Prevention of HIV and drug abuse-induced brain pathology by targeting mitochondria

通过靶向线粒体预防艾滋病毒和药物滥用引起的脑部病变

• 批准号: 10158459
• 负责人: Michal Toborek
• 金额: $ 40.46万
• 依托单位: UNIVERSITY OF MIAMI SCHOOL OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-07-01 至 2023-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10158459
• 关键词: AIDS prevention; Anti-Retroviral Agents; Biology; Biology of HIV Infection; Blood - brain barrier anatomy; Blood Vessels; Brain; Brain Pathology; Cells; Clinic; Code; Color; Data; Development; Drug abuse; Drug toxicity; Endothelial Cells; Event; Exposure to; Functional disorder; HIV; HIV Infections; HIV Seronegativity; HIV antiretroviral; Image; Individual; Infection; Knowledge; Lead; Left; Life Cycle Stages; Methamphetamine; Mitochondria; Nanotechnology; Neurocognitive; Neuroimmune; Outcome; Oxidation-Reduction; Pathogenesis; Pathology; Patients; Pericytes; Pharmaceutical Preparations; Positioning Attribute; Publishing; Reaction; Receptor Activation; Research; Residual state; Risk; Role; TLR2 gene; Tenofovir; Therapeutic; Therapeutic Intervention; Tight Junctions; Toll-like receptors; Toxic effect; Virus Replication; Work; acute infection; antiretroviral therapy; base; cell type; cerebrovascular; drug of abuse; emtricitabine; innovation; latent infection; methamphetamine exposure; mitochondrial dysfunction; neuroinflammation; neuropathology; neurovascular unit; novel; pre-exposure prophylaxis; protein complex; therapeutic target; trafficking; truvada

Abstract Drugs of abuse, such as methamphetamine (METH), can work in concert with specific anti- retroviral therapeutics and residual viral replication in HIV-infected brain, to drive the HIV-related brain pathology and neurocognitive dysfunction. The central hypothesis of this proposal is that HIV brain life cycle is influenced by exposure to METH, which facilitates the entry of HIV into the brain, establishing infection and latency, and, along with specific anti- retroviral drugs, contribute to neuroimmune activation and neuroinflammatory reactions. We will evaluate these events by focusing on novel and previously unexplored aspects of HIV biology at the blood-brain barrier (BBB). Based on our preliminary data, we propose that toll-like receptors 2 and 4 (TLR2/4) are critical players of cerebrovascular toxicity of METH, leading to dissembling of TJ protein complexes and facilitated HIV entry into the brain (Aim 1). We will next evaluate the mechanisms of METH-induced enhanced HIV replication and establishment of latent infection in BBB pericytes (Aim 2). Our pioneering findings indicated that BBB pericytes are permissive to HIV infection. In the current proposal, we will continue this novel research by focusing on the role of METH in active and latent infection in these cells. Because METH, HIV, and anti-retroviral drugs share mitochondrial dysfunction as one of the primary mechanisms of their cerebrovascular toxicity, an important part of the proposal will be devoted to exploring novel nanotechnologies aimed to target mitochondria for therapeutic protection (Aim 3). Thus, we will provide innovative therapeutic strategies to protect against cerebrovascular toxicity and neuroimmune activation, which are driven by METH and specific anti-retroviral drugs in HIV-infected brain. The proposed research is not only highly innovative, but it is likely to lead to the development of new translational knowledge for the clinic. This application will study novel and previously unrecognized mechanisms and pathogenesis underlying the development of brain infection by HIV, in the context of drug abuse and anti-retroviral strategies. With expertise in drug abuse research, BBB biology, HIV infection, and mitochondria targeting, we are uniquely positioned to perform the proposed, highly innovative project.

抽象的 滥用药物，例如甲基苯丙胺 (METH)，可以与特定的抗 逆转录病毒疗法和艾滋病毒感染大脑中的残留病毒复制，以驱动艾滋病毒相关的 脑病理学和神经认知功能障碍。该提案的中心假设是 HIV 大脑生命周期受到冰毒接触的影响，冰毒有助于进入 HIV 进入大脑，建立感染和潜伏期，并且与特定的抗 逆转录病毒药物有助于神经免疫激活和神经炎症反应。 我们将通过关注艾滋病毒的新颖和先前未探索的方面来评估这些事件 血脑屏障（BBB）的生物学。根据我们的初步数据，我们建议采用收费方式 受体 2 和 4 (TLR2/4) 是 METH 脑血管毒性的关键参与者，导致 分解 TJ 蛋白复合物并促进 HIV 进入大脑（目标 1）。我们接下来 评估 METH 诱导的 HIV 复制增强和潜在病毒建立的机制 BBB 周细胞感染（目标 2）。我们的开创性发现表明 BBB 周细胞 容易感染艾滋病病毒。在当前的提案中，我们将继续这项新颖的研究，重点关注 METH 在这些细胞的主动和潜伏感染中的作用。因为冰毒、艾滋病毒和抗逆转录病毒药物 药物与线粒体功能障碍是其脑血管疾病的主要机制之一 毒性，该提案的一个重要部分将致力于探索新型纳米技术 旨在针对线粒体进行治疗保护（目标 3）。因此，我们将提供创新的 预防脑血管毒性和神经免疫激活的治疗策略， 这是由冰毒和艾滋病毒感染大脑中的特定抗逆转录病毒药物驱动的。 拟议的研究不仅具有高度创新性，而且很可能会导致以下领域的发展： 临床的新转化知识。该应用程序将研究新颖的和以前的 脑部感染发展的未知机制和发病机制 艾滋病毒，在药物滥用和抗逆转录病毒策略的背景下。拥有药物滥用方面的专业知识 研究、BBB 生物学、HIV 感染和线粒体靶向，我们具有独特的优势 执行拟议的高度创新的项目。

项目成果

Nanotechnology in the diagnosis and treatment of stroke.

• DOI: 10.1016/j.drudis.2020.11.018
• 发表时间: 2020-11
• 期刊: Drug discovery today
• 影响因子: 7.4
• 作者: Deepaneeta Sarmah;Mainak Banerjee;Aishika Datta;K. Kalia;S. Dhar;D. Yavagal;P. Bhattacharya