权益分类	功能权益	普通用户	{{item.name}}会员
{{category.name}}	{{benefitItem.name}}

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）：本 K08 提案的主要目标是帮助我成为一名拥有 NIH R01 级别资助的独立研究者。我选择 Reen Wu 教授作为主要导师，他是该领域的国家领导者，在之前的受训者中拥有成功且长期的记录。作为一名研究员，我最初在 Nicholas Kenyon 博士的实验室工作，并学会了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进行的初步实验，以确定他汀类药物是否可以改善过敏性炎症和上皮损伤，如果可以，是通过什么机制来改善的。 2009 年，我因研究辛伐他汀通过甲羟戊酸 (MA) 途径抑制对气道重塑的影响而荣获美国胸科学会 (ATS) 职业发展奖。从那时起，我还在当地以及与其他机构的同事进行了多次合作，这些合作获得了一笔资助金（TRDRP）并出版了几本出版物。在我的研究金和博士后生涯中，我参加了区域会议和 ATS 年度国际会议的研究生课程和研讨会。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，用于测量和量化肺组织中的他汀类药物和 MA 代谢物。 2012年，我被任命为驻校助理教授，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：加州大学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、丰富的知识交流。生物科学学院每周举办分子生物学研讨会，邀请来自分子生物学各个领域的世界级演讲者。加州大学戴维斯在通过医学院和兽医学院以及加州国家灵长类动物研究中心培训肺部研究方面的博士前和博士后研究实习生方面有着悠久的历史。这些学校的肺脏研究尤其强大，许多 NIH 资助的研究人员和公认的专家都在附近工作。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，这是我在加州大学非常熟悉的资源。戴维斯.职业目标：我的总体职业目标是成为学术医疗中心的一名独立且富有成效的医师科学家，拥有哮喘等气道疾病的临床和基础科学专业知识。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，我还将指导和培训住院医生、研究员、研究生和初级教师的研究和学术生涯。职业发展计划：该计划有 4 个培训领域（在 3 年奖励期内）：研究技能、课程作业和培训、手稿和补助金。我概述了一个个性化的教育计划，其中包含不同的努力，以突出我的研究项目的发展。我将投入至少 75% 的时间进行研究，这与 25% 的临床时间非常吻合，包括严重哮喘门诊（1/2 天/周）、住院轮换（6 周/年）以及行政职责/每周研讨会/讲座。该计划包括一个指导团队和咨询委员会，并定期举行计划会议来衡量我的进展。研究项目：尽管目前进行了治疗，但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，对严重哮喘很重要。尤其是Eotaxin-3，与明显的气道和全身过敏性炎症以及哮喘易感性增加密切相关。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) 可以减轻嗜酸性粒细胞气道炎症、IL13/IL4 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 IL13 诱导的 eotaxin-2 和 -3 表达以及 STAT6 磷酸化，而不改变 eotaxin-3 mRNA 稳定性。由于嗜酸细胞活化趋化因子的表达直接受到 IL13 诱导的 JAK/STAT6 转录调控，因此我推测辛伐他汀 (1) 会抑制气道上皮细胞通过调节 IL13 诱导的 JAK/STAT6 信号传导，在转录水平上调节 eotaxin-2 和 -3 基因表达，(2) 减少严重过敏性哮喘患者的病情加重。具体目的：目的 1) 测试 Sim 是否在转录水平抑制基础和 IL13 诱导的嗜酸细胞趋化因子基因表达。目的2) 测试Sim是否抑制IL13诱导的JAK/STAT6信号通路。目标 3) 确定 Sim 是否 (A) 减少支气管上皮细胞中 TH2 过敏性炎症介质，以及 (B) 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，并将严重哮喘患者随机分为安慰剂组和 Sim 组，间隔 12 周，此外还接受标准护理吸入皮质类固醇和长效 β 受体激动剂。

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.