A5031300278- Cystic Fibrosis Research Advances
- Neonatal Respiratory Health Research
- Asthma and respiratory diseases
- Inhalation and Respiratory Drug Delivery
- Congenital Ear and Nasal Anomalies
- Tracheal and airway disorders
- Pediatric health and respiratory diseases
- Advanced biosensing and bioanalysis techniques
- Advanced MRI Techniques and Applications
- CRISPR and Genetic Engineering
- MRI in cancer diagnosis
- Child Nutrition and Feeding Issues
- Genomics and Rare Diseases
- Digestive system and related health
- Gut microbiota and health
- Infant Nutrition and Health
- Interstitial Lung Diseases and Idiopathic Pulmonary Fibrosis
- Energy Harvesting in Wireless Networks
- Lanthanide and Transition Metal Complexes
- Animal Genetics and Reproduction
- Immune Response and Inflammation
- Genetic factors in colorectal cancer
- Neuroscience of respiration and sleep
- Immunodeficiency and Autoimmune Disorders
- Helicobacter pylori-related gastroenterology studies
Case Western Reserve University
2014-2024
University School
1997-2024
University of Lisbon
2023
University of Iowa
2013-2023
University Hospitals of Cleveland
2008-2021
Rainbow Babies & Children's Hospital
2005-2019
Pediatrics and Genetics
1999-2018
Western University of Health Sciences
2014
University of North Carolina at Chapel Hill
2006-2009
Center for Human Genetics
1997-1999
Polymorphisms in genes other than the cystic fibrosis transmembrane conductance regulator (CFTR) gene may modify severity of pulmonary disease patients with fibrosis.
<h3>Context</h3>A subset (≈ 3%-5%) of patients with cystic fibrosis (CF) develops severe liver disease portal hypertension.<h3>Objective</h3>To assess whether any 9 polymorphisms in 5 candidate genes (α<sub>1</sub>-antitrypsin or α<sub>1</sub>-antiprotease [SERPINA1], angiotensin-converting enzyme [ACE], glutathione S-transferase [GSTP1], mannose-binding lectin 2 [MBL2], and transforming growth factor β1 [TGFB1]) are associated CF.<h3>Design, Setting, Participants</h3>Two-stage case-control...
In vivo genome correction holds promise for generating durable disease cures; yet, effective stem cell editing remains challenging. this work, we demonstrate that optimized lung-targeting lipid nanoparticles (LNPs) enable high levels of in cells, yielding responses. Intravenously administered gene-editing LNPs activatable tdTomato mice achieved >70% lung editing, sustaining expression >80% epithelial cells 660 days. Addressing cystic fibrosis (CF), NG-ABE8e messenger RNA (mRNA)-sgR553X...
In many genetic disorders, the responsible gene and its protein product are unknown. The technique known as "reverse genetics," in which chromosomal map positions genetically linked DNA markers used to identify clone such genes, is complicated by fact that molecular distances from closest itself often too large traverse standard cloning techniques. To address this situation, a general human chromosome jumping library was constructed allows of sequences approximately 100 kilobases away any...
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...
Abstract Cftr is directly involved in myeloid cell function, contributing to the pathophysiological phenotype of CF lung. The absence or reduction CFTR function causes and results a pulmonary milieu characterized by bacterial colonization unresolved inflammation. ineffectiveness at controlling infection species such as Pseudomonas aeruginosa suggests defects innate immunity. Macrophages, neutrophils, DCs have all been shown express mRNA but low levels, raising question whether has functional...
Cystic fibrosis (CF), the most common fatal monogenic disease in United States, results from mutations CF transmembrane conductance regulator (CFTR), a chloride channel. The mechanisms by which CFTR cause lung are not fully defined but may include altered ion and water transport across airway epithelium aberrant inflammatory immune responses to pathogens within airways. We have shown that Cftr(-/-) mice mount an exaggerated IgE response toward Aspergillus fumigatus, with higher levels of...
Serum amyloid A (SAA) is a major acute-phase plasma protein synthesized by the liver. In addition to two isoforms described in humans (SAA1 and SAA2), third form (SAA3) has been demonstrated several other species distinguished predominant extrahepatic expression. Two clones, Ch11g5-1-1 HDg1-1, containing human SAA3 gene are this report. The comparable organization SAA1 SAA2 genes shares with them 87% nucleotide identity region spanning exon 3 through 4. Sequences 5′ 3, however, strikingly...
There is growing evidence for a link between gastrointestinal bacterial communities and airway disease progression in CF. We demonstrate that infants with CF ≤1 year of age show distinct stool microbiota versus control comparable age. detected associations the gut microbiome exacerbation events cohort CF, vitro studies provided one possible mechanism this observation. These data clarify current therapeutics do not establish like healthy infants, we suggest interventions direct closer to...
Question Cystic fibrosis (CF) is characterised by the accumulation of viscous adherent mucus in lungs. While several hypotheses invoke a direct relationship with cystic transmembrane conductance regulator (CFTR) dysfunction ( i.e. acidic airway surface liquid (ASL) pH, low bicarbonate (HCO 3 − ) concentration, dehydration), dominant biochemical alteration CF remains unknown. Materials/methods We novel cell line (CFTR-KO Calu3 cells) and responses human bronchial epithelial (HBE) cells from...
The study of genetic modifiers in cystic fibrosis (CF) lung disease requires rigorous phenotyping. One type association design compares polymorphisms patients at extremes phenotype, requiring accurate classification pulmonary varying ages.To evaluate approaches to quantify severity and their ability discriminate between with CF the phenotype.DeltaF508 homozygotes (n = 828) were initially classified as "severe" (approximate lowest quartile FEV(1) (% pred) for age, 8-25 yr) or "mild" (highest...
Cystic fibrosis (CF) is a common and deadly inherited disease, caused by mutations in the CFTR gene that encodes cAMP-activated chloride channel. One outstanding manifestation of disease persistent bacterial infection inflammation lung, which claims over 90% CF mortality. It has been debated whether neutrophil-mediated phagocytic innate immunity any intrinsic defect contributes to host lung defense failure. Here we compared phagosomal targeting, hypochlorous acid (HOCl) production, microbial...
High‐field preclinical MRI scanners are now commonly used to quantitatively assess disease status and the efficacy of novel therapies in a wide variety rodent models. Unfortunately, conventional methods highly susceptible respiratory cardiac motion artifacts resulting potentially inaccurate misleading data. We have developed an initial 7.0‐T implementation MR fingerprinting (MRF) methodology which has been described previously for clinical imaging applications. The MRF technology combines...
Nonsense mutations are present in 10% of patients with CF, produce a premature termination codon CFTR mRNA causing early translation, and lead to lack function. There no currently available animal models which contain nonsense mutation the endogenous Cftr locus that can be utilized test therapies. In this study, we create CF mouse model carrying G542X using CRISPR/Cas9 gene editing. The has reduced levels, demonstrates absence function, displays characteristic manifestations mice such as...
For a cystic fibrosis transmembrane conductance regulator (CFTR) channel to enter its open state, serine residues in the R domain must be phosphorylated by cAMP-dependent protein kinase, and intracellular ATP bind nucleotide-binding folds subsequently hydrolyzed. CFTR with partially removed, ΔR(708–835)-CFTR, forms chloride that opens independently of kinase A phosphorylation, probability approximately one-third wild type channel. Deletion this portion from alters response...
Patients with cystic fibrosis have a lesion in the transmembrane conductance regulator gene (CFTR), which is associated abnormal regulation of other ion channels, glycosylation secreted and cell surface molecules, vulnerability to bacterial infection inflammation lung usually leading death these patients. The exact mechanism(s) by mutation CFTR leads not clear. Mice bearing different mutations murine homolog (Cftr) (R117H, S489X, Y122X, DeltaF508, all backcrossed C57BL/6J background) were...
Dysregulated inflammation has been implicated in cystic fibrosis (CF) airway pathophysiology. The expression of inflammatory genes, like interleukin 8 (IL8), involves chromatin remodeling through histone acetylation. Inflammatory gene hyperacetylation could explain mediator dysregulation seen CF airways. airways are exposed to high levels oxidative stress, and stress increases acetylation transcription. Loss transmembrane conductance regulator (CFTR) may even reduce protection against...
The cystic fibrosis transmembrane conductance regulator (CFTR) gene encodes a cAMP-regulated chloride channel that is important in controlling the exchange of fluid and electrolytes across epithelial cells. Mutation CFTR can lead to (CF), most common lethal genetic disease Caucasians. CF systemic illness with multiple organ systems affected including pulmonary, gastrointestinal, pancreatic, immune, endocrine, reproductive systems. To understand role various tissues which it expressed, we...
Infertility is commonly associated with cystic fibrosis (CF). Although infertility in men CF has been thoroughly investigated, the observed women not well studied. To investigate female CF, we used two independently derived mouse models of CF. Both these displayed decreased fertility characterized by a reduction litter number and size. Our findings suggest that much reduced mice originates from fertilization due to inadequate sperm transport within reproductive tract. However, our data...
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...