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.

项目摘要/摘要 该提案概述了达林·威斯纳（Darin Lwiesner）博士从他的职业发展和研究计划 博士后奖学金成为独立的学术教师职位，他将在那里调查哮喘。 候选人：到目前为止，我将科学生涯集中在T细胞引起的免疫病理学上。 当我参与一个致命的项目时，这种兴趣始于我担任技术人员的时期 艾滋病患者经历的免疫疾病。在研究生院，我倾斜了研究兴趣 要理解对浸润性肺部有害T细胞反应的启动和抑制 真菌感染。我目前沉浸在一个旨在了解肺上皮细胞的项目中 识别并应对蛋白酶过敏原，并激发T细胞依赖性过敏性炎症。 职业发展计划：在博士后家伙剩下的时间里，我将与我的 当前的导师会发展能力，这是我是一名独立研究者之后的必要能力，例如： 管理，财务和写作协议。我还将利用UW Postoc可用的资源 协会，国家研究指导网络和UW Delta计划，以帮助您进行求职。 在开始助理教授职位后，我将优先在招聘大学寻找一名导师，以帮助您 我在当地景观中浏览并在领域提供关键指导，例如：教师承诺，机构 资金来源和预期进展。总的来说，这种方法将完善我的科学技能，确定 大学/系非常合适，可以在我独立的学术生涯中取得成功。 研究项目：该提案科学部分的总体目标是更好地了解 在过敏性哮喘的初始敏化期间，上皮俱乐部细胞的参与。我已经产生了声音 初步数据支持支气管杆俱乐部细胞对吸入蛋白酶反应的前提 通过TRPV4，通量钙和信号炎症的连接损伤。因此，我会探索 机械转导和钙调神经素依赖性转录因子形成完整的信号通路 在过敏敏化期间。这些研究将支持活细胞如何感觉危险的范式转变。 此外，对俱乐部单元固有信号通路的更加巩固的理解将产生有关的信息 从俱乐部细胞中散发出来的产品来组装过敏反应。总体而言，这将为方式铺平 对于未来的赠款建议，以研究其他疾病系统中的危险途径以及新颖的免疫学 俱乐部细胞下游的电路参与哮喘。