Airway epithelial repair in chronic bronchitis: novel signaling mechanisms

慢性支气管炎的气道上皮修复：新的信号传导机制

• 批准号: 7960950
• 负责人: Andreas Schmid
• 金额: $ 12.25万
• 依托单位: UNIVERSITY OF MIAMI SCHOOL OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-09-01 至 2012-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7960950
• 关键词: Actins; Address; Agonist; Apical; Award; Be++ element; Beryllium; Biology; Cell Culture Techniques; Cell Polarity; Cell Proliferation; Cells; Cellular biology; Chronic; Chronic Bronchitis; Cilia; Complex; Critical Care; Data; Development; Developmental Cell Biology; Disease; Docking; Dysplasia; Elements; Environment; Epithelial; Epithelial Cells; Epithelium; Experimental Designs; Exposure to; Goals; Hand; Human; Immunohistochemistry; Impairment; In Vitro; Indium; Individual; Inflammation; Inflammatory; Intercellular Junctions; Internet; Laboratories; Lateral; Lead; Life; Location; Lung; Malignant Neoplasms; Measures; Medicine; Mentors; Metaplasia; Methods; Modeling; Morbidity - disease rate; Mucociliary Clearance; Mucous body substance; Natural regeneration; Normalcy; Nuclear Receptors; Organ; Outcome; Pathway interactions; Patients; Phase; Phosphorylation; Physicians; Prevention; Principal Investigator; Process; Program Development; Qualifying; Recovery; Regulation; Research; Research Personnel; Research Proposals; Rest; Sampling; Scientist; Signal Pathway; Signal Transduction; Sleep; Smoke; Smoking; Squamous Metaplasia; Stretching; Structure; Testing; Therapeutic; Therapeutic Intervention; Time; Tobacco smoke; Training; Training Programs; Training Technics; Tretinoin; Universities; Vitamin D; Western Blotting; Wnt proteins; Work; airway epithelium; base; career; cigarette smoking; cilium biogenesis; deprivation; experience; improved; in vivo; inhibitor/antagonist; kinetosome; member; mortality; non-smoker; novel; overexpression; post-doctoral training; prevent; programs; public health relevance; receptor; repaired; research study

DESCRIPTION (provided by applicant): This proposal describes a five-year training program for the development of an academic career in the field of cell and developmental biology. The principal investigator is a fully clinically trained pulmonary / critical care medicine physician with 30 months postdoctoral training in airway epithelial cell biology. This program provides a unique opportunity to acquire additional training and techniques during the mentored phase of the award that will allow me to be independent at the end of the first two years of this award. The rest of the aims will then be pursued during the independent phase bringing me closer to my long- term goal of becoming an independent physician scientist. The environment at the University of Miami is uniquely qualified to allow me to explore my hypothesis as the Laboratories for Airway Biology in the Division of Pulmonary, Critical Care and Sleep Medicine have a long record of accomplishment in airway epithelial cell biology. This group has access to high number of human airway epithelial cells through the University of Miami Life Alliance Organ Recovery Group, which allows me to pursue his research. Given the close physical location of the group, with several principal investigators clustered in the same research space, my training during the mentored phase of the award will benefit from many experienced investigators that are close by and collaborate on a routine basis. My career plan combines laboratory experience with formal course work during the mentored phase. This will allow me to pursue my hypothesis with the additional work proposed in the aims during the independent phase. This research is to further examine the relevance of RA effects on Wnt signaling and evaluate possible therapeutic options to improve ciliogenesis and prevent squamous metaplasia. These pathways are poorly studied in the airway, despite their importance for proper epithelial cell repair. The last aim has also a strong potential to develop into a translational project. Chronic inflammatory airway diseases, including smoking-induced chronic bronchitis, lead to damage of the airway epithelium with subsequent impairment of mucociliary clearance, a condition associated with increased morbidity and mortality. On the other hand, the airway epithelium has the capacity to regenerate its regular structure after damage occurred. During repair, an initial phase of cell proliferation is followed by re-differentiation of epithelial cells. This mechanism is regulated by reactivation of developmental signaling mechanism such as Wnt and the pathways stimulated by retinoic acid (RA). My preliminary observations support the hypothesis that RA deprivation and cigarette smoke exposure- induced chronic bronchitis lead to squamous metaplasia (SM) and impaired ciliogenesis via altered expression of Wnt pathway elements and that these outcomes can be improved by activation of PPAR3 receptors. This hypothesis will be investigated through research constructed to address three major aims. 7 Aim 1 will determine whether specific Wnt pathway elements are essential for ciliogenesis and prevention of squamous metaplasia and that RA is an indispensable regulator of this process (test of hypothesis in vitro). 7 Aim 2 will determine whether the expression of Wnt pathway elements is altered in patients with smoking-related chronic bronchitis and whether this alteration leads to SM and impaired ciliogenesis (test of hypothesis with samples of patients). 7 Aim 3 will determine whether activation of nuclear receptors (e.g., PPAR3 and vitamin D) prevents the development of SM and improves ciliogenesis by substituting for RA (test of possible therapeutic intervention). This research proposal addresses an important aspect of how airway epithelia are properly repaired and not misdirect their repair mechanism into a squamous metaplasia that could lead to dysplasia and in the worst-case malignancy. This research is especially critical considering the continuing rise in airway diseases, especially related to smoking. The proposed research aims to elucidate critical parameters in airway epithelial cell repair. PUBLIC HEALTH RELEVANCE: This research proposal addresses an important aspect of how airway epithelia are properly repaired and not misdirect their repair mechanism into a squamous metaplasia that could lead to dysplasia and in the worst-case cancer. This research is especially critical considering the continuing rise in airway diseases, especially related to smoking. The proposed research aims to elucidate critical parameters in airway epithelial cell repair.

描述（由申请人提供）：该提案描述了一个为期五年的培训计划，用于细胞和发育生物学领域学术职业的发展。首席研究员是一位经过全面临床培训的肺/重症监护医学医师，在气道上皮细胞生物学方面接受了 30 个月的博士后培训。该计划提供了一个独特的机会，让我在该奖项的指导阶段获得额外的培训和技术，这将使我能够在该奖项的前两年结束时独立。其余的目标将在独立阶段实现，使我更接近成为一名独立医师科学家的长期目标。迈阿密大学的环境非常适合我探索我的假设，因为肺科、重症监护和睡眠医学部门的气道生物学实验室在气道上皮细胞生物学方面拥有悠久的成就记录。该小组可以通过迈阿密大学生命联盟器官恢复小组获得大量人类气道上皮细胞，这使我能够继续他的研究。鉴于该小组的物理位置很近，几位主要研究人员聚集在同一个研究空间，我在奖励指导阶段的培训将受益于许多经验丰富的研究人员，他们在附近并定期合作。我的职业计划将实验室经验与指导阶段的正式课程工作结合起来。这将使我能够在独立阶段通过目标中提出的额外工作来追求我的假设。本研究旨在进一步研究 RA 对 Wnt 信号传导影响的相关性，并评估改善纤毛发生和预防鳞状化生的可能治疗方案。尽管这些途径对于正确的上皮细胞修复很重要，但在气道中的研究却很少。最后一个目标也具有发展为转化项目的强大潜力。慢性炎症性气道疾病，包括吸烟引起的慢性支气管炎，会导致气道上皮损伤，随后粘液纤毛清除功能受损，这种情况与发病率和死亡率增加有关。另一方面，气道上皮有能力在损伤后再生其规则结构。在修复过程中，细胞增殖的初始阶段之后是上皮细胞的再分化。该机制通过 Wnt 等发育信号机制的重新激活以及视黄酸 (RA) 刺激的途径进行调节。我的初步观察结果支持这样的假设：RA 剥夺和香烟烟雾暴露诱发的慢性支气管炎通过 Wnt 通路元件表达的改变导致鳞状上皮化生 (SM) 和纤毛发生受损，并且这些结果可以通过激活 PPAR3 受体来改善。这一假设将通过为实现三个主要目标而构建的研究进行调查。 7 目标 1 将确定特定的 Wnt 通路元件是否对于纤毛发生和预防鳞状化生至关重要，以及 RA 是该过程不可或缺的调节剂（体外假设检验）。 7 目标 2 将确定吸烟相关慢性支气管炎患者中 Wnt 通路元件的表达是否发生改变，以及这种改变是否会导致 SM 和纤毛发生受损（用患者样本检验假设）。 7 目标 3 将确定核受体（例如 PPAR3 和维生素 D）的激活是否可以通过替代 RA（测试可能的治疗干预）来阻止 SM 的发展并改善纤毛发生。这项研究提案解决了气道上皮如何正确修复的一个重要方面，并且不会将其修复机制误导为鳞状上皮化生，从而可能导致发育不良，在最坏的情况下甚至导致恶性肿瘤。考虑到气道疾病，尤其是与吸烟有关的气道疾病的持续增加，这项研究尤其重要。拟议的研究旨在阐明气道上皮细胞修复的关键参数。 公共健康相关性：这项研究提案解决了气道上皮如何正确修复的一个重要方面，并且不会将其修复机制误导为鳞状上皮化生，从而可能导致发育不良，最坏的情况下会导致癌症。考虑到气道疾病，尤其是与吸烟有关的气道疾病的持续增加，这项研究尤其重要。拟议的研究旨在阐明气道上皮细胞修复的关键参数。