D389V Variant Induces Hypercontractility in Cardiac Organoids.

, encoding cardiac myosin binding protein-C (cMyBP-C), is the most mutated gene known to cause hypertrophic cardiomyopathy (HCM). However, since little is known about the underlying etiology, additional in vitro studies are crucial to defining the underlying molecular mechanisms. Accordingly, this study aimed to investigate the molecular mechanisms underlying the pathogenesis of HCM associated with a polymorphic variant (D389V) in by using isogenic human-induced pluripotent stem cell (hiPSC)-derived cardiac organoids (hCOs).

D389V Variant Induces Hypercontractility in Cardiac Organoids.

Background: , encoding cardiac myosin binding protein-C (cMyBP-C), is the most mutated gene known to cause hypertrophic cardiomyopathy (HCM). However, since little is known about the underlying etiology, additional studies are crucial to defining the underlying molecular mechanisms. Accordingly, this study aimed to investigate the molecular mechanisms underlying the pathogenesis of HCM associated with a polymorphic variant (D389V) in by using human-induced pluripotent stem cell (hiPSC)-derived cardiac organoids (hCOs).

Airway Epithelial KIF3A Regulates Th2 Responses to Aeroallergens.

KIF3A, the gene encoding kinesin family member 3A, is a susceptibility gene locus associated with asthma; however, mechanisms by which KIF3A might influence the pathogenesis of the disorder are unknown. In this study, we deleted the mouse Kif3a gene in airway epithelial cells. Both homozygous and heterozygous Kif3a gene-deleted mice were highly susceptible to aeroallergens from Aspergillus fumigatus and the house dust mite, resulting in an asthma-like pathology characterized by increased goblet cell metaplasia, airway hyperresponsiveness, and Th2-mediated inflammation.

Vanin-1 expression and methylation discriminate pediatric asthma corticosteroid treatment response.

Background: There is considerable heterogeneity in asthma treatment response.

Objective: We sought to identify biomarkers of corticosteroid treatment response in children with asthma and evaluate the utility and mechanistic basis of these biomarkers.

Methods: Children (5-18 years) presenting to the emergency department with an acute asthma exacerbation were recruited and followed during hospitalization.

Dynamic transcriptional and epigenomic reprogramming from pediatric nasal epithelial cells to induced pluripotent stem cells.

Background: Induced pluripotent stem cells (iPSCs) hold tremendous potential, both as a biological tool to uncover the pathophysiology of disease by creating relevant human cell models and as a source of cells for cell-based therapeutic applications. Studying the reprogramming process will also provide significant insight into tissue development.

Objective: We sought to characterize the derivation of iPSC lines from nasal epithelial cells (NECs) isolated from nasal mucosa samples of children, a highly relevant and easily accessible tissue for pediatric populations.

SERPINB3/B4 contributes to early inflammation and barrier dysfunction in an experimental murine model of atopic dermatitis.

Serine proteases are critical for epidermal barrier homeostasis, and their aberrant expression and/or activity is associated with chronic skin diseases. Elevated levels of the serine protease inhibitors SERPINB3 and SERPINB4 are seen in patients with atopic dermatitis and psoriasis. However, their mechanistic role in the skin is unknown.

Epistasis between serine protease inhibitor Kazal-type 5 (SPINK5) and thymic stromal lymphopoietin (TSLP) genes contributes to childhood asthma.

Background: Epithelial genes have previously been associated with asthma but only explain a small fraction of heritability. In part, this might be due to epistasis, which is often not considered.

Objective: We sought to determine independent and epistatic associations between filaggrin (FLG), serine protease inhibitor Kazal-type 5 (SPINK5), and thymic stromal lymphopoietin (TSLP) gene variants and childhood asthma.

IL-13 receptor α2 contributes to development of experimental allergic asthma.

Background: IL-13 receptor α2 (IL-13Rα2) binds IL-13 with high affinity and modulates IL-13 responses. There are soluble and membrane forms of IL-13Rα2 generated by alternative splicing in mice, but human subjects express only the membrane form of IL-13Rα2 (memIL-13Rα2).

Objective: We determined the role of memIL-13Rα2 in the development of allergic inflammation in mouse models of asthma.

The Greater Cincinnati Pediatric Clinic Repository: A Novel Framework for Childhood Asthma and Allergy Research.

BACKGROUND: Allergic disorders, including asthma, allergic rhinitis, atopic dermatitis, eosinophilic esophagitis, and food allergy, are a major global health burden. The study and management of allergic disorders is complicated by the considerable heterogeneity in both the presentation and natural history of these disorders. Biorepositories serve as an excellent source of data and biospecimens for delineating subphenotypes of allergic disorders, but such resources are lacking.

Functional variant in the autophagy-related 5 gene promotor is associated with childhood asthma.

Rationale And Objective: Autophagy is a cellular process directed at eliminating or recycling cellular proteins. Recently, the autophagy pathway has been implicated in immune dysfunction, the pathogenesis of inflammatory disorders, and response to viral infection. Associations between two genes in the autophagy pathway, ATG5 and ATG7, with childhood asthma were investigated.

Genetic variation in small proline rich protein 2B as a predictor for asthma among children with eczema.

Background: Small proline rich protein 2B (SPRR2B) is a skin and lung epithelial protein associated with allergic inflammation in mice that has not been evaluated in human atopic diseases.

Objective: To determine whether single-nucleotide polymorphisms (SNPs) in SPRR2B are associated with childhood eczema and with the phenotype of childhood eczema combined with asthma.

Methods: Genotyping for SPRR2B and filaggrin (FLG) was performed in 2 independent populations: the Cincinnati Childhood Allergy & Air Pollution Study (CCAAPS; N = 762; birth-age, 4 years) and the Greater Cincinnati Pediatric Clinical Repository (GCPCR; N = 1152; ages 5-10 years).

Downregulation of glutathione S-transferase pi in asthma contributes to enhanced oxidative stress.

Background: Glutathione S-transferase pi (GSTPi) is the predominant redox regulator in the lung. Although evidence implicates an important role for GSTPi in asthma, the mechanism for this has remained elusive.

Objectives: We sought to determine how GSTPi is regulated in asthma and to elucidate its role in maintaining redox homeostasis.

Differences in candidate gene association between European ancestry and African American asthmatic children.

Background: Candidate gene case-control studies have identified several single nucleotide polymorphisms (SNPs) that are associated with asthma susceptibility. Most of these studies have been restricted to evaluations of specific SNPs within a single gene and within populations from European ancestry. Recently, there is increasing interest in understanding racial differences in genetic risk associated with childhood asthma.

Genetic biomarkers of health-related quality of life in pediatric asthma.

Objectives: To determine the relationship between single nucleotide polymorphisms in candidate genes associated with multiple asthma phenotypes and health-related quality of life (HRQOL).

Study Design: A cross-sectional study was conducted at a pediatric hospital in 275 school-aged children diagnosed with asthma and their caregivers. Genomic DNA was obtained from children, and caregivers completed a measure of their child's HRQOL.

Epithelial EGF receptor signaling mediates airway hyperreactivity and remodeling in a mouse model of chronic asthma.

Increases in the epidermal growth factor receptor (EGFR) have been associated with the severity of airway thickening in chronic asthmatic subjects, and EGFR signaling is induced by asthma-related cytokines and inflammation. The goal of this study was to determine the role of EGFR signaling in a chronic allergic model of asthma and specifically in epithelial cells, which are increasingly recognized as playing an important role in asthma. EGFR activation was assessed in mice treated with intranasal house dust mite (HDM) for 3 wk.

A nonredundant role for mouse Serpinb3a in the induction of mucus production in asthma.

Background: Asthma is a major public health burden worldwide. Studies from our group and others have demonstrated that SERPINB3 and SERPINB4 are induced in patients with asthma; however, their mechanistic role in asthma has yet to be determined.

Objective: To evaluate the role of Serpin3a, the murine homolog of SERPINB3 and SERPINB4, in asthma.

Genetic and environmental risk factors for childhood eczema development and allergic sensitization in the CCAAPS cohort.

Eczema is very common and increasing in prevalence. Prospective studies investigating environmental and genetic risk factors for eczema in a birth cohort are lacking. We evaluated risk factors that may promote development of childhood eczema in the Cincinnati Childhood Allergy and Air Pollution Study (CCAAPS) birth cohort (n=762) of infants with at least one atopic parent.

Comparison of anthropometric measures of obesity in childhood allergic asthma: central obesity is most relevant.

Background: Established indicators of central obesity include waist circumference, waist/height ratio, and the conicity index. Studies using such measures (as opposed to body mass index [BMI] percentiles) to characterize the association between obesity and asthma are lacking, despite the fact that these measures have been shown to be most relevant for many other chronic diseases.

Objectives: We sought to examine measures assessing the distribution of obesity in the context of childhood allergic rhinitis and asthma and to elucidate the association of obesity, including central obesity, with allergic asthma in children.

Environmental tobacco smoke and interleukin 4 polymorphism (C-589T) gene: environment interaction increases risk of wheezing in African-American infants.

Objectives: To determine whether infants exposed to environmental tobacco smoke (ETS) having the interleukin 4 (IL-4) or interleukin 13 (IL-13) gene polymorphisms were at increased risk of wheezing.

Study Design: A birth cohort of 758 infants was evaluated annually by a questionnaire, physical examination, and skin prick testing. DNA samples from 560 children were genotyped for IL-4 C-589T and IL-13 C-1112T.

Intrinsically defective skin barrier function in children with atopic dermatitis correlates with disease severity.

Background: Recent genetic evidence supports that an underlying defect in skin barrier function contributes to the pathogenesis of atopic dermatitis (AD). The integrity of the skin barrier can be assessed objectively by measuring transepidermal water loss (TEWL). Previous investigations of TEWL as a biomarker of skin barrier function have been limited by small sample size, and studies including African American subjects are lacking.

Functional effect of the R110Q IL13 genetic variant alone and in combination with IL4RA genetic variants.

Background: IL-13 is a key mediator of allergic asthma. IL-13 mediates its effects via its receptor, a heterodimer composed of IL-4R alpha and IL-13R alpha1. Polymorphic variants of both IL-13 and IL-4R alpha have been shown to be associated with atopy.

Differential expression of type IV collagen isoforms in rat glomerular endothelial and mesangial cells.

Type IV collagen, which is encoded by six genetically distinct alpha-chains (alpha 1-alpha 6), is a major component of the kidney glomerulus. The alpha 1(IV) and alpha 2(IV) chains are present predominantly in the mesangial matrix, whereas the alpha 3(IV), alpha 4(IV), and alpha 5(IV) chains are localized almost exclusively to the glomerular basement membrane (GBM). Thickening of the GBM and expansion of the mesangial matrix are believed to contribute to the pathogenesis of diabetic nephropathy.

V75R576 IL-4 receptor alpha is associated with allergic asthma and enhanced IL-4 receptor function.

Asthma is a complex polygenic disease. Many studies have implicated the importance of IL-4R alpha in the development of allergic inflammation and its gene has been implicated in the genetics of asthma and atopy. In this study, we examined the functional consequences of two of the human IL-4R alpha allelic variants that have been found to associate with asthma and atopy.

Analysis of the life cycle of stat6. Continuous cycling of STAT6 is required for IL-4 signaling.

Signal transducer and activator of transcription (Stat)6 is a transcription factor important for the development of Th2 cells and regulation of gene expression by IL-4 and IL-13. It is known that Stat6 is rapidly activated in response to IL-4; however, the fate of activated Stat6 is less clear. We examined the fate of activated Stat6 and found that during continuous exposure to IL-4, Stat6 activity was sustained for 72 h and that the maintenance of a constant level of activated Stat6 did not require new protein synthesis.