Airway epithelial repair in chronic bronchitis: novel signaling mechanisms

项目摘要/摘要 这项建议描述了一项为期五年的培训计划，以发展在美国的学术生涯 细胞和发育生物学领域。首席调查员是一位经过充分临床培训的肺科医生。 接受过30个月呼吸道上皮细胞生物学博士后培训的重症监护内科医生。这 该计划提供了一个独特的机会，可以在指导期间获得额外的培训和技术 这将使我在这个奖项的头两年结束时能够独立。 剩下的目标将在独立阶段实现，使我更接近我的长期- 学期目标是成为一名独立的内科科学家。 迈阿密大学的环境是唯一有资格让我探索我的假设的地方 肺、重症监护和睡眠医学部的呼吸道生物学实验室 在呼吸道上皮细胞生物学方面的长期成就。此组有权访问高号码 迈阿密大学生命联盟器官回收小组对人类呼吸道上皮细胞的研究， 这让我可以继续他的研究。鉴于该集团的地理位置很近，有几个 首席研究人员聚集在同一个研究空间，我在指导阶段的培训 该奖项将受益于许多经验丰富的调查人员，他们在日常工作中密切合作 基础。我的职业生涯规划将实验室经验与正式课程工作相结合 相位。这将使我能够利用AIMS中提出的额外工作来继续我的假设 独立阶段。本研究旨在进一步研究RA对Wnt信号转导的影响 并评估改善纤毛生成和预防鳞状化生的可能治疗方案。 这些通路在呼吸道中的研究很少，尽管它们对正确的上皮细胞修复很重要。 最后一个目标也有很强的潜力发展成一个翻译项目。 慢性炎症性呼吸道疾病，包括吸烟引起的慢性支气管炎，会导致 呼吸道上皮细胞继发粘液纤毛清除受损，这是一种与 发病率和死亡率增加。另一方面，呼吸道上皮有能力 在损坏发生后，重新生成其规则结构。在修复过程中，细胞增殖的初始阶段 其次是上皮细胞的再分化。这一机制由重新激活的 发育信号机制，如Wnt和维甲酸(RA)刺激的信号通路。我的 初步观察支持这样一种假设，即RA剥夺和吸烟暴露- 诱导的慢性支气管炎导致鳞状化生(SM)和纤毛发生障碍 Wnt途径元件的表达，这些结果可以通过激活PPAR来改善 感受器。 这一假设将通过旨在解决三个主要目标的研究来进行调查。 目的1将确定特定的Wnt途径元件是否对纤毛发生和 预防鳞状化生，RA是这一过程中不可或缺的调节因素 (假说的体外检验)。 目的2将确定Wnt通路元件在慢性粒细胞白血病患者中的表达是否发生改变 吸烟相关的慢性支气管炎以及这种改变是否导致SM和损害 纤毛发生(对患者样本的假设检验)。 目标3将确定核受体(如PPAR和维生素D)的激活 通过替代RA来预防SM的发展并改善纤毛生成(可能性测试 治疗干预)。 这项研究建议解决了呼吸道上皮细胞如何正确修复和修复的一个重要方面 不要将其修复机制误导为可能导致不典型增生的鳞状化生，而在 最坏的情况是恶性。考虑到呼吸道的持续上升，这项研究尤为重要。 疾病，尤其是与吸烟有关的疾病。这项拟议的研究旨在阐明 呼吸道上皮细胞修复。

Project Summary / Abstract 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 PPAR¿ receptors. This hypothesis will be investigated through research constructed to address three major aims. ¿ 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). ¿ 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). ¿ Aim 3 will determine whether activation of nuclear receptors (e.g., PPAR¿ 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.