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

• 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
• 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

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，拥有成功和成功的经验。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，这导致我在小鼠和人类呼吸道上皮细胞中进行了初步实验，以确定是否存在这种情况。他汀类药物可改善过敏性炎症和上皮损伤，如果是的话，具体机制是什么？ 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获得美国胸科学会 (ATS) 职业发展奖。我还与当地以及其他机构的同事进行了多次合作，这些合作获得了资助（TRDRP）并在我参加研究期间和博士后期间发表了几篇论文。作为一名现任 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。这一任命是有益的，体现了我们机构对我的职业发展的承诺。环境：加州大学戴维斯分校的整体研究环境非常出色，非常适合我的研究和职业发展目标。生物科学学院每周举办分子生物学研讨会，由来自分子生物学各个领域的世界级演讲者参加，该课程有着悠久的历史。通过医学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的博士前和博士后研究实习生，这些学校的肺部研究特别强大，有许多 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，这是我在加州大学戴维斯分校非常熟悉的资源。学术医疗中心的多产医师科学家，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。最终，我还将指导和培训住院医师、研究员、研究生和初级教师的研究和学术生涯：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 我已经概述了一个个性化的教育计划，其中有不同的努力，以突出我的研究计划的发展，我将投入至少 75% 的时间进行研究，这与 25 非常吻合。 % 临床时间，包括严重哮喘门诊（1/2 天/周）、住院轮换（6 周/年）和行政职责/每周研讨会/讲座 该计划包括一个指导团队和咨询委员会，定期举行计划会议。测量我的研究项目：尽管目前进行了治疗，但某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) 是强效的 TH2 嗜酸性粒细胞特异性趋化因子，对于严重哮喘尤其重要。显着的气道和全身过敏性炎症以及哮喘易感性增加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小鼠模型中的肺部健康。 (Sim) 使用原代正常人支气管上皮细胞，减轻嗜酸性气道炎症、IL13/IL4 产生和气道高反应性，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，因此我勇敢地面对辛伐他汀 (1)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，以及 (2) 严重过敏性哮喘患者的病情加重。 具体目标： 目标 1) 测试 Sim 是否同时抑制基础和 IL13。目的 2) 测试 Sim 是否抑制 IL13 诱导的 JAK/STAT6 信号通路。 (A) 减少支气管上皮细胞中 TH2 过敏性炎症介质，(B) 减少急性加重并改善肺功能 我将进行为期 30 周的前瞻性、双盲、交叉早期 II 期临床试验，并对严重的患者进行随机分组。哮喘患者除了标准护理吸入皮质类固醇和长效 β 受体激动剂外，还服用安慰剂和 Sim，间隔 12 周。

项目成果

Vocal Hoarseness and a Subglottic Mass: An Uncommon Diagnosis for a Common Complaint.

声音嘶哑和声门下肿块：常见主诉的罕见诊断。

• 发表时间: 2015
• 作者: Rafizadeh, Sassan;Yoneda, Ken;Zeki, Amir A
• 通讯作者: Zeki, Amir A

Editorial (Thematic Issue: New Insights into a Classical Pathway: Key Roles of the Mevalonate Cascade in Different Diseases (Part I)).

社论（专题：经典途径的新见解：甲羟戊酸级联在不同疾病中的关键作用（第一部分））。

• 发表时间: 2017
• 影响因子: 2.7
• 作者: Ghavami, Saeid;Kenyon, Nicholas J;Yeganeh, Behzad;Zeki, Amir A
• 通讯作者: Zeki, Amir A

Update on the spider and the fly: An extended commentary on "Oxidized LDL induced extracellular trap formation in human neutrophils via TLR-PKC-IRAK-MAPK and NADPH-Oxidase activation".

蜘蛛和苍蝇的更新：对“氧化 LDL 通过 TLR-PKC-IRAK-MAPK 和 NADPH 氧化酶激活在人类中性粒细胞中诱导细胞外陷阱形成”的扩展评论。

• 发表时间: 2016-07
• 影响因子: 7.4
• 作者: Cross, Carroll E;Zeki, Amir A
• 通讯作者: Zeki, Amir A

Mevalonate Cascade Inhibition by Simvastatin Induces the Intrinsic Apoptosis Pathway via Depletion of Isoprenoids in Tumor Cells.

辛伐他汀的甲羟戊酸级联抑制通过消耗肿瘤细胞中的类异戊二烯来诱导内在细胞凋亡途径。

• 发表时间: 2017-03-27
• 影响因子: 4.6
• 作者: Alizadeh, Javad;Zeki, Amir A;Mirzaei, Nima;Tewary, Sandipan;Rezaei Moghadam, Adel;Glogowska, Aleksandra;Nagakannan, Pandian;Eftekharpour, Eftekhar;Wiechec, Emilia;Gordon, Joseph W;Xu, Fred Y;Field, Jared T;Yoneda, Ken Y;Kenyon, Nicholas J;Ha
• 通讯作者: Ha

Autophagy and the unfolded protein response promote profibrotic effects of TGF-β1 in human lung fibroblasts.

• DOI: 10.1152/ajplung.00372.2017
• 发表时间: 2018-03-01
• 期刊: American journal of physiology. Lung cellular and molecular physiology
• 作者: S. Ghavami;B. Yeganeh;A. Zeki;S. Shojaei;N. Kenyon;S. Ott;Afshin Samali;J. Patterson;Javad Alizadeh
• 通讯作者: Javad Alizadeh