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

上皮细胞中的机械传感和钙信号传导驱动对蛋白酶过敏原的过敏反应

• 批准号: 10596974
• 负责人: Darin L Wiesner
• 金额: $ 10.8万
• 依托单位: RUTGERS BIOMEDICAL AND HEALTH SCIENCES
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-04-01 至 2024-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10596974
• 关键词: Acceleration; Acquired Immunodeficiency Syndrome; Address; Affect; Allergens; Allergic; Allergic inflammation; Applications Grants; Area; Asthma; Binding Sites; Biology; CD4 Positive T Lymphocytes; CRISPR/Cas technology; Calcineurin; Calcium; Calcium Channel; Calcium Signaling; Cell Nucleus; Cells; Child; Chronic Disease; Collaborations; Computer Analysis; Cytoskeleton; Data; Development Plans; Disease; Eosinophilia; Epithelial Attachment; Epithelial Cell Junction; Epithelial Cells; Epithelium; Exposure to; Extrinsic asthma; Faculty; Fellowship; Funding Agency; Fungal Components; Future; Gene Expression; Genes; Genetic Transcription; Goals; Immune; Immune System Diseases; Immunologics; Immunology; Inflammation; Inflammation Mediators; Inflammatory; Inhalation; Institution; Intercellular Junctions; Irritants; Knock-out; Knowledge; Lung; Lymphocyte; Mechanics; Mentors; Molds; Mus; Mycoses; Nuclear; Nuclear Translocation; Occupations; Pathway interactions; Peptide Hydrolases; Periodicals; Persons; Phosphoric Monoester Hydrolases; Piezo 1 ion channel; Positioning Attribute; Postdoctoral Fellow; Protein Isoforms; Protocols documentation; Publishing; Pulmonary Inflammation; Research; Research Personnel; Research Project Grants; Resources; Respiratory distress; Ribosomes; Scientist; Signal Pathway; Signal Transduction; Structure; Surface; System; T cell response; T-Lymphocyte; Time; Transgenic Mice; Universities; Work; Writing; airway epithelium; allergic response; asthmatic; career; career development; cell type; clinically relevant; cytokine; environmental allergen; experience; fungus; graduate school; immunopathology; improved; in vivo; in vivo Model; insight; interest; mechanical force; mechanotransduction; novel; nuclear factors of activated T-cells; programs; recruit; release of sequestered calcium ion into cytoplasm; research and development; response; skills; sound; tool; transcription factor; wound healing

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.

项目总结/摘要 该提案概述了Darin L Wiesner博士的职业发展和研究计划，以便从他的 博士后奖学金到一个独立的学术教师的位置，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解开T细胞引起的免疫病理学。 这种兴趣始于我作为技术人员的时候，当时我参与了一个项目， 艾滋病患者经历的免疫疾病。在研究生院，我把我的研究兴趣 为了理解对侵袭性肺动脉炎的有害T细胞反应的引发和抑制， 真菌感染我目前正沉浸在一个项目中，旨在了解肺上皮细胞 识别并应答蛋白酶过敏原，并引发T细胞依赖性过敏性炎症。 职业发展计划：在博士后工作的剩余时间里，我将与我的同事密切合作， 现任导师培养我成为独立调查员后所需的能力，例如： 管理、财务和撰写协议。我还将利用UW Postdoc提供的资源 协会，国家研究指导网络，和华盛顿大学三角洲计划，以帮助导航求职。 在开始助理教授职位时，我会优先在招聘大学找到一位可以提供帮助的导师 我导航当地的景观，并提供关键的指导领域，如：教师的承诺，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，确定一个 大学/部门是一个很好的适合，并在一个位置，以成功在我的独立学术生涯。 研究项目：提案科学部分的总体目标是更好地了解 过敏性哮喘初始致敏过程中上皮俱乐部细胞的参与我制造了声音 初步数据支持这样的前提，即细支气管俱乐部细胞通过感知 通过TRPV 4的连接损伤、钙流动和炎症信号传导。因此，我将探索 机械传导和钙调神经磷酸酶依赖性转录因子，形成一个完整的信号通路 在过敏性致敏过程中。这些研究将支持活细胞如何感知危险的范式转变。 此外，对俱乐部细胞内在信号传导途径的更坚实的理解将产生以下信息： 由棒状细胞产生的聚集过敏反应的产物。总的来说，这将为 用于研究其他疾病系统中的危险途径以及新的免疫学 与哮喘有关的俱乐部细胞下游回路。