Novel role of inflammasome activation in ART neurotoxicity

炎症小体激活在 ART 神经毒性中的新作用

• 批准号: 10163270
• 负责人: Michal Toborek
• 金额: $ 19.19万
• 依托单位: UNIVERSITY OF MIAMI SCHOOL OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-05-12 至 2024-02-29
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10163270
• 关键词: AIDS prevention; Adaptor Signaling Protein; Adult; Affect; Animal Experiments; Anti-Retroviral Agents; Blood - brain barrier anatomy; Blood Vessels; Brain; Brain Pathology; CASP1 gene; Cells; Cerebrovascular system; Communication; Complex; Endothelium; Environmental Risk Factor; Exhibits; Exposure to; HIV; Impaired cognition; In Vitro; Individual; Infectious Agent; Inflammasome; Inflammation; Inflammatory; Innate Immune System; Interleukin-1 Receptors; Interleukin-1 beta; Laboratories; Mitochondria; Neurons; Outcome; Pathway interactions; Pattern recognition receptor; Peptide Hydrolases; Pharmaceutical Preparations; Plasma; Population; Process; Production; Proteins; Role; Stimulus; Therapeutic; Toxic effect; Treatment-related toxicity; Work; adult neurogenesis; antiretroviral therapy; base; brain endothelial cell; brain parenchyma; cerebrovascular; effective therapy; experimental study; in vivo; intercellular communication; interest; mitochondrial dysfunction; nerve stem cell; neurogenesis; neuroinflammation; neurotoxicity; new therapeutic target; novel; paracrine; pre-exposure prophylaxis; receptor; relating to nervous system; response; sensor; stem cell function; stem cells

ABSTRACT Toxicity of ART contributes to brain pathology and cognitive decline observed in HIV-infected individuals; however, the mechanisms are not fully understood. The importance of ART toxicity has been further enhanced by the introduction of pre-exposure prophylaxis (PrEP) into HIV prevention. The blood-brain barrier (BBB) is on the first line of exposure to antiretroviral drugs, making the brain endothelium particularly relevant in studies on toxicity of ART. While antiretroviral drugs frequently achieve only sub-therapeutic levels in the brain parenchyma, their plasma concertations are sufficient to negatively impact the brain vasculature, making the brain endothelium the main target of ART toxicity in the CNS. The current application is based on our exciting findings indicating that ART exposure results in mitochondrial dysfunction and alterations of neurogenesis of neural progenitor cells (NPCs). Mitochondrial dysregulation is a strong inducer of inflammasome, and indeed, our results implicate inflammasome activation in ART-induced cerebral vascular toxicity. Mechanistically, the proposed work is focused on a novel pathway of intercellular communication between the brain endothelium and perivascular NPCs via activation of inflammasome. The central hypothesis is that ART activates inflammasome in brain endothelial cells, followed by release of IL1β, which then affects adult neurogenesis of NPCs, diminishing their differentiation into mature neurons and contributing to cognitive decline. Throughout the proposal, we will differentiate the impact of ART with high CNS penetrating efficacy (CPE) vs. ART with low CPE. Our application offers a unique, mechanistic, and translational perspective on ART-induced toxicity and neuroinflammation that results in cognitive impairment. The completion of the proposed study promises to establish new therapeutic targets to protect against toxicity of ART.

抽象的 艺术的毒性有助于脑病理学和认知下降。 个人但是，这些机制尚未完全理解。艺术毒性的重要性 通过将暴露前预防（PREP）引入HIV，进一步增强了 预防。血脑屏障（BBB）处于暴露于抗逆转录病毒药物的第一线中， 使脑内皮在艺术的毒性研究中特别相关。尽管 抗逆转录病毒药物经常仅在脑实质中达到亚治疗水平， 等离子体的其有对脑脉管系统产生负面影响，使大脑产生负面影响 内皮是中枢神经系统中艺术毒性的主要靶标。当前的应用程序基于我们 令人兴奋的发现表明，艺术暴露会导致线粒体功能障碍和改变 神经元基因细胞（NPC）的神经发生。线粒体失调是一种强诱导剂 炎性体，实际上，我们的结果暗示了艺术诱导的炎症体激活 脑血管毒性。从机械上讲，拟议的工作集中于一条新颖的途径 通过激活，脑内皮和血管周围NPC之间的细胞间通信 炎症。中心假设是艺术激活大脑中的炎症体 内皮细胞，然后释放IL1β，然后影响成年神经发生 NPC，减少其分化为成熟神经元并有助于认知 衰退。通过提案，我们将与高中枢神经系统区分艺术的影响 渗透效率（CPE）与CPE低的艺术。我们的应用程序提供了独特，机械的 并翻译了有关艺术引起的毒性和神经炎症的观点，这导致了 认知障碍。拟议研究的完成有望建立新的 预防艺术毒性的治疗靶标。