Role of the BBB in HIV brain infection during methamphetamine abuse

BBB 在甲基苯丙胺滥用期间 HIV 脑部感染中的作用

• 批准号: 8996684
• 负责人: Michal Toborek
• 金额: $ 37.99万
• 依托单位: UNIVERSITY OF MIAMI SCHOOL OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-04-01 至 2020-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8996684
• 关键词: Adult; Behavior Therapy; Biological; Blood; Blood - brain barrier anatomy; Brain; Brain Pathology; Cells; Clinic; Development; Drug abuse; Endothelium; Environment; Event; Exercise; Exposure to; Functional disorder; HIV; HIV Infections; HIV Long Terminal Repeat; HIV tat Protein; HIV-1; Health; Homeostasis; Impaired cognition; Impairment; Infection; Knowledge; Laboratories; Lead; Link; Maintenance; Mediating; Methamphetamine; Neurocognitive; Neurocognitive Deficit; Neurodegenerative Disorders; Neurons; Outcome; Physical activity; Play; Property; Proteins; Research; Risk Factors; Role; Stem cells; Stream; Structure; Therapeutic; Tight Junctions; Toxic effect; base; brain endothelial cell; cerebrovascular; innovation; methamphetamine abuse; methamphetamine exposure; nerve stem cell; neurogenesis; neurotoxicity; new therapeutic target; novel; novel therapeutic intervention; occludin; pathogen; prevent; progenitor; protective effect; transcription factor; translational approach

 DESCRIPTION (provided by applicant): The blood-brain barrier (BBB) is the most prominent barrier of the CNS and represents the essential interface between the CNS and the blood stream. The intact BBB is maintained by tight junction (TJ) proteins and is a paramount determinant of brain homeostasis. Disruption of the BBB is frequently observed during drug abuse and brain infections by various pathogens, including HIV. Our critically important results indicate that occludin, one of the major TJ proteins, is decreased upon methamphetamine (METH) exposure and that diminished occludin levels not only lead to the loss of integrity of the BBB but also stimulate HIV replication. The proposed research is built on these exciting findings by its focus on the central hypothesis that cerebrovascular alterations at the BBB level induced by METH have profound impact on establishing and outcome of the brain infection by HIV. Guided by the preliminary findings, this application offers a unique perspective on the interactions between METH and HIV via targeting the BBB. In Aim 1, we will evaluate the impact of METH-induced decrease in occludin expression on activation of NF-¿B and SP-1, enhancing interactions of this transcription factors with the HIV long-terminal repeats (LTRs) and thus stimulating HIV replication. In Aim 2, we will study the impact of METH and HIV-induced disruption of BBB on aberrant neurogenesis of neural progenitor cells resulting in the development of cognitive dysfunction. Aim 3 will focus on behavioral intervention based on exercise for protection against METH and HIV-induced BBB dysfunction and neurocognitive alterations. The proposed research is highly innovative and is likely to lead to the development of new translational knowledge for the clinic and identification of new regulatory mechanisms of HIV replication. The completion of this application has the potential to change our understanding of the cellular role of occludin in HIV infection and the role of the BBB in the development of METH and/or HIV-associated cognitive dysfunction. Furthermore, the expected results are likely to be also relevant to other neurodegenerative diseases that have significant cerebrovascular components.