Targeting Inflammasomes in Substance Abuse and HIV

针对药物滥用和艾滋病毒中的炎症小体

基本信息

批准号：
10404960
负责人：
Michal Toborek
金额：
$ 43.63万
依托单位：
UNIVERSITY OF MIAMI SCHOOL OF MEDICINE
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-07-15 至 2025-05-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10404960
关键词：
Antioxidants Area Belief Blood Vessels Brain CASP1 gene Cells Cerebrum Chronic Clinical Complex Data Development Drug abuse Drug toxicity Event Exposure to Grant HIV HIV Infections Infection Inflammasome Inflammatory Interleukin-1 beta Interleukin-18 Ischemic Stroke Laboratories Link Mitochondria Morphine Mus Nanotechnology Nature Opioid Opioid abuser Outcome Oxycodone Pathologic Patients Pattern recognition receptor Population Predisposition Process Publications Publishing Reaction Recovery Reporting Research Role Stimulus Stroke Substance abuse problem Text Therapeutic Intervention Time Tissues Toxic effect Work antiretroviral therapy base comorbidity compare effectiveness innovation insight interest ischemic injury mitochondrial dysfunction nanoparticle neuroinflammation novel opioid abuse opioid exposure post stroke prescription opioid response stroke outcome stroke recovery therapeutic effectiveness therapeutic target virtual

项目摘要

ABSTRACT This application aims to investigate the impact of HIV brain infection and prescription opioids on ischemic stroke, a major co-morbidity in the infected population and opioid abusers. We recently identified that brain infection by HIV increases susceptibility to ischemic stroke, leading to reactivation of HIV. Importantly, this effect was associated with activation of the inflammasome. While the impact of opioids, such as morphine and oxycodone, on these events is unknown, we have evidence that chronic exposure to opioids can enhance tissue damage in ischemic stroke and activate the inflammasome. In line with these observations, the central hypothesis of the current grant is that HIV and prescription opioids activate inflammasome in the CNS that can worsen stroke outcome, including post-stroke HIV reactivation in the CNS and egress into the periphery. In Aim 1 of the proposed work, we will evaluate the mechanisms of inflammasome activation by HIV infection and prescription opioids. In Aim 2, we will therapeutically target mitochondria for protection against HIV and opioid-induced inflammasome activation, leading to improvement of stroke outcome and recovery. In Aim 3, we will study the impact of opioid-induced inflammasome activation on HIV reactivation in the CNS and egress into the periphery in ischemic stroke. Several conceptual, mechanistic, and technical aspects of this application are highly innovative. For example, the focus on the impact of HIV and prescription opioids on ischemic stroke outcome is an understudied area of research and constitutes a conceptual innovation of the proposal. Our findings that the inflammasome can be involved in HIV reactivation from brain reservoirs has never been reported before. In concert, Aims 1 and 2 will provide critical insight into the role of inflammasome in stroke development of HIV-infected patients who are opioid abusers. Aim 3 will provide important information on the reactivation of HIV from the brain and seeding into the periphery as the result of inflammasome activation in stroke. The proposed research is highly innovative because of its focus on novel mechanisms underlying vascular comorbidities, such as ischemic stroke, in the HIV-infected brain in the context of opioid abuse. These studies are also likely to identify new opportunities for therapeutic intervention.

抽象的该应用程序旨在调查艾滋病毒脑感染和处方阿片类药物对缺血性中风，这是感染人群和阿片类药物滥用者的主要合并症。我们最近确定艾滋病毒的大脑感染增加了缺血性中风的敏感性，导致艾滋病毒的重新激活。重要的是，这种作用与炎性体的激活有关。虽然阿片类药物（例如吗啡和羟考酮）对这些事件的影响尚不清楚，但我们有证据表明长期暴露于阿片类药物可以增强缺血性中风的组织损伤并激活炎症体。与这些观察结果一致当前的赠款是艾滋病毒和处方阿片类药物激活中枢神经系统的炎症体可能会恶化中风结果，包括中风后HIV重新激活和出口进入外围。在拟议工作的目标1中，我们将评估艾滋病毒感染和处方阿片类药物激活炎症。在AIM 2中，我们将在治疗上靶向线粒体，以防止艾滋病毒和阿片类药物诱导的炎症体激活，导致中风结果和恢复的改善。在AIM 3中，我们将研究阿片类药物诱导的炎性体激活对中枢神经系统中HIV重新激活的影响，并出口到缺血性中风的外围。这几个概念，机械和技术方面应用是高度创新的。例如，关注艾滋病毒和处方的影响关于缺血性中风结果的阿片类药物是研究的研究领域，构成提案的概念创新。我们的发现，炎症体可能涉及艾滋病毒脑部储层的重新激活以前从未报道过。在协调的情况下，目标1和2将提供对炎症体在中风中的作用的批判性见解艾OPIOS滥用者的HIV感染患者的发展。 AIM 3将提供重要的结果，有关HIV从大脑重新激活并播种到周围的信息中风中的炎性体激活。拟议的研究具有很高的创新性关注血管合并症（例如缺血性中风）的新型机制在阿片类药物滥用的背景下，艾滋病毒感染的大脑。这些研究也可能识别出新的治疗干预的机会。