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: 9925422
• 负责人: Michal Toborek
• 金额: $ 23.03万
• 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 2022-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9925422
• 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; Cell physiology; 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 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.

摘要 抗逆转录病毒疗法的毒性导致在艾滋病毒感染者中观察到的脑病理学和认知能力下降 个人;然而，机制并不完全清楚。ART毒性的重要性 通过将暴露前预防（PrEP）引入艾滋病毒， 预防血脑屏障（BBB）是抗逆转录病毒药物暴露的第一线， 使脑内皮在ART毒性研究中特别相关。 抗逆转录病毒药物经常在脑实质中仅达到亚治疗水平， 血浆浓度足以对脑血管系统产生负面影响， 内皮是CNS中ART毒性的主要靶点。当前的应用程序基于我们的 令人兴奋的发现表明ART暴露导致线粒体功能障碍和改变， 神经前体细胞（NPC）的神经发生。线粒体失调是一种强诱导剂 事实上，我们的研究结果表明，在ART诱导的炎症反应中， 脑血管毒性从机制上讲，拟议的工作集中在一个新的途径， 脑内皮和血管周围NPC之间通过激活的细胞间通讯 炎性小体中心假设是ART激活脑内炎性小体 内皮细胞，然后释放IL 1 β，然后影响成体神经发生， NPCs，减少其分化为成熟神经元，并有助于认知 下降在整个提案中，我们将区分ART与高CNS的影响， 渗透功效（CPE）对比具有低CPE的ART。我们的应用程序提供了一个独特的，机械的， ART诱导的毒性和神经炎症，导致 认知障碍拟议研究的完成有望建立新的 治疗靶点，以防止ART的毒性。