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Innate immune regulation of lung inflammation through mitochondrial dynamics

通过线粒体动力学调节肺部炎症的先天免疫

基本信息

批准号：
10659953
负责人：
Laurel Anne Monticelli
金额：
$ 80.95万
依托单位：
WEILL MEDICAL COLL OF CORNELL UNIV
依托单位国家：
美国
项目类别：
财政年份：
2023
资助国家：
美国
起止时间：
2023-05-02 至 2027-04-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10659953
关键词：
Activities of Daily Living Adoptive Transfer Affect Age Allergens Asthma Automobile Driving Biochemical Bioenergetics Catabolism Cell physiology Cells Cellular biology Cessation of life Chemicals Child Clinical Cytokine Signaling Data Development Disease Economics Effector Cell Exposure to Flow Cytometry Generations Glucose Glycolysis Human Imaging Techniques Immune Immunobiology Impairment Individual Inflammation Inflammatory Knockout Mice Knowledge Link Lung Lymphoid Cell Metabolic Metabolism Mitochondria Molecular Morphology Mus Nutrient Papain Pathologic Pathway interactions Peptide Hydrolases Physicians Pilot Projects Population Production Public Health Pulmonary Inflammation Role Scientist Signal Transduction Source Structure of parenchyma of lung Techniques Testing Therapeutic Tissues airway inflammation allergic airway inflammation asthmatic asthmatic patient chronic inflammatory lung disease conditional knockout cytokine glucose metabolism glucose uptake immunoregulation improved inflammatory lung disease liquid chromatography mass spectrometry live cell imaging lung development mitochondrial fitness mitochondrial membrane mouse model novel prevent response restraint transcriptome sequencing

项目摘要

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.

项目总结