛分析，我们 确定HIV和可卡因深刻诱导了小胶质细胞特异性基因的过表达 脱羧酶1（ACOD1）。 ACOD1将三羧酸（TCA）中间体顺式酸转换为Itaconate 在炎症期间。 Itaconate激活抗炎转录因子，从而保护巨噬细胞 来自感染触发的细胞死亡。虽然已经表征了Itaconate感染的衰减 在外围巨噬细胞中，免疫代谢的作用，包括ITACONATE的产生，尚未研究 在HIV和可卡因暴露的小胶质细胞中。这项创新的建议将描述Itaconate动作的新目标 在大脑中。该提议的假设是Itaconate通过激活来平衡神经炎症 HIV感染的小胶质细胞的抗炎途径，因此细胞死亡减弱 允许维持小胶质的HIV储藏。此外，我们假设抑制Itaconate HIV感染的小胶质细胞中的合成和下游途径具有选择性消除HIV的潜力 脑组织中的水库 - 即一种创新的“非激活冲击和杀伤”方法。相反，我们 还将探索细胞和血脑屏障（BBB）渗透的强抗炎潜力 Itaconate的改性衍生物 - 二甲基二酮（DMI）和4-辛基 - 乙酸酯。我们的初步结果显示 该4-辛基 - 丙酮酸盐可保护原发性神经元免受HIV-TAT和可卡因毒性的侵害。持续激活 BBB - 五渗酸ITACONATE衍生物的Itaconate途径可能是该方法的替代方法 手丢失的手的治疗。这项创新的提议采用了一种新颖的方法，以此为中心 在靶向HIV感染的小胶质细胞中尚未考虑的免疫力学。其他代谢物的酯， 包括富马酸盐包括牛皮癣和关节炎等炎症性疾病，增加 这些令人兴奋的研究的临床相关性。