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Principal Investigator: Eunice Na Young Kim
Organization: STATE UNIVERSITY NEW YORK STONY BROOK
Fiscal Year: 2024
Award: $41,340
Funding agency: National Heart Lung and Blood Institute
PROJECT SUMMARY
Airway motile cilia play an important role in mucociliary clearance, the primary innate defense mechanism of
the lung, by propelling inhaled pathogens trapped in mucus up and out of the respiratory tract. Impaired ciliary
function is commonly found in patients with chronic pulmonary diseases, and genetic mutations that result in
aberrant cilia formation and loss of function often lead to the development of genetically heterogenous,
multisystem disorders called ciliopathies. The current body of literature suggests that the unique composition
and morphology of the ciliary membrane that envelopes the cilium are involved in maintaining cilia function and
homeostasis. However, the molecular players and mechanisms underlying the formation and maintenance of
the ciliary membrane remain poorly understood. The overarching objective of this proposal is to define the
physiological roles of the membrane-binding proteins ciBAR1 and 2 (formerly known as FAM92A and B) in
ciliogenesis and airway ciliated cell differentiation by using novel knockout mouse models. Both ciBAR proteins
possess a single Bin/Amphiphysin/Rvs (BAR) domain, which allows them to dimerize and form crescent-
shaped structures to preferentially sense and sculpt curved membranes. Previous studies have shown that
ciBAR1 and 2 bind to the ciliary protein Chibby1 (Cby1), which acts in preciliary vesicle recruitment and basal
body docking during early stages of ciliated cell differentiation. ciBAR 1 and 2 colocalize with Cby1 at the ciliary
base and play crucial roles in ciliogenesis, but their in vivo functions are currently unknown. The central
hypothesis of this proposal is that ciBAR1 and 2 play key roles in ciliogenesis and differentiation of
airway ciliated cells via their membrane-binding and shaping activity. To address this hypothesis, I will
use novel ciBAR1-/- and ciBAR2-/- knockout mouse models developed by our laboratory and propose the
following Specific Aims. In Aim 1, I will investigate if the loss of ciBAR1 or ciBAR2 in mice results in ciliary
defects in the trachea. In Aim 2, I will examine the roles of ciBAR proteins in formation and maintenance of
ciliary membranes during ciliogenesis using primary cell cultures, biochemical methods, and cell biological
approaches. Collectively, my proposed project will shed light on the in vivo functions of ciBAR1 and 2 in
ciliogenesis and airway ciliated cell differentiation and advance our existing knowledge of how the ciliary
membrane is generated and maintained throughout the process of ciliogenesis.
Terms: <Address><Affect><Age><Antibodies><Apical><Autoregulation><Binding><Binding Proteins><Biochemical><Biogenesis><Biologic Models><Biological><Biological Function><Biological Models><Biological Process><Biology><Biosensor><Body System><COVID-19 infection><COVID-19 virus infection><COVID19 infection><Cell Body><Cell Differentiation><Cell Differentiation process><Cell Membrane Lipids><Cell membrane><Cell surface><Cells><Centrioles><Chronic><Chronic lung disease><Cilia><Complex><Culturing, in vitro Vertebrate, Primary><Cytoplasmic Membrane><DNA Alteration><DNA Sequence Alteration><DNA mutation><Data><Defect><Defense Mechanisms><Development><Dimerization><Disease><Disorder><Distal><Docking><Drugs><Dysfunction><Endocytosis><Epithelial Cells><Exhibits><Functional disorder><Genetic mutation><Goals><Hair><Histology><Homeostasis><Human><Immunofluorescence><Immunofluorescence Immunologic><Impairment><In Vitro><Inhalation><Inhaling><Innate Immunity><KO mice><Knock-out Mice><Knockout Mice><Knowledge><Label><Laboratories><Ligand Binding Protein><Ligand Binding Protein Gene><Link><Lipids><Liposomal><Liposomes><Literature><Lung><Lung Diseases><Lung Respiratory System><Maintenance><Mammalian Cell><Mediating><Medication><Membrane><Membrane Lipids><Methods><Mice><Mice Mammals><Micro-tubule><Microtubules><Model System><Modern Man><Molecular><Molecular Interaction><Morphology><Mucociliary Clearance><Mucociliary Transport><Mucous body substance><Mucus><Murine><Mus><Native Immunity><Natural Immunity><Non-Specific Immunity><Nonspecific Immunity><Null Mouse><Organ><Organ System><Organelles><Origin of Life><Patients><Peptide Domain><Pharmaceutical Preparations><Phenotype><Phosphatides><Phospholipids><Physiologic><Physiological><Physiological Homeostasis><Physiopathology><Plasma Membrane><Play><Preventative treatment><Preventive treatment><Primary Cell Cultures><Process><Property><Protein Binding><Protein Dimerization><Protein Domains><Proteins><Pulmonary Body System><Pulmonary Diseases><Pulmonary Disorder><Pulmonary Organ System><Reporting><Research><Respiration Disorders><Respiratory Disorder><Respiratory System><Respiratory Tracts><Respiratory tract structure><Role><SARS-CoV-2 infection><SARS-CoV2 infection><Scanning Electron Microscopy><Sedimentation process><Sequence Alteration><Severe acute respiratory syndrome coronavirus 2 infection><Shapes><Staining method><Stains><Structure><System><Tertiary Protein Structure><Testing><Trachea><Trachea Proper><Tracheal Epithelium><Transmission Electron Microscopy><Vesicle><ages><amphiphysin><apical membrane><basal body><base><bases><biologic><biological sensor><bound protein><breathing disorder><cellular differentiation><chronic pulmonary disease><ciliogenesis><ciliopathy><cilium biogenesis><cilium motility><clinical phenotype><coronavirus disease 2019 infection><developmental><dimer><disease of the lung><disorder of the lung><drug/agent><genomic alteration><in vitro Assay><in vivo><infected with COVID-19><infected with COVID19><infected with SARS-CoV-2><infected with SARS-CoV2><infected with coronavirus disease 2019><infected with severe acute respiratory syndrome coronavirus 2><insight><kinetosome><loss of function><lung disorder><membrane assembly><membrane structure><mouse model><mucous><murine model><novel><pathogen><pathophysiology><plasmalemma><psychological defense mechanism><pulmonary><recruit><respiratory dysfunction><sedimentation><social role><symptom treatment><symptomatic treatment><treat symptom><wasting><windpipe>