TRANSENDOTHELIAL MIGRATION MONONUCLEAR LEUKOCYTES HIV1

跨内皮迁移 单核白细胞 HIV1

• 批准号: 2546431
• 负责人: HOLLY H BIRDSALL
• 金额: $ 22.6万
• 依托单位: BAYLOR COLLEGE OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 1993
• 资助国家: 美国
• 起止时间: 1993-12-15 至 2000-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/2546431
• 关键词: HIV infections; T lymphocyte; biological signal transduction; cell adhesion; cell migration; chemokine; clinical research; extracellular matrix proteins; human immunodeficiency virus 1; human subject; interferon gamma; interleukin 10; interleukin 4; interleukin 6; leukocyte activation /transformation; leukocyte adhesion molecules; macrophage; monocyte; tissue /cell culture; tumor necrosis factor alpha; vascular endothelium

DESCRIPTION (adapted from the Abstract): Distinctive clinical syndrome involving nervous system, myocardium, and muscle develop in the course of HIV-1 infection. Clinical manifestations of these syndromes, including AIDS-dementia complex, have been attributed to pro-inflammatory molecules and virus-encoded proteins released by leukocytes that migrate into affected tissues. Despite new anti-retroviral therapies, little is achieved in treating extravascular manifestations. The long-term goal of this application is to identify mechanisms whereby HIV-1 infection influences the migration of mononuclear leukocytes (MNLs) across vascular endothelial barrier and the accumulation of infected cells in tissues outside of the vascular compartment. During the previous period of funding the Principal Investigator and coworkers found that the number of HIV-1 infected patients' leukocytes migrating across vascular endothelial cells is determined by the activation state of the leukocytes. The guiding hypothesis in this application is that HIV-1 infection generates cytokines and chemokines that facilitate adhesion between T cells, monocytes, and endothelial cells; increase leukocyte random locomotion; and promote the development of extravascular foci of infected macrophages. Possibly, certain strains of HIV-1 may stimulate migration of the leukocytes they infect. Alternatively, these strains of HIV-1 infect preferentially those leukocytes that are already endowed with ability to migrate across vascular barriers. Three specific aims are proposed to test these hypotheses: (1) to characterize patients' MNLs that carry HIV-1 across endothelial barriers and identify influences that promote migration of these cells; (2) to determine whether migratory T cells can transmit HIV-1 to co-migrating monocytes and how infection may be modulated by signaling from adjacent endothelial cells, extracellular matrix proteins, and co-migrating MNLs; and (3) to identify the molecular basis for the observed effects of HIV-1 on transendothelial migration of T cells and monocytes.

描述(摘自摘要)：独特的临床症状 累及神经系统、心肌和肌肉的过程中 HIV-1感染。这些症状的临床表现，包括 艾滋病-痴呆复合体，已被归因于促炎分子 以及由白细胞释放的病毒编码蛋白，这些蛋白迁移到受影响的 纸巾。尽管有新的抗逆转录病毒疗法，但在以下方面收效甚微 治疗血管外表现。这样做的长期目标是 应用是确定HIV-1感染影响 单核细胞在血管内皮细胞间的迁移 屏障和感染细胞在组织中的聚集 血管隔间。在前一段资助期间，本金 调查人员和同事发现，感染HIV-1的患者数量 白细胞在血管内皮细胞间的迁移由 白细胞的激活状态。其中的指导性假设 应用是HIV-1感染产生的细胞因子和趋化因子 促进T细胞、单核细胞和内皮细胞之间的黏附； 增加白细胞的随机移动，促进糖尿病的发展 感染巨噬细胞的血管外病灶。可能，某些菌株 HIV-1可能会刺激它们感染的白细胞的迁移。或者， 这些HIV-1毒株优先感染那些 已经被赋予了跨越血管屏障的迁移能力。三 提出了检验这些假说的具体目标：(1)表征 患者携带HIV-1跨越内皮屏障并识别的单核细胞 促进这些细胞迁移的影响；(2)确定 迁移性T细胞能否将HIV-1传播给共同迁移的单核细胞及其途径 感染可能通过邻近内皮细胞的信号进行调节， 细胞外基质蛋白和共迁移的MNL；以及(3)鉴定 HIV-1对跨内皮细胞影响的分子基础 T细胞和单核细胞的迁移。