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: 6491683
• 负责人: ADELA COTA-GOMEZ
• 金额: $ 10.21万
• 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/6491683
• 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; 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 （申请人的摘要）感染人类免疫缺陷病毒-1（HIV-1） 导致并发症，例如心肌炎，肺泡炎和肺部 高血压不能归因于病毒或细菌病原体， 导致心肺功能障碍，发病率和死亡率。 艾滋病毒 - 1 TAT蛋白，一种病毒的病毒转录调节剂 复制是由未感染细胞吸收的感染细胞分泌的 并充当细胞转录激活剂。 弗洛雷斯博士发现 可溶性TAT通过抑制抗氧化剂诱导氧化应激 并激活促炎分子。 加入弗洛雷斯博士的第1组 发现TAT上调NF-KB家庭成员的表达 relb。 RELB调节免疫反应，包括抗原表现和 炎。 该提议基于这样的前提 本质上，relb重置炎症的阈值，导致“启动” 免疫系统对进一步炎症越来越敏感 刺激。 研究计划涉及TAT介导的RELB的机制 激活以及TAT是否影响体内RERB表达。 使用一个in 体外组织培养系统，以下特定问题将是 解决：1）TAT介导的RELB上调的机制是什么？ 2） TAT激活的Relb的下游效应是什么？ 转基因小鼠 由Dr. Dr.设计的具有TAT靶向表达的模型 弗洛雷斯（Flores）将用于解决以下特定问题：1） 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还是肺泡巨噬细胞中上调？ 3）TAT是否增强了内毒素介导的RELB过表达？ 这 拟议的研究计划应提供有关机制机制的新见解 艾滋病的炎症失调。 作为候选人职业发展的一部分，将有一个 由共同成员组成的咨询委员会以及另外三个 在与项目相关的各个领域具有专业知识的成员。 这 候选人将经常与委员会进行沟通，并会见面 每年至少一次评估进度。 候选人将注册 与研究相关的材料的正式课程工作，并将获得 在体内放射性标记的技术中的进一步经验 LSU医疗中心的Granger博士实验室。 该计划旨在 将候选人塑造成独立和研究者。