Role of RelB in HIV-1 Tat-mediated immune responses

RelB 在 HIV-1 Tat 介导的免疫反应中的作用

• 批准号: 6914842
• 负责人: ADELA COTA-GOMEZ
• 金额: $ 11.33万
• 依托单位: UNIVERSITY OF COLORADO DENVER
• 依托单位国家: 美国
• 财政年份: 2002
• 资助国家: 美国
• 起止时间: 2002-07-01 至 2007-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6914842
• 关键词: cell line; genetically modified animals; human immunodeficiency virus 1; immunoregulation; inflammation; laboratory mouse; nuclear factor kappa beta; transcription factor; vascular endothelium; virus protein; virus replication

DESCRIPTION (Applicant's abstract) Infection with human immunodeficiency virus-1 (HIV-1) leads to complications such as myocarditis, alveolitis and pulmonary hypertension that cannot be attributed to viral or bacterial pathogens, resulting in cardiopulmonary dysfunction, morbidity and mortality. The HIV- 1 Tat protein, a viral transcriptional regulator essential for viral replication, is secreted from infected cells, taken up by uninfected cells and acts as a cellular transcription activator. Dr. Flores found that soluble Tat induces oxidative stress via inhibition of antioxidant enzymes and activates proinflammatory molecules. Upon joining Dr. Flores' group 1 discovered that Tat up-regulates expression of the NF-kB family member, RelB. RelB regulates immune responses including antigen presentation and inflammation. This proposal is based on the premise that higher levels of RelB in essence reset the threshold for inflammation resulting in a "primed" immune system that is increasingly sensitive to further inflammatory stimuli. The research plan addresses the mechanisms of Tat-mediated RelB activation and whether Tat affects RelB expression in vivo. Using an in vitro tissue culture system, the following specific questions will be addressed: 1) What are the mechanisms of Tat-mediated RelB up-regulation? 2) What are the downstream effects of Tat-activated RelB? A transgenic mouse model with targeted expression of Tat in the lungs, engineered by Dr. Flores, will be used to address the following specific question: 1) Is there evidence of inflammation in the lungs of Tat-transgenic mice? 2) Is RelB up-regulated in transgenic mouse lung tissues or in alveolar macrophages? 3) Does Tat enhance endotoxin-mediated Relb overexpression in lungs? The proposed research plan should provide new insights into the mechanisms of dysregulated inflammation in AIDS. As part of the career development of the candidate, there will be an advisory committee composed of the co-members as well as three additional members with expertise in various areas relevant to the project. The candidate will be in frequent communication with the committee and will meet at least once a year to assess progress. The candidate will enroll in formal course work on material relevant to the research and will obtain further experience on the technique of in vivo radiolabeling in Dr. Granger's laboratory at LSU Medical Center. The plan is designed to shape the candidate into an independent and investigator.

描述 （申请人摘要）人类免疫缺陷病毒-1（HIV-1）感染 导致心肌炎、肺泡炎、肺结核等并发症 不能归因于病毒或细菌病原体的高血压， 导致心肺功能障碍、发病率和死亡率。 艾滋病毒- 1 Tat 蛋白，一种病毒转录调节因子，对病毒至关重要 复制，从受感染的细胞分泌，被未受感染的细胞吸收 并充当细胞转录激活剂。 弗洛雷斯博士发现 可溶性 Tat 通过抑制抗氧化酶诱导氧化应激 并激活促炎分子。 加入弗洛雷斯博士的小组 1 后 发现 Tat 上调 NF-kB 家族成员的表达， 相关 B. RelB 调节免疫反应，包括抗原呈递和 炎。 该提议的前提是更高层次的 RelB本质上重置了炎症的阈值，从而导致“启动” 免疫系统对进一步的炎症越来越敏感 刺激。 该研究计划探讨 Tat 介导的 RelB 机制 激活以及 Tat 是否影响体内 RelB 表达。 使用一个 in 体外组织培养系统，以下具体问题将 解决：1）Tat 介导的 RelB 上调机制是什么？ 2） Tat 激活的 RelB 的下游效应是什么？ 转基因小鼠 由 Dr. 设计的肺部靶向表达 Tat 的模型 Flores，将用于解决以下具体问题：1）是否存在 Tat 转基因小鼠肺部炎症的证据？ 2) 是RelB 在转基因小鼠肺组织或肺泡巨噬细胞中上调？ 3) Tat 是否会增强肺部内毒素介导的 Relb 过度表达？ 这 拟议的研究计划应为机制提供新的见解 艾滋病中的炎症失调。 作为候选人职业发展的一部分，将会有一个 由共同成员和另外三名成员组成的咨询委员会 成员在与项目相关的各个领域具有专业知识。 这 候选人将与委员会经常沟通并会面 每年至少评估一次进展情况。 候选人将报名参加 与研究相关的材料的正式课程作业并将获得 体内放射性标记技术的进一步经验 路易斯安那州立大学医学中心格兰杰博士的实验室。 该计划旨在 将候选人塑造成一个独立的研究者。