Evaluating the Role and Regulation of Wnt Signaling in Proximal Airway Homeostasis and Injury Repair

项目总结/摘要 肺癌是世界上最致命的癌症，占所有癌症死亡的27%。肺鳞状细胞 癌症被认为是通过癌前中间体逐步发展的，为我们提供了 在它成为侵入性之前进行干预的机会。因此，一种新的方法来治疗肺部患者， 癌症是发展一种有针对性的化学预防策略，以防止肺癌前病变的形成 （PMLs）首先。我们实验室以前的工作已经证明，肺癌前病变代表了一种 损伤后气道基底干细胞（ABSC）过度自我更新的状态， 阻止向粘膜纤毛上皮分化。然而，人们对这种机制知之甚少， 调控ABSC对损伤的增殖反应及其对PML形成的影响。 使用体内损伤模型，观察到Wnt信号传导对于早期增殖阶段是必需的。 修复。另外，ABSC和软骨间质的上皮下成纤维细胞分泌Wnt。 区域（ICZ），近端气道中特征不明显的小生境，可向ABSC发出信号。这些数据表明 双自分泌和旁分泌Wnt信号促进修复。此外，过度的Wnt/β-连环蛋白信号传导 驱动ABSC过度增殖，类似于患者中观察到的PMLs， 治疗靶点高通量药物筛选鉴定了一种未注释的Wnt信号传导抑制剂，术语Wnt 抑制剂化合物1（WIC 1）。允许开发一种新的肺部化学预防策略， 癌前病变，以防止ABSC过度增殖。该提案的目标是制定一项 对近端气道上皮生态位内ABSC稳态和相互作用的微妙理解， 在制定一种新的肺癌前病变化学预防策略方面取得进展。具体目标1 将阐明自分泌和旁分泌Wnt/β-catenin信号在体内损伤修复中的作用。的必要性 将评估自分泌Wnt信号传导驱动修复的能力，并将 被识别。具体目标2将分析WIC 1在体内气道修复和PML预防中的作用。 这些研究将在加州大学洛杉矶分校的大卫格芬医学院进行， 赞助商Brigitte Gomperts博士的指导，Brigitte Gomperts博士是一位在肺部癌前生物学方面非常有成就的研究者 以及共同发起人凯瑟琳普拉斯博士，在干细胞命运的决定专家， 单细胞转录组学这项提案中提到的重要生物学可能性， 阐明近端气道稳态和肺癌前病变的调节机制。而这 反过来，可以为我们开发新的靶向化学预防治疗的策略提供信息，并可以设置 为我未来的医学科学家生涯做准备。

PROJECT SUMMARY / ABSTRACT Lung cancer is the deadliest cancer worldwide, accounting for 27% of all cancer deaths. Squamous lung cancer is thought to develop in a stepwise fashion through premalignant intermediates, providing us with the opportunity to intervene before it becomes invasive. Therefore, a novel approach to cure patients of lung cancer is to develop a targeted chemoprevention strategy to prevent the formation of lung premalignant lesions (PMLs) in the first place. Previous work from our lab has demonstrated that lung premalignancy represents a state of excessive self-renewal of airway basal stem cells (ABSCs) following injury that is accompanied by a block in differentiation to the mucociliary epithelium. However, little is known about the mechanisms that govern ABSC proliferation in response to injury and their influence on PML formation. Using an in vivo injury model, Wnt signaling was observed to be necessary for the early proliferative phase of repair. Wnts were additionally secreted by both ABSCs and subepithelial fibroblasts of the intercartilaginous zone (ICZ), a poorly characterized niche in the proximal airway that can signal to ABSCs. These data suggest that dual autocrine and paracrine Wnt signaling promote repair. Further, excessive Wnt/β-catenin signaling drove ABSC hyperproliferation that resembled PMLs seen in patients, offering this pathway as tractable therapeutic target. High-throughput drug screening identified an unannotated Wnt signaling inhibitor, term Wnt Inhibitor Compound 1 (WIC1). allow the development of a novel chemoprevention strategy for lung premalignancy to prevent the excessive ABSC proliferation. The goal of this proposal is to a develop a nuanced understanding of ABSC homeostasis and interactions within the proximal airway epithelial niche and to make strides in formulating a novel chemoprevention strategy for lung premalignancy. Here, Specific Aim 1 will elucidate the roles of autocrine and paracrine Wnt/-catenin signaling in injury repair in vivo. The necessity of autocrine Wnt signaling to drive repair will be assessed and the Wnt-secreting fibroblast cell population will be identified. Specific Aim 2 will analyze the role of WIC1 in airway repair and PML prevention in vivo. These studies will be conducted at the David Geffen School of Medicine at UC Los Angeles under the mentorship of sponsor Dr. Brigitte Gomperts, a highly accomplished investigator in lung premalignancy biology and airway homeostasis as well as co-sponsor Dr. Kathrin Plath, an expert in stem cell fate decisions and single cell transcriptomics. The important biology that is being addressed in this proposal likelihood that we will elucidate the regulatory mechanisms underlying proximal airway homeostasis and lung premalignancy. This, in turn, could inform our strategies for developing a novel targeted chemopreventive therapeutic and could set the stage for my future career as a physician scientist.