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

• 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
• 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

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.

该副本是利用众多研究子项目之一 由NIH/NCRR资助的中心赠款提供的资源。子弹和 调查员（PI）可能已经从其他NIH来源获得了主要资金， 因此可以在其他清晰的条目中代表。列出的机构是 对于中心，这不一定是调查员的机构。 美国每年在美国慢性阻塞性肺疾病（COPD）造成近12.5万人丧生，该国损失了372亿美元。吸烟占所有COPD病例的8090％。香烟烟雾迅速增加了气道上皮的渗透性，尤其是在患有COPD的人中。 完整上皮的屏障功能由相邻细胞之间的紧密连接保持。 关于呼吸上皮的紧密连接功能的机制知之甚少。 我们的远程目标是定义负责香烟烟雾引起的肺上皮细胞功能改变的机制，以制定有效的治疗策略以抑制这种改变的功能。 该提案的目的是建立一种机制，通过这种机制，来自市场相关香烟的新鲜香烟烟雾调节Rho GTPase在人肺上皮细胞中的活性。该提议的中心假设是，来自市场相关的香烟的烟雾通过对鸟嘌呤核苷酸交换因子（GEF）和GTPase激活蛋白（GAP）的联合调节而激活RHO。该建议的理由是，识别RHO的激活因子将允许定义控制肺上皮细胞功能的机制，从而确定治疗干预措施的潜在靶标。 将测试中央假设，并通过两个具体目的来实现目标：1）确定罗格夫在人类肺上皮细胞中暴露于香烟烟雾的人类肺上皮细胞中Rho的可逆激活程度； 2）确定RHOGAP在暴露于​​香烟烟雾的人类肺上皮细胞中RHO可逆激活的程度。 提出的工作具有创新性，因为它建立在最近开发的技术基础上，该技术在模仿体内肺内暴露条件的条件下，在体外暴露肺上皮细胞。 我们的期望是，这种方法将通过RHO的调节来确定Rhogef，GEF-H1和Rhogap DCL-1有助于香烟烟雾引起的屏障功能的丧失。 结果很重要，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，并将为控制上皮完整性丧失的策略提供见解。 拟议的研究实现了近亲计划的目标，以提高阿拉斯加inbre网络内的生物医学研究能力，使学生参与研究工作，并改善主要是本科伙伴机构的研究环境。