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Principal Investigator: Laurel Anne Monticelli
Organization: WEILL MEDICAL COLL OF CORNELL UNIV
Fiscal Year: 2024
Award: $809,496
Funding agency: National Institute of Allergy and Infectious Diseases
PROJECT SUMMARY
In the US alone, asthma affects approximately 24 million individuals, 6 million of whom are children under the
age of 18, and is responsible for over 3,000 deaths annually1,2. A population of immune cells, called group 2
innate lymphoid cells (ILC2s), are integral in driving lung inflammatory diseases including asthma through
production of type 2 cytokines in response to tissue `alarmin' cytokine signals. Despite these advances on ILC2
function, there is a fundamental gap in our knowledge of the intracellular pathways that control this pathologic
capacity within pro-inflammatory ILC2s. In new preliminary studies, we uncovered a novel link between
intracellular changes in the structural morphology of ILC2 mitochondria and the pro-inflammatory capacity
within these cells that results in lung airway inflammation. We found that upon exposure to lung tissue
inflammatory signals, ILC2s increased mitochondrial mass and remodeled their mitochondrial morphology
network from a state of elongated `fusion' to fragmented `fission'. Furthermore, we found that inhibition of
fission during a murine model of papain allergen exposure strongly curtailed ILC2 responses and altered their
metabolic programming, thereby resulting in protection from severe lung inflammation. However, despite these
advances, fundamental gaps in knowledge remain about 1) how remodeling of mitochondrial network
morphology affects ILC2-intrinsic airway inflammation and 2) the identification of the metabolic mechanisms by
which mitochondrial dynamics control ILC2 pro-inflammatory function. Here I propose two Aims consisting of
cutting-edge techniques in cellular metabolism and immunobiology to dissect the role of mitochondrial
morphology dynamics in controlling ILC2 metabolic programming and pathological function during murine and
human allergic airway inflammation.
Terms: <0-11 years old><Activities of Daily Living><Activities of everyday life><Adoptive Transfer><Affect><Age><Allergens><Asthma><Automobile Driving><Biochemical><Bioenergetics><Body Tissues><Bronchial Asthma><Catabolism><Cell Body><Cell Communication and Signaling><Cell Function><Cell Physiology><Cell Process><Cell Signaling><Cells><Cellular Function><Cellular Physiology><Cellular Process><Cellular biology><Cessation of life><Chemicals><Child><Child Youth><Children (0-21)><Clinical><Cytokine Signal Transduction><Cytokine Signaling><D-Glucose><Data><Death><Development><Dextrose><Disease><Disorder><Economics><Effector Cell><Esteroproteases><Exposure to><Flow Cytofluorometries><Flow Cytofluorometry><Flow Cytometry><Flow Microfluorimetry><Flow Microfluorometry><Generations><Glucose><Glycolysis><Human><Imaging Procedures><Imaging Technics><Imaging Techniques><Immune><Immunes><Immunobiology><Immunomodulation><Immunophysiology><Impairment><Individual><Inflammation><Inflammatory><Intermediary Metabolism><Intracellular Communication and Signaling><KO mice><Knock-out Mice><Knockout Mice><Knowledge><LC/MS><Link><Lung><Lung Inflammation><Lung Parenchyma><Lung Respiratory System><Lung Tissue><Lymphoid Cell><Metabolic><Metabolic Processes><Metabolism><Mice><Mice Mammals><Mitochondria><Modern Man><Molecular><Morphology><Murine><Mus><Null Mouse><Nutrient><Papain><Pathologic><Pathway interactions><Peptidases><Peptide Hydrolases><Physicians><Pilot Projects><Pneumonitis><Population><Production><Protease Gene><Proteases><Proteinases><Proteolytic Enzymes><Public Health><Pulmonary Inflammation><RNA Seq><RNA sequencing><RNAseq><Role><Scientist><Signal Transduction><Signal Transduction Systems><Signaling><Source><Structure of parenchyma of lung><Subcellular Process><Techniques><Testing><Therapeutic><Tissues><ages><airway epithelium inflammation><airway inflammation><allergic airway epithelium inflammation><allergic airway inflammation><asthma patient><asthmatic><asthmatic patient><biological signal transduction><cell biology><chronic inflammatory lung disease><conditional knock-out><conditional knockout><cytokine><daily living function><daily living functionality><developmental><driving><economic><flow cytophotometry><functional ability><functional capacity><glucose metabolism><glucose uptake><immune modulation><immune regulation><immunologic reactivity control><immunomodulatory><immunoregulation><immunoregulatory><improved><inflammatory lung disease><kids><liquid chromatography mass spectrometry><live cell image><live cell imaging><live cellular image><live cellular imaging><lung development><mitochondria fitness><mitochondrial><mitochondrial fitness><mitochondrial membrane><mouse model><murine model><novel><pathway><pilot study><prevent><preventing><pulmonary><respiratory inflammation><respiratory tract inflammation><response><restraint><social role><transcriptome sequencing><transcriptomic sequencing><youngster>