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