A5076474764- Cystic Fibrosis Research Advances
- Neonatal Respiratory Health Research
- Epigenetics and DNA Methylation
- Genomics and Rare Diseases
- Glycosylation and Glycoproteins Research
- Tracheal and airway disorders
- Digestive system and related health
- Pneumonia and Respiratory Infections
- Carbohydrate Chemistry and Synthesis
- Pediatric Hepatobiliary Diseases and Treatments
- Genetic and Kidney Cyst Diseases
- Transplantation: Methods and Outcomes
- Infant Nutrition and Health
- Esophageal and GI Pathology
- Cancer Genomics and Diagnostics
- Liver Disease and Transplantation
- Pediatric health and respiratory diseases
- Genomic variations and chromosomal abnormalities
- Animal health and immunology
- HER2/EGFR in Cancer Research
- Liver Disease Diagnosis and Treatment
- Hepatitis Viruses Studies and Epidemiology
- Congenital heart defects research
- Pneumocystis jirovecii pneumonia detection and treatment
- Cerebrospinal fluid and hydrocephalus
University of North Carolina at Chapel Hill
2013-2024
Lung Institute
2015-2024
Indiana University School of Medicine
2016
YAP is a multifunctional adapter protein and transcriptional coactivator with several binding partners well described in vitro cell culture.To explore vivo requirements for YAP, we generated mice carrying targeted disruption of the Yap gene.Homozygosity tm1Smil allele (Yap ؊/؊ ) caused developmental arrest around E8.5.Phenotypic characterization revealed requirement yolk sac vasculogenesis.Yolk endothelial erythrocyte precursors were specified as shown by histology, PECAM1 immunostaining,...
Diabetes is a common age-dependent complication of cystic fibrosis (CF) that strongly influenced by modifier genes. We conducted genome-wide association study in 3,059 individuals with CF (644 CF-related diabetes [CFRD]) and identified single nucleotide polymorphisms (SNPs) within 5′ to the SLC26A9 gene associated CFRD (hazard ratio [HR] 1.38; P = 3.6 × 10−8). Replication was demonstrated 694 (124 CFRD) (HR, 1.47; 0.007), combined analysis significant at 9.8 10−10. an epithelial...
Rationale: The severity of cystic fibrosis (CF) lung disease varies widely, even for Phe508del homozygotes. Heritability studies show that more than 50% the variability reflects non-cystic transmembrane conductance regulator (CFTR) genetic variation; however, full extent pertinent variation is not known.Objectives: We sought to identify novel CF disease-modifying mechanisms using an integrated approach based on analyzing "in vivo" airway epithelial gene expression complemented with...
Abstract Background Primary ciliary dyskinesia (PCD) is a mostly autosomal recessive, genetic disease of abnormal motile cilia function, resulting in bronchiectasis, infertility, organ laterality defects, and chronic otolaryngology disease. Though motile, ependymal influencing cerebrospinal fluid flow the central nervous system share many aspects structure function with respiratory tract, hydrocephalus rarely associated PCD. Recently, pathogenic variants FOXJ1 (Chr 17q25.1) were identified...
Inefficient adenoviral vector (AdV)-mediated gene transfer to the ciliated respiratory epithelium has hindered strategies for treatment of cystic fibrosis lung disease. In part, inefficiency is due an absence coxsackie B and adenovirus type 2 5 receptor (CAR) from apical membranes polarized epithelia. this study, using in vitro model human airway epithelium, we show that providing a glycosylphosphatidylinositol (GPI)-linked AdV (GPI-CAR) at surface did not significantly improve efficiency...
Abstract Genetic studies of lung disease in cystic fibrosis (CF) are hampered by the lack a severity measure that accounts for chronic progression and mortality attrition. Further, combining analyses across requires common phenotypes robust to study design patient ascertainment. Using data from North American Cystic Fibrosis Modifier Consortium (Canadian CF Studies, Johns Hopkins University Twin Sibling Study, Carolina/Case Western Reserve Gene Study), authors calculated age‐specific...
Variability in cystic fibrosis (CF) lung disease is partially due to non-CFTR genetic modifiers. Mucin genes are very polymorphic, and mucins play a key role the pathogenesis of CF disease; therefore, mucin strong candidates as DNA from patients recruited for extremes phenotype was analyzed by Southern blot or PCR define variable number tandem repeat (VNTR) length polymorphisms MUC1, MUC2, MUC5AC, MUC7. VNTR were tested association with severity linkage disequilibrium (LD) flanking single...
Despite modern sequencing efforts, the difficulty in assembly of highly repetitive sequences has prevented resolution human genome gaps, including some coding regions genes with important biological functions. One such gene, MUC5AC, encodes a large, secreted mucin, which is one two major mucins airways. The MUC5AC region contains gap reference (hg19) across repetitive, and complex central exon. This exon predicted to contain imperfect tandem repeat multiple conserved cysteine-rich (CysD)...
Adenosine is a multifaceted signaling molecule mediating key aspects of innate and immune lung defenses. However, abnormally high airway adenosine levels exacerbate inflammatory diseases. This study identifies the mechanisms regulating elimination from apical surface human epithelia. Experiments conducted on polarized primary cultures nasal bronchial epithelial cells showed that extracellular eliminated by metabolism cellular uptake. The conversion to inosine was completely inhibited...
It is not known why severe cystic fibrosis (CF) liver disease (CFLD) with portal hypertension occurs in only ~7% of people CF. We aimed to identify genetic modifiers for CFLD improve understanding mechanisms.
Previous reports of lung function in cystic fibrosis (CF) patients with liver disease have shown worse, similar, or even better forced expiratory volume 1 second (FEV1), compared to CF without disease. Varying definitions likely contribute these inconsistent relationships reported between and We retrospectively evaluated spirometric data 179 subjects (62% male; 58% Phe508del homozygous) severe (CFLD; defined by presence portal hypertension due cirrhosis). FEV1 values were referenced both a...
Genome wide association studies (GWAS) have identified several genomic loci with candidate modifiers of cystic fibrosis (CF) lung disease, but only a small proportion the expected genetic contribution is accounted for at these loci. We leveraged expression data from CF cohorts, and Genotype-Tissue Expression (GTEx) reference sets multiple human tissues to generate predictive models, which were used impute transcriptional regulation variance in our GWAS population. The imputed gene was tested...
Calcineurin inhibitors (CIs) cyclosporin and tacrolimus form the basis for immunosuppression in lung transplantation, yet also exert biological effects on nonlymphoid tissue. With advent of inhaled cyclosporin, we hypothesize that airway epithelium is subject to CI at high doses. The aim this study was identify human tracheobronchial epithelial cell (hTBEC) calcineurin gene expression quantify CIs hTBEC growth, interleukin‐1‐β stimulated IL‐8 production phenotype. Cyclophillin B...
Published genome-wide association studies (GWASs) identified an intergenic region with regulatory features on chr11p13 associated cystic fibrosis (CF) lung disease severity. Targeted resequencing in n=377, followed by imputation to n=6,365 CF subjects, was used identify unrecognized genetic variants (including indels and microsatellite repeats) phenotype. Highly significant associations were strong linkage disequilibrium seen only Phe508del homozygous indicating a CFTR genotype-specific mechanism.