INBRE-2 REGULATORS OF RHO IN LUNG EPITHELIAL CELLS EXPOSED TO CIGARETTE SMOKE

暴露于香烟烟雾的肺上皮细胞中 RHO 的 INBRE-2 调节因子

基本信息

批准号：
8167414
负责人：
CINDY M KNALL
金额：
$ 7.09万
依托单位：
UNIVERSITY OF ALASKA FAIRBANKS
依托单位国家：
美国
项目类别：
财政年份：
2010
资助国家：
美国
起止时间：
2010-03-01 至 2011-02-28
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8167414
关键词：
Accounting Alaska Biomedical Research Build-it Cell physiology Cells Chronic Obstructive Airway Disease Cigarette Computer Retrieval of Information on Scientific Projects Database Country Development Environment Epithelial Epithelial Cells Epithelium Funding GTPase-Activating Proteins Goals Grant Guanine Nucleotide Exchange Factors Human In Vitro Institution Lung Marketing Outcome Permeability Regulation Research Research Personnel Resources Signal Transduction Pathway Smoke Source Structure of respiratory epithelium Students Techniques Testing Therapeutic Therapeutic Intervention Tight Junctions United States United States National Institutes of Health Work airway epithelium cigarette smoke-induced cigarette smoking cigarette smoking cost expectation improved in vivo innovation insight killings programs rho rho GTP-Binding Proteins rho GTPase-activating protein

项目摘要

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Chronic obstructive pulmonary disease (COPD) in the United States annually kills nearly 125,000 people and costs this country $37.2 billion. Cigarette smoking accounts for 8090% of all cases of COPD. Cigarette smoke rapidly increases the permeability of airway epithelium, especially in those with COPD. The barrier function of an intact epithelium is maintained by tight junctions between adjacent cells. Little is known about the mechanisms underlying tight junction function in respiratory epithelium. Our long-range goal is to define the mechanisms responsible for cigarette smoke induced alterations in lung epithelial cell function in order to develop effective therapeutic strategies to inhibit this altered function. The objective of this proposal is to establish the mechanism by which fresh, whole cigarette smoke from market relevant cigarettes regulates the activity of Rho GTPase in human lung epithelial cells. The central hypothesis of this proposal is that smoke from market relevant cigarettes activates Rho through the combined regulation of both a guanine nucleotide exchange factor (GEF) and a GTPase activating protein (GAP). The rationale for this proposal is that identifying the activators of Rho will allow mechanisms that control lung epithelial cell function to be defined, resulting in the identification of potential targets for therapeutic interventions. The central hypothesis will be tested and the objective accomplished through two specific aims: 1) determine the extent to which a RhoGEF contributes to the reversible activation of Rho in human lung epithelial cells exposed to cigarette smoke; 2) determine the extent to which a RhoGAP contributes to the reversible activation of Rho in human lung epithelial cells exposed to cigarette smoke. The proposed work is innovative because it builds on a recently developed technique to expose lung epithelial cells in vitro under conditions that mimic the exposure conditions within the in vivo lung. Our expectation is that this approach will establish that the RhoGEF, GEF-H1, and the RhoGAP, DCL-1, through there regulation of Rho contribute to the cigarette smoke induced loss of barrier function. The outcome is significant because it will define the signal transduction pathways that regulate Rho activation in lung epithelium exposed to cigarette smoke, and will provide insights for the development of strategies to control the loss of epithelial integrity. The proposed study fulfills the INBRE program objectives to increase biomedical research capacity within the Alaska INBRE network, to engage students in the research endeavor and to improve the research environment at a primarily undergraduate partner institution.

该子项目是利用该技术的众多研究子项目之一资源由 NIH/NCRR 资助的中心拨款提供。子项目及研究者 (PI) 可能已从 NIH 的另一个来源获得主要资金，因此可以在其他 CRISP 条目中表示。列出的机构是对于中心来说，它不一定是研究者的机构。在美国，慢性阻塞性肺病 (COPD) 每年导致近 125,000 人死亡，并给国家造成 372 亿美元的损失。吸烟占所有 COPD 病例的 80-90%。香烟烟雾会迅速增加气道上皮的通透性，尤其是患有慢性阻塞性肺病的患者。完整上皮的屏障功能由相邻细胞之间的紧密连接维持。关于呼吸道上皮紧密连接功能的机制知之甚少。我们的长期目标是确定香烟烟雾引起肺上皮细胞功能改变的机制，以便开发有效的治疗策略来抑制这种功能改变。该提案的目的是建立市场相关香烟的新鲜完整香烟烟雾调节人肺上皮细胞中 Rho GTP 酶活性的机制。该提案的中心假设是，市场相关香烟的烟雾通过鸟嘌呤核苷酸交换因子 (GEF) 和 GTP 酶激活蛋白 (GAP) 的联合调节来激活 Rho。该提议的基本原理是，识别 Rho 激活剂将允许定义控制肺上皮细胞功能的机制，从而确定治疗干预的潜在靶点。将通过两个具体目标来测试中心假设并实现目标：1）确定 RhoGEF 对暴露于香烟烟雾的人肺上皮细胞中 Rho 可逆激活的贡献程度； 2) 确定 RhoGAP 对暴露于香烟烟雾的人肺上皮细胞中 Rho 可逆激活的贡献程度。这项工作具有创新性，因为它建立在最近开发的一项技术之上，可在模拟体内肺内暴露条件的条件下在体外暴露肺上皮细胞。我们期望这种方法将确定 RhoGEF、GEF-H1 和 RhoGAP、DCL-1 通过 Rho 的调节导致香烟烟雾诱导的屏障功能丧失。这一结果意义重大，因为它将定义调节暴露于香烟烟雾的肺上皮中 Rho 激活的信号转导途径，并将为制定控制上皮完整性丧失的策略提供见解。拟议的研究实现了 INBRE 计划的目标，即提高阿拉斯加 INBRE 网络内的生物医学研究能力，吸引学生参与研究工作，并改善主要本科合作机构的研究环境。