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Our Work

Our current work focuses on the mechanisms and the role perturbation of autophagy plays in neurodegeneration and neuroinflammation after brain injury and during brain aging. We are also investigating whether inhibition of autophagy and lysosomal function contributes to increased prevalence of neurodegenerative diseases in patients with history of TBI. Finally, we are looking at the interaction between autophagy and lipid metabolism and their contribution to neuroinflammation after TBI and during brain aging.

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Why is autophagy inhibited in microglia and macrophages after TBI?

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Above: DESI-MSI demonstrating cholesterol ester (CE 18:0) accumulation in the perilesion area and in both ipsi- and contra-lateral hippocampus after TBI. DESI images generated in collaboration with the lab of Dr. Maureen Kane, UMSOP.

Background: IF image showing lipid accumulation (BODIPY - green) in microglia/macrophages (IBA1 - purple) with inhibited autophagy (p62 - red).

We recently demonstrated that autophagy is inhibited in activated microglia and infiltrating macrophages after TBI and that this inhibition exacerbates inflammatory responses and contributes to poor functional outcomes after injury. We are now investigating the mechanisms causing this inhibition of autophagy. We hypothesize that similar to what is observed in atherosclerosis and multiple sclerosis, phagocytosis of lipid and especially cholesterol-rich myelin debris leads to lysosomal damage and consequent defects in autopahgy.

Does autophagy contribute to increased prevalence of neurodegenerative diseases after TBI?

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RNAseq data demonstrating differential gene expression patterns during aging of the mouse brain with and without prior exposure to TBI (at 2 months).

Inhibition of autophagy is known to contribute to development of many age-related neurodegenerative diseases. Our data indicate that autopahgy is also inhibited in neurons and microglia after TBI. We hypothesize that the TBI-induced inhibition of auophagy may contribute to increased predisposition to neurodegenrative disease in individuals with history of TBI. To test this hypothesis we are comparing brain aging trajectories in mice with wnd without exposure to TBI.

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How do changes in autophagy affect microglial lipid metabolism during brain aging?

Brain has higher lipid content than any other tissue except adipose and contains up to 25% of body cholesterol. Recent data indicate that lipid environment can affect cellular processes, including autophagy-lysosomal function. Coversely, autophagy is involved in cellular lipid metabolism, including lipid efflux. We are using transgenic mouse movels and in vitro studies to dissect interaction between lipid metabolism and autophagy after TBI and during brain aging.

Right: LC-MS/MS data demonstrating differential lipid abundance in lysosomes purified from young (3 month old) and aged (18 month old) mouse cortex. Left panel - PCA analysis demonstrating significant differences in lysosomal lipid profiles; 95% confidence intervals are shown. Right panel - heatmap displaying top differential features. Data generated in collaboration with the lab of Dr. Jace Jones, UMSOP.

Background: IF image demonstrating continued presence of lipid droplets (BODIPY - green) in the injured mouse cortex 4 months after TBI.

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What is the role of LC3 associated phagocytosis (LAP) in TBI?

In addition to canonical autophagy, an autophagy related pathway termed LC3-associated phagocytosis (LAP) has been suggested to regulate inflammatory responses. Since LAP is needed for phagocytosis of dead cells and DAMPs which are known to accumulate after TBI, we hypothesize that it is activated after injury and involved in regulation of inflammatory responses in microglia and macrophages. We are also investigating whether LAP may participate in myelin phagocytosis.

Decreased accumulation of intracellular myelin (FluoroMyelin - green) in LAP deficient BMDM exposed to mouse myelin.

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Can we improve how we study lipid-protein interactions during brain aging?

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Interactions between proteins, lipids and metabolites, give rise to higher cellular, tissue and organismal phenotypes and functions. These interactions are affected not only by the overall tissue abundance of individual components but also by their distribution between specific cell types and localization to intracellular compartments such as lysosomes or mitochondria. Together with collaborators, Dr. Maureen Kane at UMSOP and Dr. Michael Cummings at UMCP, we are developing an analytical multi-omics pipeline to identify cell-type and organelle-specific functional relationships between lipids, proteins and metabolites, and their effects on organellar, cellular and organismal function during brain aging.

Outline of the proposed multi-omics pipeline.

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