Wednesday, May 8, 2024
5/8/2024
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.
HHS’ Tracking Accountability in Government Grants System (TAGGS) website provides access to detailed descriptions of grants, loans, aggregated direct payments and other types of financial assistance awarded by the HHS Operating Divisions (OPDIVs) and the Office of the Secretary Staff Divisions (STAFFDIVs).
