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

描述 (申请人摘要)感染人类免疫缺陷病毒-1(HIV-1) 导致心肌炎、肺泡炎和肺部等并发症 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，由感染的细胞分泌，由未感染的细胞摄取 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。在加入弗洛雷斯博士的小组1之后 发现TAT上调了核因子-kB家族成员的表达， Re B。RelB调节免疫反应，包括抗原提呈和 发炎。这项提议是基于这样一个前提，即更高水平的 从本质上讲，RelB重置了炎症的阈值，导致了 免疫系统对进一步的炎症越来越敏感 刺激物。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RelB的表达。使用输入 试管组织培养系统中，以下具体问题将 解决：1)TAT介导的RelB上调的机制是什么？2) TAT激活的RelB的下游影响是什么？转基因小鼠 在肺中靶向表达TAT的模型，由Dr。 Flores，将用来解决以下具体问题：1)是否有 TAT转基因小鼠肺部发炎的证据？2)是RelB 转基因小鼠肺组织或肺泡巨噬细胞上调？ 3)TAT是否增强内毒素介导的肺组织中REB的过度表达？这个 拟议的研究计划应该为以下机制提供新的见解 艾滋病患者的炎症反应失调。 作为候选人职业发展的一部分，将有一个 由共同成员和另外三名成员组成的咨询委员会 在与项目相关的各个领域拥有专业知识的成员。这个 候选人将与委员会保持频繁沟通，并将举行会议 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工作，并将获得 对活体放射性标记技术的进一步认识 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 把候选人塑造成一名独立的调查员。

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.