HIV-Associated Dementia and the Urokinase Plasminogen Activation System

HIV 相关痴呆和尿激酶纤溶酶原激活系统

• 批准号: 7119411
• 负责人: Paola Cinque
• 金额: $ 16.5万
• 依托单位: FONDAZONE CENT/SAN RAFFAELE/DEL MONTE
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-08-10 至 2008-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7119411
• 关键词: AIDS dementia complex; HIV infections; RNA interference; biomarker; cell cell interaction; central nervous system; cerebrospinal fluid; chemotaxis; clinical research; dementia; endopeptidases; enzyme activity; enzyme linked immunosorbent assay; extracellular; human therapy evaluation; human tissue; immunocytochemistry; international cooperation; patient oriented research; plasminogen activator inhibitors; polymerase chain reaction; proteolysis; receptor binding; urokinase

DESCRIPTION (provided by applicant): This application has the purpose of investigating the role of the urokinase plasminogen activation (uPA) system in HIV infection of the central nervous system (CNS) and its most important clinical consequence, HIV dementia (HIV-D), in order to define novel pathogenetic mechanisms and provide markers useful for clinical management (prevention, diagnosis, prognosis and treatment). The uPA system is composed of uPA, its receptor uPAR, its inhibitors plasminogen activator inhibitor (PAI-1) and protease nexin-1 (PN-1), a second plasminogen activator - tPA (tissue type plasminogen activator) and various binding molecules including the substrate plasminogen and the uPAR interactors formyl peptide receptor-like 1 (FPRL1), integrins and vitronectin. The proposed study will address the working hypothesis that the uPA system may be involved in the pathophysiology of HIV-D through interaction with HIV at a cellular level and subsequent dysregulation of uPA system functions, namely extracellular proteolysis and chemotaxis. To these aims, the experimental approach will include: 1) Measurement of cerebrospinal fluid (CSF) and plasma levels of key- molecules belonging to or functionally associated with the uPA system, in order to establish associations with HIV-D and other HIV-related conditions, HIV-1 replication in the CSF and concentrations of classical immune activation CSF markers, as well as the changes induced by HAART; 2) Immunohistochemical studies of expression of the same molecules in post-mortem brain tissues from both ART-untreated and HAART-treated patients with HIV-related lesions or other HIV-related conditions. Cellular source as well as co-localization with other markers or HIV antigens will be evaluated. 3) In vitro studies evaluating the mutual interactions between the uPA system and HIV-1 in monocytic/macrophage culture systems. Although expected findings will be only correlative, these might represent the basis for functional studies in other models and evaluation of new therapeutic strategies.

描述（由申请人提供）：本申请旨在研究尿激酶纤溶酶原激活（uPA）系统在中枢神经系统（CNS）HIV感染及其最重要的临床后果HIV痴呆（HIV-D）中的作用，以确定新的发病机制并提供可用于临床管理（预防、诊断、预后和治疗）的标志物。uPA系统由uPA、其受体uPAR、其抑制剂纤溶酶原激活物抑制剂（派-1）和蛋白酶连接蛋白-1（PN-1）、第二纤溶酶原激活物- tPA（组织型纤溶酶原激活物）和各种结合分子（包括底物纤溶酶原和uPAR相互作用物甲酰肽受体样1（FPRL 1）、整合素和玻连蛋白）组成。拟议的研究将解决的工作假设，uPA系统可能参与HIV-D的病理生理学通过在细胞水平上与HIV的相互作用和随后的uPA系统功能失调，即细胞外蛋白水解和趋化性。为了这些目的，实验方法将包括：1）测量属于uPA系统或与uPA系统功能相关的关键分子的脑脊液（CSF）和血浆水平，以建立与HIV-D和其他HIV相关病症、CSF中的HIV-1复制和经典免疫活化CSF标记物的浓度以及HAART诱导的变化的关联; 2）来自ART未治疗和HAART治疗的具有HIV相关病变或其他HIV相关病症的患者的死后脑组织中相同分子表达的免疫组织化学研究。将评价细胞来源以及与其他标志物或HIV抗原的共定位。3)评价单核细胞/巨噬细胞培养系统中uPA系统和HIV-1之间相互作用的体外研究。虽然预期的结果将只是相关的，这些可能代表在其他模型和新的治疗策略的评价功能研究的基础。