Sunday, October 6, 2024
10/6/2024
PROJECT SUMMARY Clearance of apoptotic cells (efferocytosis) is significantly reduced in lungs of patients with the fibrosing lung disorder, idiopathic pulmonary fibrosis (IPF). Mechanism/s responsible for halted efferocytosis and the potential benefit of restoring efferocytosis to fibrosis resolution has yet to be determined. The major goal of the proposed studies is to establish how AMP-activated protein kinase (AMPK) affects macrophage population dynamics, including influx of monocyte-derived transitional macrophages that promote fibrosis persistence versus efferocytosis-competent populations involved in resolution of fibrosis. Macrophage dynamics and secretome will be investigated in young-adult mice with resolving fibrosis, as well as the effect of AMPK-dependent stimulation of efferocytosis and induced fibrosis resolution in aged mice. For specific role of AMPK in lung macrophages, we will use AMPK deficient mice and adoptive transfer studies of macrophages in aged mice. The central hypothesis is that: Senomorphic effects of AMPK promotes efferocytosis and resolution of age-associated persistent lung fibrosis. Our Specific AIMs are designed to determine how AMPK activation affects macrophage phenotypes for clearance of apoptotic cells during established lung fibrosis versus resolution (AIM 1). AIM2 will establish the impact of AMPK activation in distinct areas of fibrotic vs. resolution niche, using spatial transcriptomics, with focus on AMPK-dependent regulation of mitochondrial and lysosomal biogenesis to restore efferocytotic competence in lung macrophages. AIM3 will delineate how AMPK activation reverses the non- autonomous mechanism of efferocytosis suppression. Our findings will characterize efferocytosis-competent macrophages in the fibrosis resolution niche, as well as the impact of AMPK on pro-fibrogenic population of MФs (CX3CR1+SiglecF+). Furthermore, our findings is expected to motivate clinical studies of metformin or newer classes of direct allosteric activators (e.g., MK-8722) of AMPK to test the gero-protective role of AMPK in chronic fibrotic disorders such as IPF.
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