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The Modulation of Eotaxin Expression by Statins: Implications for Asthma Therapy

他汀类药物对嗜酸细胞活化趋化因子表达的调节：对哮喘治疗的影响

基本信息

批准号：
8991504
负责人：
Amir A. Zeki
金额：
$ 17.03万
依托单位：
UNIVERSITY OF CALIFORNIA AT DAVIS
依托单位国家：
美国
项目类别：
财政年份：
2014
资助国家：
美国
起止时间：
2014-01-01 至 2017-12-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8991504
关键词：
Academic Medical Centers Acute Adrenal Cortex Hormones Advisory Committees Affect Agonist Allergic Allergic inflammation American Appointment Asthma Attenuated Award Basic Science Biological Sciences Biology Biopsy Breathing Bronchoalveolar Lavage Bronchoalveolar Lavage Fluid California Cell Line Cells Center for Translational Science Activities Chest Cholesterol Chronic Obstructive Airway Disease Clinic Clinical Clinical Research Clinical Sciences Clinical Trials Coenzyme A Collaborations Collection Data Development Development Plans Disease Double-Blind Method Down-Regulation Elements Environment Eosinophilia Eotaxin Epithelial Epithelial Cells Exhalation Extrinsic asthma Faculty Fellowship Foundations Funding Future Gene Expression Genes Genetic Crossing Over Goals Grant Guanosine Triphosphate Phosphohydrolases Health Human IL4 gene IL5 gene IgE In Vitro Infiltration Inflammation Injury Innovative Therapy Institution Interleukin-13 International K-Series Research Career Programs Knowledge Laboratories Lead Learning Link Lipids Lung Lung diseases Manuscripts Measures Mediating Mediator of activation protein Medicine Mentors Methodology Molecular Biology Molecular and Cellular Biology Mus Nitric Oxide Nuclear Observational Study Ovalbumin Oxidoreductase Pathway interactions Patients Pharmaceutical Preparations Phase II Clinical Trials Phosphorylation Physicians Placebos Postdoctoral Fellow Predisposition Primates Production Publications Pulmonary Function Test/Forced Expiratory Volume 1 Randomized Randomized Clinical Trials Recording of previous events Research Research Infrastructure Research Personnel Research Project Grants Resources Respiratory System Respiratory physiology Respiratory tract structure Rewards Rotation Running SECTM1 gene SERPINB2 gene STAT6 gene Schools Scientist Secure Series Serum Severities Signal Pathway Signal Transduction Simvastatin Small inducible cytokine A24 Societies Sputum Steroids Sterols Structure of parenchyma of lung Symptoms System Techniques Testing Time Training Transcriptional Regulation Translational Research United States National Institutes of Health Veterinary Medicine Vision Work airway epithelium airway hyperresponsiveness airway inflammation airway remodeling arm asthmatic asthmatic patient career career development chemokine cholesterol biosynthesis chromatin immunoprecipitation clinical efficacy clinically relevant college comparative differential expression eosinophil faculty research genetic signature graduate student immortalized cell improved lectures mRNA Stability medical schools meetings metabolomics mevalonate molecular phenotype mouse model new therapeutic target novel novel therapeutics professor programs promoter prospective research and development research study residence respiratory rho skills standard of care symposium

项目摘要

DESCRIPTION (provided by applicant): The primary goal of this K08 proposal is to help me become an independent investigator with NIH R01 level funding. I have chosen as primary mentor Professor Reen Wu, who is a national leader in his field with a successful and long track record of prior mentees. As a fellow I initially worked in the laboratory of Dr. Nicholas Kenyon and learned to use the ovalbumin mouse model. This led to preliminary experiments in mouse and human airway epithelial cells to determine whether statins ameliorate allergic inflammation and epithelial injury, and if so, by what mechanisms. In 2009, I was awarded an American Thoracic Society (ATS) Career Development Award to study simvastatin's effects on airway remodeling via mevalonate (MA) pathway inhibition. Since then I also formed several collaborations both locally and with colleagues at other institutions that have led to a funded grant (TRDRP) and several publications. Throughout my fellowship and post-doctoral years I attended post-graduate courses and seminars at regional meetings and at the ATS annual international conferences. As a current K12 (KL2) scholar, I helped co-develop novel methodologies via our Metabolomics Core for measuring and quantifying the statins and MA metabolites in lung tissue. In 2012, I was appointed as an Assistant Professor in Residence, which is a research-focused academic series. This appointment is rewarding and demonstrates our Institution's commitment to my career development. This K08 proposal builds on my prior work and will lay the foundations to secure future R01 funding. Environment: The overall research environment at U.C. Davis is outstanding and well-suited for my research and career development goals. The Center for Comparative Respiratory Biology & Medicine provides for first class continuous and rich intellectual exchange among research faculty, graduate students, and clinical fellows. The College of Biological Sciences holds weekly Seminars in Molecular Biology that feature world- class speakers from all fields of molecular biology. U.C. Davis has a long history of training pre- and post- doctoral research trainees in pulmonary research through the Schools of Medicine and Veterinary Medicine, and California National Primate Research Center. Lung research in these schools is particularly strong with many NIH-funded investigators and recognized experts working in close proximity. Our Clinical and Translational Science Center (CTSC) and CTSC Clinical Research Center provide for continuous research infrastructure support, a resource I am very familiar with here at U.C. Davis. Career Goals: My overarching career goal is to become an independent and productive physician-scientist at an academic medical center, with clinical and basic science expertise in airway diseases such as asthma. My vision is to lead a laboratory that will investigate airway epithelial biology and pathogenic mechanisms relevant to airway diseases and perhaps other lung diseases, and develop innovative and novel therapies. Eventually, I will also mentor and train residents, fellows, graduate students, and junior faculty in their research and academic careers. Career Development Plan: This plan has 4 domains of training (during a 3-year award period): Research Skills, Coursework and Training, Manuscripts, and Grants. I have outlined an individualized educational plan with different percent efforts to highlight the development of my research program. I will devote at least 75% of my time to research, which fits well with the 25% clinical time including severe asthma clinic (1/2 day/week), in- patient rotations (6 weeks/year), and administrative duties/weekly seminars/lectures. This plan includes a mentoring team and Advisory Committee with regular planned meetings to gauge my progress. Research Project: Asthma symptoms remain poorly controlled in some asthmatics despite current treatments. The eotaxins(-1,2,3) are potent TH2 eosinophil-specific chemokines, important in severe asthma. Eotaxin-3 in particular is strongly associated with marked airway and systemic allergic inflammation, and increased asthma susceptibility. Observational studies and small clinical trials suggest that the lipid-lowering statin drugs may improve lung health. In our mouse model, we found that simvastatin (Sim) attenuates eosinophilic airway inflammation, IL13/IL4 production, and airway hyperreactivity. Using primary normal human bronchial epithelial cells, Sim suppressed basal and IL13-induced eotaxin-2 and -3 expression and STAT6 phosphorylation, without altering eotaxin-3 mRNA stability. Since eotaxin expression is under direct IL13-induced JAK/STAT6 transcriptional regulation, I hypothesize that simvastatin (1) inhibits airway epithelial eotaxin-2 and -3 gene expression at the transcriptional level through modulation of IL13-induced JAK/STAT6 signaling, and (2) reduces exacerbations in patients with severe allergic asthma. Specific Aims: Aim 1) To test whether Sim inhibits both basal and IL13-induced eotaxin gene expression at the transcriptional level. Aim 2) To test whether Sim inhibits the IL13-induced JAK/STAT6 signaling pathway. Aim 3) To determine whether Sim (A) decreases mediators of TH2 allergic inflammation in bronchial epithelial cells, and (B) reduces acute exacerbations and improves lung function. I will perform a 30-week prospective, double-blinded, cross-over early Phase II clinical trial and randomize severe asthma patients to both placebo and Sim for 12 week intervals, in addition to standard-of-care inhaled corticosteroid and long-acting β-agonist.

描述（由申请人提供）：这个K08提案的主要目标是帮助我成为一个独立的研究者与NIH R01级的资金。我选择了Reen Wu教授作为主要导师，他是该领域的国家领导者，在以前的学员中有着成功和长期的记录。作为一名研究员，我最初在Nicholas Kenyon博士的实验室工作，学习使用卵清蛋白小鼠模型。这导致了在小鼠和人类气道上皮细胞中的初步实验，以确定他汀类药物是否改善过敏性炎症和上皮损伤，如果是这样，通过什么机制。2009年，我被授予美国胸科学会（ATS）职业发展奖，研究辛伐他汀通过抑制甲羟戊酸（MA）通路对气道重塑的影响。从那时起，我还在当地和其他机构的同事建立了几个合作项目，这些项目获得了资助赠款（TRDRP）和几篇出版物。在我的奖学金和博士后生涯中，我参加了研究生课程和区域会议和ATS年度国际会议的研讨会。作为目前的K12（KL2）学者，我通过我们的代谢组学核心帮助共同开发了新的方法，用于测量和定量肺组织中的他汀类药物和MA代谢物。在2012年，我被任命为助理教授在住宅，这是一个以研究为重点的学术系列。这次任命是有意义的，也体现了我们机构对我职业发展的承诺。这个K08提案建立在我之前的工作基础上，将为确保未来的R01资金奠定基础。环境：U.C.的整体研究环境。戴维斯非常出色，非常适合我的研究和职业发展目标。比较呼吸生物学与医学中心为研究人员，研究生和临床研究员提供一流的持续和丰富的知识交流。生物科学学院每周举行分子生物学研讨会，来自分子生物学各个领域的世界级演讲者。U.C.戴维斯有一个长期的历史，培训前和博士后研究学员在肺部研究通过医学院和兽医学院，和加州国家灵长类动物研究中心。这些学校的肺部研究特别强大，许多NIH资助的研究人员和公认的专家在附近工作。我们的临床和转化科学中心（CTSC）和CTSC临床研究中心提供持续的研究基础设施支持，这是我在U.C.非常熟悉的资源。戴维斯职业目标：我的总体职业目标是成为一个独立的和富有成效的医生，科学家在学术医疗中心，与临床和基础科学知识的气道疾病，如哮喘。我的愿景是领导一个实验室，研究气道上皮生物学和与气道疾病以及其他肺部疾病相关的致病机制，并开发创新和新颖的疗法。最终，我还将指导和培训居民，研究员，研究生和初级教师在他们的研究和学术生涯。职业发展计划：该计划有4个培训领域（在3年的奖励期内）：研究技能，课程和培训，人工智能和赠款。我已经概述了一个个性化的教育计划与不同的百分比努力，以突出我的研究计划的发展。我将投入至少75%的时间用于研究，这与25%的临床时间非常吻合，包括严重哮喘门诊（每周1/2天），住院患者轮换（每年6周）和行政职责/每周研讨会/讲座。该计划包括一个指导小组和咨询委员会，定期举行计划会议，以评估我的进展。研究项目：尽管目前的治疗，一些哮喘患者的哮喘症状仍然控制不佳。嗜酸性粒细胞趋化因子（-1，2，3）是有效的TH2嗜酸性粒细胞特异性趋化因子，在严重哮喘中很重要。特别是嗜酸性粒细胞趋化因子-3与显著的气道和全身过敏性炎症以及增加的哮喘易感性密切相关。观察性研究和小型临床试验表明，降脂他汀类药物可以改善肺部健康。在我们的小鼠模型中，我们发现辛伐他汀（Sim）减弱嗜酸性粒细胞气道炎症，IL 13/IL 4的产生，和气道高反应性。使用原代正常人支气管上皮细胞，Sim抑制基础和IL 13诱导的eotaxin-2和-3表达以及STAT6磷酸化，而不改变eotaxin-3 mRNA的稳定性。由于嗜酸细胞活化趋化因子的表达直接受IL 13诱导的JAK/STAT6转录调控，我推测辛伐他汀（1）抑制气道上皮细胞的表达，通过调节IL 13诱导的JAK/STAT6信号传导，在转录水平上调节嗜酸细胞活化趋化因子-2和-3基因表达，和（2）减少患有严重过敏性哮喘的患者的急性发作。1）测试Sim是否在转录水平抑制基础和IL 13诱导的嗜酸细胞活化趋化因子基因表达。目的2）检测Sim是否抑制IL 13诱导的JAK/STAT6信号通路。目的3）确定Sim（A）是否减少支气管上皮细胞中的TH 2过敏性炎症介质，以及Sim（B）是否减少急性加重并改善肺功能。我将进行一项为期30周的前瞻性、双盲、交叉早期II期临床试验，将重度哮喘患者随机分为安慰剂组和Sim组，间隔12周，此外还将接受标准治疗吸入性皮质类固醇和长效β激动剂。

项目成果

期刊论文数量（21）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Simvastatin inhibits smoke-induced airway epithelial injury: implications for COPD therapy.

DOI：
10.1183/09031936.00042512
发表时间：
2013-08
期刊：
The European respiratory journal
影响因子：
0
作者：
Davis BB;Zeki AA;Bratt JM;Wang L;Filosto S;Walby WF;Kenyon NJ;Goldkorn T;Schelegle ES;Pinkerton KE
通讯作者：
Pinkerton KE

Definition of critical asthma syndromes.