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Principal Investigator: Elizabeth Lane
Organization: HARVARD MEDICAL SCHOOL
Fiscal Year: 2024
Award: $81,892
Funding agency: National Institute of Diabetes and Digestive and Kidney Diseases
Summary/abstract
Cystic Fibrosis (CF) is genetic disorder that effects approximately 30,000 people in the United states and more
then 70,000 worldwide. CF is caused by mutations in the epithelial chloride channel CF transmembrane
conductance regulator (CFTR) gene. In CF, loss-of-function mutations in CFTR, reduces chloride efflux from
cells, and elevates the activity of the epithelial sodium channel (ENaC) through a mechanism that is not fully
understood. This results in an increase sodium and water reabsorption, which ultimately leads to dehydration of
the epithelial surface and reduction in mucus transport in multiple mucin-producing organs, such as the lungs,
sinuses, intestine, pancreas, and reproductive organs. CF patients develop clinical symptoms in all these mucus-
producing organs. In particular, most CF patients have shortened lifespans because of loss of CFTR in the
respiratory tract, but also develop gut phenotypes early in the progression of the disease. These gut phenotypes
are less studied than the lung phenotypes of CF but still significantly impact CF patients lives. While CF is caused
by many different mutations in CFTR, the differences in CFTR function cannot explain the differences in patient
symptoms. This indicates that many of the clinical phenotypes of CF are influenced by genetic modifiers and/or
environmental factors. These genetic modifiers and environmental factors could be additional targets to develop
treatments for CF that could be used to treat all patients regardless of the mutation they harbor. However, many
of the potential genetic modifiers of CF are not well studied and the mechanism by which they modify CF
phenotypes is unknown.
Our lab has recently identified a Drosophila ortholog of the CFTR gene and established a CF model in
the fly gut epithelium. In addition to observing CF phenotypes in the gut epithelium of CFTR mutant flies, we
uncovered a micro RNA, mir263a, as a negative regulator of ENaC activity. Interestingly, the expression of
mir263a is decreased in CFTR mutant flies, suggesting that that the regulation of ENAC by CFTR is regulated
in part by mir263a. Here, I propose to further characterize the pathology of the fly mutant model including
examining how bacteria can modulate disease phenotypes in this model. I will then use the fly CF model to gain
new insight into ENaC, a known modifier of the CF phenotype. Finally, as the short lifespan, low cost, and genetic
tractability of the fly makes it an ideal model organism to perform genetic screens, I propose to identify new
potential genetic modifiers of CF. Altogether this work will establish Drosophila as a useful model to study CF
and potentially provide new molecular targets for treatment of the disease.
Terms: <0-4 weeks old><Accessory Sinuses><Affect><Assay><Bacteria><Basal Transcription Factor><Basal transcription factor genes><Bioassay><Biological Assay><CF patients><CFTR><CFTR Protein><Candidate Disease Gene><Candidate Gene><Cell Body><Cell Line><CellLine><Cells><Chloride Channels><Chloride Ion Channels><Chlorides><Clinical><Colon><Cystic Fibrosis><Cystic Fibrosis Transmembrane Conductance Regulator><Dehydration><Disease><Disease Progression><Disorder><Drosophila><Drosophila genus><ENaC><Environmental Factor><Environmental Risk Factor><Epithelial Cells><Epithelium><European><Flies><General Transcription Factor Gene><General Transcription Factors><Genes><Genetic><Genetic Alteration><Genetic Change><Genetic Diseases><Genetic Screening><Genetic defect><Germ-Free><Goals><Gut Epithelium><Human><Hydrogen Oxide><Intestinal><Intestinal Motility><Intestines><Ion Channel><Ionic Channels><Lung><Lung Respiratory System><Membrane Channels><Messenger RNA><Micro RNA><MicroRNAs><Modeling><Modern Man><Mucins><Mucous body substance><Mucoviscidosis><Mucus><Mucus Glycoprotein><Mutation><Na element><Nasal Sinuses><Nasal cavity/Paranasal><Nasal cavity/Paranasal sinuses><Newborn Infant><Newborns><Organ><Ortholog><Orthologous Gene><Other Genetics><Outcome><Pancreas><Pancreatic><Paranasal Sinuses><Pathology><Patients><Persons><Phenotype><Proliferating><Pulmonary Body System><Pulmonary Organ System><Regulation><Regulator Genes><Respiratory System><Respiratory Tracts><Respiratory tract structure><Signal Pathway><Sinus><Sodium><Strains Cell Lines><Surface><Symptoms><Therapeutic><Time><Toxic effect><Toxicities><Transcription Factor Proto-Oncogene><Transcription factor genes><Transcriptional Regulatory Elements><United States><Up-Regulation><Upregulation><Water><Work><absorption><autosome><body water dehydration><bowel><clinical phenotype><clinical relevance><clinically relevant><cohort><cost><cultured cell line><cystic fibrosis patients><cystic fibrosis transmembrane regulator><differential expression><differentially expressed><disease phenotype><drug action><dysbacteriosis><dysbiosis><dysbiotic><environmental risk><epithelial Na+ channel><epithelial sodium channel><fly><fruit fly><gastrointestinal epithelium><genetic condition><genetic disorder><genetic recessive><genome mutation><individuals with CF><individuals with cystic fibrosis><inhibitor><insight><knock-down><knockdown><life span><lifespan><loss of function mutation><mRNA><miRNA><miRNAs><microbial imbalance><microbiome><model organism><molecular targeted therapeutics><molecular targeted therapies><molecular targeted treatment><mucous><mutant><new drug target><new druggable target><new pharmacotherapy target><new therapeutic target><new therapy target><newborn child><newborn children><novel drug target><novel druggable target><novel pharmacotherapy target><novel therapeutic target><novel therapy target><overexpress><overexpression><patients with CF><patients with cystic fibrosis><pulmonary><recessive genetic trait><recessive trait><regulatory gene><reproductive organ><sensor><therapeutic target><trans acting element><transcription factor><transcriptional differences>