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: 7081243
• 负责人: ADELA COTA-GOMEZ
• 金额: $ 11.78万
• 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 2009-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7081243
• 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 导致并发症，如心肌炎，肺泡炎和肺 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达特蛋白，一种病毒转录调节因子， 复制，从受感染的细胞分泌，被未感染的细胞吸收， 并充当细胞转录激活剂。 弗洛雷斯博士发现， 可溶性达特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第一组后 发现达特上调NF-κ B家族成员的表达， RelB. RelB调节免疫应答，包括抗原呈递， 炎症 这一建议的前提是， RelB实质上重置了炎症阈值，导致"引发" 免疫系统对进一步的炎症反应越来越敏感 刺激。 该研究计划涉及Tat介导的RelB的机制 活化和达特是否影响体内RelB表达。 使用一项 体外组织培养系统，将提出以下具体问题 问题：1）Tat介导的RelB上调机制是什么？（二） Tat激活的RelB的下游效应是什么？ 转基因小鼠 在肺中靶向表达达特的模型，由Dr. 弗洛雷斯，将被用来解决以下具体问题：1）是否有 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)达特是否增强肺内毒素介导的Relb过表达？ 的 拟议的研究计划应提供新的见解， 艾滋病的炎症失调 作为候选人职业发展的一部分， 咨询委员会由共同成员和另外三名成员组成 成员具备与项目相关的各个领域的专业知识。 的 候选人将经常与委员会沟通，并将会见 至少每年一次，评估进展情况。 候选人将报名参加 正式的课程工作材料相关的研究，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的格兰杰博士实验室。 该计划旨在 把候选人塑造成一个独立的调查者。