A5068591179- Cystic Fibrosis Research Advances
- Neonatal Respiratory Health Research
- Tracheal and airway disorders
- Inhalation and Respiratory Drug Delivery
- Asthma and respiratory diseases
- Immunodeficiency and Autoimmune Disorders
- Endoplasmic Reticulum Stress and Disease
- CRISPR and Genetic Engineering
- Cancer Cells and Metastasis
- Planarian Biology and Electrostimulation
- Wireless Body Area Networks
- 3D Printing in Biomedical Research
- Heat shock proteins research
- Helicobacter pylori-related gastroenterology studies
- Fuel Cells and Related Materials
- Immune Cell Function and Interaction
- Pediatric health and respiratory diseases
- Bacillus and Francisella bacterial research
- Autophagy in Disease and Therapy
- Infant Nutrition and Health
- Genetics and Neurodevelopmental Disorders
- Chromosomal and Genetic Variations
- Phosphodiesterase function and regulation
- Corrosion Behavior and Inhibition
- Nematode management and characterization studies
Lung Institute
2014-2024
University of North Carolina at Chapel Hill
2006-2023
Johns Hopkins University
2023
Johns Hopkins Medicine
2023
Johns Hopkins Children's Center
2023
Cystic Fibrosis Research Foundation
2022
Cystic Fibrosis Foundation
2018
Indiana University School of Medicine
2016
Ivacaftor, a CFTR potentiator drug used for cystic fibrosis, destabilizes rescued ΔF508 and interferes with the action of drugs that correct function.
Rationale: Identification of the specific cell types expressing CFTR (cystic fibrosis [CF] transmembrane conductance regulator) is required for precision medicine therapies CF. However, a full characterization expression in normal human airway epithelia missing. Objectives: To identify that contribute to and function within proximal–distal axis lung. Methods: Single-cell RNA (scRNA) sequencing (scRNA-seq) was performed on freshly isolated large small epithelial cells. scRNA situ...
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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...
Summary Telomeres vary greatly in size among plants and, most higher plants, consist of a long array 5′‐TTTAGGG‐3′/3′‐AAATCCC‐5′ (TTTAGGG) repeats. Recently, telomeric DNA human, mouse, oxytricha, and trypanosome chromosomes have been found arranged into loops (t‐loops), proposed to sequester the telomere from unwanted repair events prevent activation damage checkpoints. We asked whether t‐loops exist order plant Pisum sativum (garden pea). was isolated shoots root tips germinating seeds....
Intestinal current measurements (ICM) from rectal biopsies are a sensitive means to detect cystic fibrosis transmembrane conductance regulator (CFTR) function, but have not been optimized for multicenter use. We piloted standard operating procedures (SOPs) CFTR activity by ICM and examined key questions use in clinical trials. SOPs using human were developed across three centers used characterize ion transport non-CF CF subjects (two severe mutations). All data centrally evaluated blinded...
The transmembrane Hsp40 DNAJB12 and cytosolic Hsp70 cooperate on the endoplasmic reticulum's (ER) cytoplasmic face to facilitate triage of nascent polytopic membrane proteins for folding versus degradation. N1303K is a common mutation that causes misfolding ion channel CFTR, but unlike F508del-CFTR, biogenic functional defects in N1303K-CFTR are resistant correction by modulators. reported arrest CFTR at late stage after partial assembly its N-terminal domains. intermediates clients...
Expansion of novel therapeutics to all patients with cystic fibrosis (CF) requires personalized CFTR modulator therapy. We have developed nasospheroids, a primary cell culture–based model derived from individual CF and healthy subjects by minimally invasive nasal biopsy. Confocal microscopy was utilized measure activity analyzing changes in cross-sectional area over time that resulted CFTR-mediated ion fluid movement. Both the rate change AUC were calculated. Non-CF nasospheroids active...
In cystic fibrosis (CF), defective biogenesis and activity of the transmembrane conductance regulator (CFTR) leads to airway dehydration impaired mucociliary clearance, resulting in chronic infection inflammation. The most common CFTR mutation, F508del, results a processing defect which protein is retained endoplasmic reticulum does not reach apical surface. corrector compounds address this promote mutant transfer membrane. When coupled with potentiators increase channel activity, these...
Cystic fibrosis (CF) is a lethal recessive genetic disease caused primarily by the F508del mutation in CF transmembrane conductance regulator (CFTR). The potentiator VX-770 was first CFTR modulator approved FDA for treatment of patients with gating G551D. Orkambi drug containing and corrector VX809 homozygous F508del, which has folding defects. At least 30% are heterozygous other allele encoding one many different rare mutations. Treatment VX-809 had limited success, so it important to...
Conditional reprogramming has enabled the development of long-lived, normal epithelial cell lines from mice and humans by in vitro culture with ROCK inhibitor on a feeder layer. We applied this technology to mouse small intestine create 2D intestinal monolayers (IEC monolayers) genetic models for functional analysis. IEC form colonies that proliferate layer are able maintain their genotype over long-term passage. 3D spheroids matrigel transwell inserts making them useful analyses. derived...
In cystic fibrosis (CF), deletion of phenylalanine 508 (F508del) in the transmembrane conductance regulator (CFTR) anion channel causes misfolding and premature degradation. Considering numerous effects F508del mutation on assembly processing CFTR protein, combination therapy with several pharmacological correctors is likely to be required treat CF patients. Recently, it has been reported that thymosin α-1 (Tα-1) multiple beneficial could lead a single-molecule-based for patients F508del....
Pulmonary diseases offer many targets for oligonucleotide therapeutics. However, effective delivery of oligonucleotides to the lung is challenging. For example, splicing mutations in cystic fibrosis transmembrane conductance regulator (CFTR) affect a significant cohort Cystic Fibrosis (CF) patients. These individuals could potentially benefit from treatment with splice switching (SSOs) that can modulate CFTR and restore its activity. previous studies cell culture used transfection methods...
Cyclic adenosine 3′,5′-monophosphate (cAMP)–elevating agents, such as β 2 -adrenergic receptor (β -AR) agonists and phosphodiesterase (PDE) inhibitors, remain a mainstay in the treatment of obstructive respiratory diseases, conditions characterized by airway constriction, inflammation, mucus hypersecretion. However, their clinical use is limited unwanted side effects because unrestricted cAMP elevation airways distant organs. Here, we identified A-kinase anchoring protein phosphoinositide...
RNF5 E3 ubiquitin ligase has multiple biological roles and been linked to the development of severe diseases such as cystic fibrosis, acute myeloid leukemia, certain viral infections, emphasizing importance discovering small-molecule modulators for research drug development. The present study describes synthesis a new benzo[b]thiophene derivative, FX12, that acts selective inhibitor degrader RNF5. We initially identified previously reported STAT3 inhibitor, Stattic, an dislocation misfolded...
Cystic fibrosis transmembrane conductance regulator (CFTR) modulators promote robust clinical improvements in people with cystic (pwCF) qualifying genotypes [1, 2]. A triple combination therapy consisting of two CFTR folding correctors (elexacaftor and tezacaftor) plus potentiator ivacaftor, referred to as ETI, has been approved by the FDA European agencies (<https://www.fda.gov/news-events/press-announcements/fda-approves-new-breakthrough-therapy-cystic-fibrosis>,...
Hyper IgE syndrome (STAT3-HIES), also known as Job's syndrome, is a rare immunodeficiency disease typically caused by dominant-negative STAT3 mutations. STAT3-HIES characterized chronic pulmonary infection and inflammation, suggesting impairment of innate host defense.
People with cystic fibrosis (pwCF) suffer from chronic and recurring bacterial lung infections that begin very early in life contribute to progressive failure. CF is caused by mutations the transmembrane conductance regulator (CFTR) gene, which encodes an ion channel important for maintaining proper hydration of pulmonary surfaces. When CFTR function ablated or impaired, airways develop thickened, adherent mucus contributes a vicious cycle infection inflammation. Therapeutics pwCF, called...
Cystic fibrosis, CF, occurs due to the loss of epithelial, cAMP-mediated Cl− channel, CFTR. Airway epithelia also contain a second pathway for secretion, referred as calcium activated conductance (CaCC). Several members recently identified gene family (Bestrophin) have been shown function Ca2+ channels. Bestrophin isoforms from variety species and mutations in hBestrophin1 product are associated with vitelliform macular dystrophy-type 2 (VMD2), known “Best’s disease”. We hypothesize that...