Mechanosensing and calcium signaling in epithelial cells drives allergic response to protease allergen

项目摘要/摘要 该提案概述了达林·L·维斯纳博士的职业发展和研究计划，从他的 将博士后职位转为独立的学术教职，在那里他将研究哮喘。 候选人：到目前为止，我的科学生涯主要集中在揭开T细胞引起的免疫病理。 这种兴趣始于我作为技术员的时候，当时我参与了一个项目，该项目研究了一个致命的 艾滋病患者所患的免疫性疾病。在研究生院，我倾斜了我的研究兴趣 了解有害T细胞对侵袭性肺损伤反应的启动和抑制 真菌感染。我目前正在参与一个项目，该项目旨在了解肺上皮细胞如何 识别和应对蛋白水解酶过敏原，并引发T细胞依赖的过敏性炎症。 职业发展计划：在剩下的博士后时间里，我将与我的 目前的导师将培养我成为独立调查员后所需的能力，例如： 管理、财务和编写协议。我还将利用密歇根大学博士后提供的资源 协会、国家研究指导网络和UW Delta计划帮助您顺利找到工作。 在开始担任助理教授时，我会优先在招聘大学找到一位可以提供帮助的导师 我在当地环境中导航，并在以下领域提供批判性指导：教师承诺、机构 资金来源和任期前的进展。总的来说，这种方法将完善我的科学技能集，确定一个 大学/系是一个很好的选择，能够在我的独立学术生涯中取得成功。 研究项目：该提案的科学部分的首要目标是更好地理解 过敏性哮喘初期致敏过程中上皮俱乐部细胞的参与。我已经发出了声音 初步数据支持细支气管会细胞通过感知对吸入的蛋白水解酶作出反应的前提 通过TRPV4、钙离子通量和信号炎症造成的连接损伤。因此，我将探索 形成完整信号通路的机械转导和钙调神经磷酸酶依赖的转录因子 在过敏反应过程中。这些研究将支持活细胞感知危险的范式转变。 此外，对俱乐部细胞内在信号通路的更坚实的理解将产生关于 从俱乐部细胞发出的产物来组装过敏反应。总体而言，这将为 未来的拨款建议，用于研究其他疾病系统中的危险途径以及新的免疫学 参与哮喘的俱乐部细胞下游的回路。

PROJECT SUMMARY/ABSTRACT This proposal outlines a career development and research plan for Dr. Darin L Wiesner to transition from his postdoctoral fellowship into an independent academic faculty position, where he will investigate asthma. Candidate: Thus far, I have focused my scientific career on unravelling immunopathologies caused by T cells. This interest began during my time as a technician when I was involved in a project that examined a deadly immune disease experienced by persons living with AIDS. In graduate school, I tilted my research interests towards understanding the priming and suppression of detrimental T cell responses to invasive pulmonary fungal infection. I am currently immersed in a project that aims to understand how lung epithelial cells recognize and respond to protease allergen and instigate T cell-dependent allergic inflammation. Career development plan: During the remaining time as a postdoctoral fellow, I will work closely with my current mentor to develop abilities that will be necessary after I am an independent investigator, such as: management, finances, and writing protocols. I will also leverage resources available at UW Postdoc Association, National Research Mentoring Network, and UW Delta Program to help navigate the job search. Upon starting an assistant professorship, I will prioritize finding a mentor at the hiring university that can help me navigate the local landscape and provide critical guidance in areas, like: faculty commitments, institutional funding sources, and pre-tenure progress. Collectively, this approach will refine my scientific skill set, identify a University/Department that is a good fit, and be in a position to succeed in my independent academic career. Research project: The overarching goal of the scientific portion of the proposal is to better understand the involvement of epithelial club cells during initial sensitization of allergic asthma. I have generated sound preliminary data that supports the premise that bronchiolar club cells respond to inhaled protease by sensing junction damage via TRPV4, fluxing calcium, and signaling inflammation. Therefore, I will explore mechanotransduction and calcineurin-dependent transcription factors that form a complete signaling pathway during allergic sensitization. These studies will support a paradigm shift in how living cells sense danger. Moreover, a more solidified understanding of club cell intrinsic signaling pathways will yield information about the products that emanate from club cells to assemble the allergic response. Collectively, this will pave the way for future grant proposals to study danger pathways in other diseases systems, as well as novel immunologic circuits downstream of club cells involved in asthma.