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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：
10645136
负责人：
Michal Toborek
金额：
$ 43.02万
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/10645136
关键词：
Antioxidants Area Belief Blood Vessels Brain Cells Cerebrum Chronic Clinical Complex Data Development Drug abuse Drug toxicity Event Exposure to Grant HIV HIV Infections IL18 gene Infection Inflammasome Inflammatory Interleukin-1 beta 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 comorbidity compare effectiveness improved 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.

摘要

项目成果

期刊论文数量（29）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Extracellular vesicle-Serpine-1 affects neural progenitor cell mitochondrial functions and synaptic density: modulation by amyloid beta and HIV-1.

细胞外囊泡-Serpine-1 影响神经祖细胞线粒体功能和突触密度：β 淀粉样蛋白和 HIV-1 的调节。

DOI：
10.21203/rs.3.rs-2551245/v1
发表时间：
2023
期刊：
Research square
影响因子：
0
作者：
András,IbolyaE;Serrano,Nelson;Djuraskovic,Irina;Fattakhov,Nikolai;Sun,Enze;Toborek,Michal
通讯作者：
Toborek,Michal

Methamphetamine Enhances HIV-Induced Aberrant Proliferation of Neural Progenitor Cells via the FOXO3-Mediated Mechanism.

DOI：
10.1007/s12035-021-02407-9
发表时间：
2021-11
期刊：
Molecular neurobiology
影响因子：
5.1
作者：
Park M;Baker W;Cambow D;Gogerty D;Leda AR;Herlihy B;Pavlenko D;Van Den Nieuwenhuizen S;Toborek M
通讯作者：
Toborek M

Extracellular Vesicle-Serpine-1 Affects Neural Progenitor Cell Mitochondrial Networks and Synaptic Density: Modulation by Amyloid Beta and HIV-1.

DOI：
10.1007/s12035-023-03456-y
发表时间：
2023-11
期刊：
MOLECULAR NEUROBIOLOGY
影响因子：
5.1
作者：
Andras, Ibolya E.;Serrano, Nelson;Djuraskovic, Irina;Fattakhov, Nikolai;Sun, Enze;Toborek, Michal
通讯作者：
Toborek, Michal

Circadian rhythms in the blood-brain barrier: impact on neurological disorders and stress responses.

DOI：
10.1186/s13041-023-00997-0
发表时间：
2023-01-12
期刊：
MOLECULAR BRAIN
影响因子：
3.6
作者：
Schurhoff, Nicolette;Toborek, Michal
通讯作者：
Toborek, Michal

Cerebral Vascular Toxicity of Antiretroviral Therapy.

DOI：
10.1007/s11481-019-09858-x
发表时间：
2021-03
期刊：
Journal of neuroimmune pharmacology : the official journal of the Society on NeuroImmune Pharmacology
影响因子：
0
作者：
Bertrand L;Velichkovska M;Toborek M
通讯作者：
Toborek M