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.

项目概要/摘要 该提案概述了达林·L·威斯纳 (Darin L Wiesner) 博士的职业发展和研究计划，以从他的 博士后奖学金进入一个独立的学术教职职位，他将在那里研究哮喘。 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上。 这种兴趣是在我担任技术人员期间开始的，当时我参与了一个检查致命物质的项目。 艾滋病患者经历的免疫疾病。在研究生院，我倾斜了我的研究兴趣 旨在了解有害 T 细胞对侵袭性肺部反应的启动和抑制 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如何 识别并响应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：在博士后剩余的时间里，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、财务和编写协议。我还将利用华盛顿大学博士后提供的资源 协会、国家研究指导网络和威斯康星大学三角洲计划帮助指导求职。 开始担任助理教授后，我将优先在招聘大学寻找一位可以提供帮助的导师 我了解当地情况并在以下领域提供关键指导：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，确定 非常适合我的大学/院系，并且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总体目标是更好地理解 过敏性哮喘初始致敏过程中上皮俱乐部细胞的参与。我已经生成了声音 初步数据支持细支气管棒状细胞通过感知对吸入的蛋白酶作出反应的前提 通过 TRPV4、流动钙和信号炎症导致的连接损伤。因此，我将探索 机械转导和钙调神经磷酸酶依赖性转录因子形成完整的信号通路 过敏致敏期间。这些研究将支持活细胞感知危险方式的范式转变。 此外，对俱乐部细胞内在信号通路的更深入的了解将产生以下信息： 俱乐部细胞产生的产生过敏反应的产物。总的来说，这将为 未来资助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的下游电路。