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Heat-shock protein 90 modulates goblet cell metaplasia in human airway epithelia

热休克蛋白 90 调节人气道上皮杯状细胞化生

基本信息

批准号：
10549769
负责人：
Alejandro Antonio Pezzulo
金额：
$ 12.45万
依托单位：
UNIVERSITY OF IOWA
依托单位国家：
美国
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-02-01 至 2024-01-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10549769
关键词：
Address Affect Animal Model Apical Asthma Biological Assay Biology Blocking Antibodies Budgets CRISPR/Cas technology Cell Death Cell Death Induction Cells Chronic Bronchitis Chronic lung disease Cystic Fibrosis Data Development Developmental Biology Disease model EGFR gene ERBB2 gene Epidermal Growth Factor Receptor Epithelium Exposure to Faculty Future Genes Goals Goblet Cells Grant HSP 90 inhibition Health Health Care Costs Heat-Shock Proteins 90 Hospitalization Human IL17 gene In Vitro Individual Interleukin-13 Iowa K-Series Research Career Programs Knowledge Latino Learning Lung Lung diseases Manuscripts Mediating Membrane Mentors Metaplasia Mission Mucins Mucous body substance Mus National Heart, Lung, and Blood Institute Patients Persons Phosphorylation Phosphotransferases Physicians Production Protein Family Protein Isoforms Proteins Recording of previous events Research Role Scientist Signal Transduction Testing Therapeutic Training Translating Universities Viral Vector Writing airway epithelium apical membrane basolateral membrane career cell type clinical practice cost disabling symptom exposed human population extracellular gene therapy improved in vivo inhibitor mortality mouse model mucus hypersecretion novel regenerative biology skills small molecule inhibitor stem cell biology student training therapeutic target timeline tool transdifferentiation

项目摘要

PROJECT SUMMARY / ABSTRACT Mucus hypersecretion and goblet cell metaplasia are central features of many lung diseases. No treatments exist for goblet cell metaplasia in Th2-low asthma, chronic bronchitis, and cystic fibrosis. In contrast, Th2-high asthma has well-described drivers (e.g., IL13) and available treatments. Patients with untreated goblet cell metaplasia suffer disabling symptoms, frequent hospitalizations, and high healthcare costs. The overall objective of this proposal is to determine the role of heat-shock protein 90 (HSP90) in airway goblet cell metaplasia. My central hypothesis is that inhibition of HSP90 induces goblet to ciliated cell transdifferentiation. Robust preliminary data supports this hypothesis: 1) IL13 induces goblet cell metaplasia in human airway epithelia, with a negative correlation between goblet and ciliated cell abundance, 2) HSP90 inhibition reverts IL13- and IL17-induced goblet cell metaplasia without inducing cell death, and 3) HSP90 inhibition blocks ERBB2/EGFR signaling in IL13-stimulated airway epithelia. I propose three specific aims: Specific Aim 1: Is HSP90 required for goblet cell metaplasia in airway epithelia? I will address this aim using human and mouse deletion of HSP90 gene isoforms. I will expose gene-edited mice and human airway cells in vitro to IL13 or IL17. Specific Aim 2: Does HSP90 inhibition induce transdifferentiation of goblet cells into ciliated cells? I will address this aim with lineage tracing of human airway cells exposed to IL13, IL17, and HSP90 inhibitors. Specific Aim 3: Is apical membrane HSP90 localization required for ERBB2 signaling in goblet cell metaplasia? I will address this aim with protein phosphorylation and localization assays. I will expose human airway epithelia to HSP90 blocking antibodies before and after IL13 or IL17 stimulation. With the completion of this proposal, I expect to have identified novel mechanisms and treatment targets to revert airway goblet cell metaplasia. Treating goblet cell metaplasia caused by various triggers (e.g., IL13 and IL17) may improve many lung diseases. The University of Iowa has a longstanding history of support to its junior faculty. My mentor, Dr. Zabner, is also a Latino Physician-Scientist. Dr. Zabner is a national leader in epithelial lung biology, cystic fibrosis, and gene therapy. He has mentored several K awardees to independence and successful careers as Physician-Scientists. This K-award will expand my research skills to developmental biology and viral vectors. These tools may enable gene therapy in the future and support a cure for chronic bronchitis.

项目摘要/摘要

项目成果

期刊论文数量（1）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Suspected COVID-19 Reinfections at a Tertiary Care Center, Iowa, 2020.

DOI：
10.1093/ofid/ofab188
发表时间：
2021-07
期刊：
Open forum infectious diseases
影响因子：
4.2
作者：
Kobayashi T;Ortiz ME;Imborek KL;Alsuhaibani M;Holley SA;Trannel A;Marra AR;Etienne W;Jenn KE;Abosi OJ;Meacham H;Sheeler LL;Dains A;Kukla ME;McCray PB Jr;Perlman S;Ford B;Diekema DJ;Wellington M;Salinas JL;Pezzulo AA
通讯作者：
Pezzulo AA