A5034522642- Asthma and respiratory diseases
- IL-33, ST2, and ILC Pathways
- Neonatal Respiratory Health Research
- Respiratory viral infections research
- Immune Cell Function and Interaction
- Glycosylation and Glycoproteins Research
- Inhalation and Respiratory Drug Delivery
- Tracheal and airway disorders
- Single-cell and spatial transcriptomics
- Proteoglycans and glycosaminoglycans research
- RNA Interference and Gene Delivery
- Monoclonal and Polyclonal Antibodies Research
- COVID-19 Clinical Research Studies
- Endoplasmic Reticulum Stress and Disease
- Eosinophilic Esophagitis
- Cystic Fibrosis Research Advances
- RNA and protein synthesis mechanisms
- Helicobacter pylori-related gastroenterology studies
- Pediatric health and respiratory diseases
- SARS-CoV-2 and COVID-19 Research
- PARP inhibition in cancer therapy
- Immune responses and vaccinations
- Respiratory and Cough-Related Research
- Respiratory Support and Mechanisms
- Interstitial Lung Diseases and Idiopathic Pulmonary Fibrosis
University of California, San Francisco
2014-2023
City College of San Francisco
2019-2022
Cardiovascular Institute Hospital
2017-2021
Wellcome Centre for Cell-Matrix Research
2017
University of Manchester
2017
Manchester Academic Health Science Centre
2017
The development of pathologic mucus, which is not readily cleared from the airways, an important contributor to morbidity and mortality associated with asthma. It clear how major airway mucins MUC5AC MUC5B are organized within mucus gel or this contributes obstruction in Here, we demonstrated that plugs individuals fatal asthma heterogeneous gels distinct MUC5AC- MUC5B-containing domains. Stimulation cultured human bronchial epithelial cells IL-13, a key mediator asthma, induced formation...
Rationale: Activation of type 2 cytokine pathways plays a central role in large subset subjects with asthma. Th2-high and Th2-low asthma have distinct clinical, pathologic, molecular phenotypes respond differently to therapy. The factors that initiate responses some are unknown.Objectives: To determine whether expression epithelial cytokines IL-25, IL-33, thymic stromal lymphopoietin associated predict response inhaled corticosteroid (ICS) asthma.Methods: We analyzed pulmonary function...
Rationale: Quantification of type 2 inflammation provided a molecular basis for heterogeneity in asthma. Non–type pathways that contribute to asthma pathogenesis are not well understood.Objectives: To identify dysregulated beyond inflammation.Methods: We applied RNA sequencing airway epithelial brushings obtained from subjects with stable mild on corticosteroids (n = 19) and healthy control 16). Sequencing reads were mapped human viral genomes. In the same cohort, separate group severe 301),...
BACKGROUND. Chronic obstructive pulmonary disease (COPD) is a heterogeneous smoking-related characterized by airway obstruction and inflammation. This inflammation may persist even after smoking cessation responds variably to corticosteroids. Personalizing treatment biologically similar "molecular phenotypes" improve therapeutic efficacy in COPD. IL-17A involved neutrophilic corticosteroid resistance, thus be particularly important COPD molecular phenotype.
Asthma is associated with chronic changes in the airway epithelium, a key target of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Many epithelial changes, including goblet cell metaplasia, are driven by type cytokine IL-13, but effects IL-13 on SARS-CoV-2 infection unknown. We found that stimulation differentiated human bronchial cells (HBECs) cultured at air–liquid interface reduced viral RNA recovered from SARS-CoV-2–infected and decreased double-stranded RNA, marker...
BackgroundDiffuse airway mucus obstruction is an important feature of severe and fatal asthma. MUC5AC MUC5B are the principal gel-forming mucins found in mucus. The mucin composition likely affects its functional properties.MethodsWe quantified sputum age-matched children with acute stable asthma healthy control subjects by using Western blotting.ResultsSputum samples from 38 (13 asthma, 15 10 subjects) were obtained. Sputum concentrations 7.6 μg/mL subjects, 22.4 those (P = .17), 44.7 <...
IL-13–induced goblet cell metaplasia contributes to airway remodeling and pathological mucus hypersecretion in asthma. miRNAs are potent modulators of cellular responses, but their role regulation is largely unexplored. We hypothesized that epithelial play roles regulation. miR-141 highly expressed human mouse epithelium, altered bronchial brushings from asthmatic subjects at baseline, induced shortly after allergen exposure. established a CRISPR/Cas9-based protocol target primary cells were...
Asthma is characterized by mucus abnormalities. Airway epithelial metaplasia results in changes stored and secreted mucin the production of a pathologic gel. Mucus transport impaired culminating plugging airway obstruction, major cause morbidity asthma. The polymeric mucins MUC5AC MUC5B are integral components mucus. gene expression altered asthma recent work sheds light on their contribution to pathogenesis. Herein we review our current understanding role dysfunction
The human airway epithelium is essential in homeostasis, and epithelial dysfunction contributes to chronic disease. Development of flow-cytometric methods characterize subsets cells will enable further dissection biology. Leveraging single-cell RNA-sequencing data combination with known cell type–specific markers, we developed panels antibodies isolate the major (basal, ciliated, secretory cells) from bronchial epithelial-cell cultures. We also identified molecularly distinct subpopulations...
Primary human bronchial epithelial cell (HBEC) cultures are a useful model for studies of lung health and major airway diseases. However, mechanistic have been limited by our ability to selectively disrupt specific genes in these cells. Here we optimize methods gene targeting HBECs direct delivery single guide RNA (sgRNA) rCas9 (recombinant Cas9) complexes electroporation, without requirement plasmids, viruses, or antibiotic selection. Variations the method delivery, sgRNA concentrations,...
Protein disulfide isomerase (PDI) family members regulate protein folding and calcium homeostasis in the endoplasmic reticulum (ER). The PDI member anterior gradient (AGR) 3 is expressed airway, but localization, regulation, function of AGR3 are poorly understood. Here we report that AGR3, unlike its closest homolog AGR2, restricted to ciliated cells airway epithelium not induced by ER stress. Mice lacking viable develop with normal-appearing cilia. However, ciliary beat frequency was lower...
Puerto Ricans have the highest childhood asthma prevalence in United States (23.6%); however, etiology is uncertain.
Abstract SARS coronavirus-2 (SARS-CoV-2) is causing a global pandemic with large variation in COVID-19 disease spectrum. SARS-CoV-2 infection requires host receptor ACE2 on lung epithelium, but epithelial underpinnings of are largely unknown. We capitalized comprehensive organoid assays to report remarkable rates organoids from different subjects. Tropism highest for TUBA- and MUC5AC-positive cells, levels TUBA-, MUC5A-, or ACE2-positive cells do not predict rate. identify surface molecule...
Epithelial responses to the cytokine interleukin-13 (IL-13) cause airway obstruction in asthma. Here we utilized multiple genomic techniques identify IL-13-responsive regulatory elements bronchial epithelial cells and used these data develop a CRISPR interference (CRISPRi)-based therapeutic approach downregulate obstruction-inducing genes cell type- IL-13-specific manner. Using single-cell RNA sequencing (scRNA-seq) acetylated lysine 27 on histone 3 (H3K27ac) chromatin immunoprecipitation...
Ancestral SARS coronavirus-2 (SARS-CoV-2) and variants of concern (VOC) caused a global pandemic with spectrum disease severity. The mechanistic explaining variations related to airway epithelium are relatively understudied. Here, we biobanked organoids (AO) by preserving stem cell function. We optimized viral infection H1N1/PR8 comprehensively characterized epithelial responses SARS-CoV-2 in phenotypically stable AO from 20 different subjects. discovered Tetraspanin-8 (TSPAN8) as...
Asthma is associated with chronic changes in the airway epithelium, a key target of SARS-CoV-2. Many epithelial are driven by type 2 cytokine IL-13, but effects IL-13 on SARS-CoV-2 infection unknown. We sought to discover how and other cytokines affect expression genes encoding SARS-CoV-2-associated host proteins human bronchial cells (HBECs) determine whether stimulation alters susceptibility infection. used bulk single cell RNA-seq identify cytokine-induced gene HBECs. related these...
Abstract The human airway epithelium is essential in homeostasis, and epithelial dysfunction contributes to chronic disease. Development of flow cytometric methods characterize subsets cells will enable further dissection biology. Leveraging single cell RNA-sequencing (scRNA-seq) data combination with known type-specific markers, we developed panels antibodies isolate the major (basal, ciliated, secretory cells) from bronchial cultures. We also identified molecularly distinct subpopulations...
Abstract SARS coronavirus-2 (SARS-CoV-2) is causing a global pandemic with large variation in COVID-19 disease spectrum. SARS-CoV-2 infection requires host receptor ACE2 on lung epithelium, but epithelial underpinnings of are largely unknown. We capitalized comprehensive organoid assays to report remarkable rates organoids from different subjects. Tropism highest for TUBA- and MUC5AC-positive cells, levels TUBA-, MUC5A-, or ACE2- positive cells do not predict rate. identify surface molecule...