A5022315311- Digestive system and related health
- Cystic Fibrosis Research Advances
- Helicobacter pylori-related gastroenterology studies
- Gastrointestinal motility and disorders
- Ion Transport and Channel Regulation
- Celiac Disease Research and Management
- IL-33, ST2, and ILC Pathways
- Immunodeficiency and Autoimmune Disorders
- Viral gastroenteritis research and epidemiology
- Endoplasmic Reticulum Stress and Disease
- Genetic factors in colorectal cancer
- Inhalation and Respiratory Drug Delivery
- Congenital gastrointestinal and neural anomalies
- Neonatal Respiratory Health Research
- Inflammatory Bowel Disease
- Gut microbiota and health
- Inflammasome and immune disorders
- Child Nutrition and Feeding Issues
- Gastrointestinal disorders and treatments
- Neutrophil, Myeloperoxidase and Oxidative Mechanisms
- Lipid Membrane Structure and Behavior
- Tracheal and airway disorders
- Intestinal Malrotation and Obstruction Disorders
- Single-cell and spatial transcriptomics
- Pharmaceutical studies and practices
Boston Children's Hospital
2016-2025
Harvard University
2016-2025
Boston Children's Museum
2017-2024
Boston University
2022-2024
SickKids Foundation
2020
University of California, San Francisco
2002-2013
Massachusetts General Hospital
2012-2013
MaineGeneral Medical Center
2013
University of Virginia
2002
King's College London
2001-2002
Secretory diarrhea is the leading cause of infant death in developing countries and a major morbidity adults. The cystic fibrosis transmembrane conductance regulator (CFTR) protein required for fluid secretion intestine airways and, when defective, causes lethal genetic disease fibrosis. We screened 50,000 chemically diverse compounds inhibition cAMP/flavone-stimulated Cl(-) transport epithelial cells expressing CFTR. Six CFTR inhibitors 2-thioxo-4-thiazolidinone chemical class were...
Secretory diarrhea is the leading cause of infant death in developing countries and a major morbidity adults. The cystic fibrosis transmembrane conductance regulator (CFTR) protein required for fluid secretion intestine airways and, when defective, causes lethal genetic disease fibrosis. We screened 50,000 chemically diverse compounds inhibition cAMP/flavone–stimulated Cl– transport epithelial cells expressing CFTR. Six CFTR inhibitors 2-thioxo-4-thiazolidinone chemical class were...
Reactive oxygen species (ROS) regulate the activities of inflammasomes, which are innate immune signaling organelles that induce pyroptosis. The mechanisms by ROS control inflammasome unclear and may be multifaceted. Herein, we report protein gasdermin D (GSDMD), forms membrane pores upon cleavage inflammasome-associated caspases, is a direct target ROS. Exogenous endogenous sources ROS, ROS-inducing stimuli prime cells for pyroptosis induction, promote oligomerization cleaved GSDMD, leading...
Next-generation sequencing has enabled precision therapeutic approaches that have improved the lives of children with rare diseases. Congenital diarrhea and enteropathies (CODEs) are associated high morbidity mortality. Although treatment these disorders is largely supportive, emerging targeted therapies based on genetic diagnoses include specific diets, pharmacologic treatments, surgical interventions. We analyzed exomes or genomes infants suspected monogenic congenital diarrheal disorders....
TMEM16A was found recently to be a calcium-activated CU channel (CaCC). CaCCs perform important functions in cell physiology, including regulation of epithelial secretion, cardiac and neuronal excitability, smooth muscle contraction. CaCC modulators are potential utility for treatment hypertension, diarrhea, cystic fibrosis. Screening drug natural product collections identified tannic acid as an inhibitor TMEM16A, with IC50 ∼ 6 µM ∼100% inhibition at higher concentrations. Tannic inhibited...
Significance The extracellular production of hydrogen peroxide (H 2 O ) by membrane or secreted oxidases has been linked to epithelial wound repair, defense against infection, and inflammation. Here, we elucidate the pathway that explains how H transduces a signal into cell induce these critical functions. Our study shows central component this in mammalian colon is -conducting aquaglyceroporin AQP3 implicates channel innate immune responses at mucosal surfaces.
Epithelial cells lining mucosal surfaces of the gastrointestinal and respiratory tracts uniquely express ERN2/IRE1β, a paralogue most evolutionarily conserved endoplasmic reticulum stress sensor, ERN1/IRE1α. How ERN2 functions at host-environment interface why second evolved remain incompletely understood. Using conventionally raised germ-free Ern2-/- mice, we found that was required for microbiota-induced goblet cell maturation mucus barrier assembly in colon. This occurred only after...
Importance Newborn genome sequencing (NBSeq) can detect infants at risk for treatable disorders currently undetected by conventional newborn screening. Despite broad stakeholder support NBSeq, the perspectives of rare disease experts regarding which diseases should be screened have not been ascertained. Objective To query about their on NBSeq and gene-disease pairs they consider appropriate to evaluate in apparently healthy newborns. Design, Setting, Participants This survey study, designed...
A novel long wavelength fluorescent Cl− indicator was used to test whether endosomal conductance provides the principal electrical shunt permit acidification. The green Cl−-sensitive chromophore 10,10′-bis[3-carboxypropyl]-9,9′-biacridinium dinitrate (BAC) conjugated aminodextran together with red Cl−-insensitive tetramethylrhodamine (TMR). BAC fluorescence is pH-insensitive and quenched by Cl−with a Stern-Volmer constant of 36 m−1. Endosomes in J774 Chinese hamster ovary (CHO) cells were...
Two aquaporin (AQP)-type water channels are expressed in mammalian cornea, AQP1 endothelial cells and AQP5 epithelial cells. To test whether these aquaporins involved corneal fluid transport transparency, we compared thickness, permeability, response to experimental swelling wild type mice transgenic null lacking AQP5. Corneal thickness fixed sections was remarkably reduced increased mice. By z-scanning confocal microscopy, vivo (in μm, mean ± S.E.,n = 5 mice) 123 1 (wild type), 101 2 (AQP1...
Recent evidence has implicated the involvement of aquaporins (AQPs) in cellular functions that are unrelated to transepithelial water transport. Although AQPs expressed gastrointestinal tract, their importance so far been unclear. AQP3 is a water/glycerol transporter at basolateral membrane colonic epithelial cells. The aim this study was investigate enterocyte proliferation using mouse models inflammatory bowel disease.Expression and function epithelium were established. Colitis induced...
<h3>Background</h3> Rotavirus is the most common cause of severe secretory diarrhoea in infants and young children globally. The rotaviral enterotoxin, NSP4, has been proposed to stimulate calcium-activated chloride channels (CaCC) on apical plasma membrane intestinal epithelial cells. We previously identified red wine small molecule CaCC inhibitors. <h3>Objective</h3> To investigate efficacy a extract synthetic molecule, CaCC<sub>inh</sub>-A01, inhibiting CaCCs diarrhoea. <h3>Design</h3>...
Background & AimsConstipation is a common clinical problem that negatively impacts quality of life and associated with significant health care costs. Activation the cystic fibrosis transmembrane conductance regulator (CFTR) chloride channel primary pathway drives fluid secretion in intestine, which maintains lubrication luminal contents. We hypothesized direct activation CFTR would cause reverse excessive dehydration stool found constipation.MethodsA cell-based, high-throughput screen was...
IRE1β is an ER stress sensor uniquely expressed in epithelial cells lining mucosal surfaces. Here, we show that intestinal expressing have attenuated unfolded protein response to stress. When modeled HEK293 and with purified protein, diminishes expression inhibits signaling by the closely related IRE1α. can assemble inhibit IRE1α suppress stress-induced XBP1 splicing, a key mediator of response. In comparison IRE1α, has relatively weak splicing activity, largely explained nonconserved amino...
Background & AimsMutations in the tetratricopeptide repeat domain 7A gene (TTC7A) cause intestinal epithelial and immune defects. Patients can become deficient develop apoptotic enterocolitis, multiple atresia, recurrent stenosis. The disease patients with TTC7A deficiency is severe untreatable, it recurs despite resection or allogeneic hematopoietic stem cell transplant. We screened drugs for those that prevent apoptosis of cells tested their effects an animal model disease.MethodsWe...
Airway submucosal glands have been proposed as a primary site for initiating and sustaining airway disease in cystic fibrosis (CF). However, it has difficult to define the role of CFTR gland fluid secretion because concerns interpreting experiments on diseased CF human airways subjected chronic infection inflammation. Here, we test by using selective inhibitor (CFTRinh-172) pig airways. Measurements single-gland rates showed inhibition both cholinergic cAMP-stimulated CFTRinh-172. Secreted...