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Research Directions

Unraveling molecular mechanisms and targeting neuroinflammation and neurodegeneration

(1) Crosstalk between neuroinflammation and metabolic dysfunctions

The Lo Team investigates the crosstalk between autolysosomal/mitochondrial dysfunctions and TNF/TNFR1 mediated necroptosis (inflammatory cell death) in Alzheimer's disease (AD) and multiple sclerosis (MS). The Zeng Team studies metabolic dysfunction and inflammation in obesity-induced metabolic disorders such as non-alcoholic fatty liver disease (NAFLD) and type 2 diabetes (T2D). Both Teams have a long term goal of examining how chronic peripheral inflammation caused by obesity could induce neuroinflammation and neurodegeneration through body-brain interaction. To dissect these mechanisms, we use a range of models including primary cells, transgenic mice, and post-mortem human brain tissues, as well as multi-omics characterizations including single-cell spatial analysis.

Image 1 - crosstalk TNF and autolyso.jpg

Selected publications:

(1) Crosstalk between autolysosomal defect and TNFR1-induced necroptosis in AD (Asimakidou et al., NRR, 2023)

(2) Autolysosomal dysfunction contributes to TNFR1-mediated neuronal necroptosis in AD  (Lo et al., BioRxiv, 2023)

(3) Data mining and bioinformatics analysis for translational neuroscience (O'Connor et al., J Pharm Analysis, 2023)

(4) Metabolic dysfunctions in pancreatic/liver cells under obesity-induced T2D/NAFLD (Zeng et al., Nat Commun, 2023)

(5) Body-brain interaction in obesity-induced neuroinflammation & neurodegeneration  (Asimakidou et al., NRR, 2024)

(2) IDP misfolding and autolysosomal dysfunctions in neurodegenerative diseases 

The Lo Team is interested in conformation remodeling of toxic tau oligomers using biophysical approaches and understanding how these tau oligomers disrupt lysosomal functions and autophagy pathways in neurons and astrocytes. Furthermore, we investigate metabolic dysfunctions in reactive astrocytes when subjected to inflammatory cytokines such as TNF. The Zeng Team focuses on studying alpha-synuclein (αSyn) toxicity, including the effect of preformed fibrils (PFF) in dopaminergic neurons. Both Teams utilize primary neurons/astrocytes and mouse models of Alzheimer's disease (AD) and Parkinson's disease (PD), as well as high-resolution confocal microscopy to investigate the role of autophagy, lysosomal, and mitochondrial dysfunctions in neurodegenerative diseases.   

Image 2 - Lyso in Neuro.jpg

Selected publications: 

(1) Remodeling of toxic tau oligomers by small molecule modulators (Lo et al., Alzheimer’s & Dementia, 2019)

(2) Heterogeneity of reactive astrocytes in multiple sclerosis (Lo et al., Frontiers in Cellular Neuroscience, 2021)

(3) Impaired lysosomal acidification in microglia-mediated neuroinflammation (Quick et al., J Neuroinflammation, 2023)

(4) Neurotoxin-induced autolysosomal and mitochondrial defects in Parkinson's disease (Zeng et al., I&EC, 2019)

(5) A30P αSyn-induced autolysosomal acidification impairments in dopaminergic neurons (Lo et al., BioRxiv, 2024)

(3) Drug discovery and nanomedicine engineering for translational neurobiology

The Lo Team engineers fluorescent biosensors for fluorescence resonance energy transfer (FRET) measurements to understand protein-protein interactions in tau oligomerization as well as TNF receptor conformational dynamics. Using these biosensors, we also develop FRET-based high-throughput screening (HTS) platforms and launch drug discovery campaigns to identify small molecule and peptide-based modulators targeting toxic tau oligomers or aberrant TNFR1 signaling. The Zeng Team synthesizes novel nanomaterials and develops new drug delivery platforms to target metabolic dysfunctions and promote the clearance of toxic protein aggregates in the brain. Both Teams have research focus on developing blood-brain barrier (BBB) penetrating nanomedicine and therapeutics as well as identifying alterations in blood exosomal profiles as biomarkers for AD/PD/MS. We conduct proof-of-concept testing of these potential therapies and blood exosomal biomarkers identification using primary cells and relevant mouse models.   

Image 3 - Drug discovery and nanomedicine engineering.jpg

Selected publications: 

(1) Engineering of tau biosensors & developing HTS platforms for drug discovery (Lo et al., Bioeng & Transl Med, 2021)

(2) Small molecules & peptide-based inhibitors of TNFR1 signaling (Lo et al., Sci Sig, 2019 & Zeng et al., PNAS, 2024)

(3) Development of lysosome-acidifying nanoparticles (Zeng et al., Adv Healthc Mat, 2019 & Lo et al., ACS Nano, 2024)

(4) Defective lysosomal acidification as prognostic marker & therapeutic target  (Lo & Zeng, Transl Neurodegener, 2023)

(5) Engineering of BBB penetrating therapeutics to target AD/PD/MS (Asimakidou et al., Pharmaceuticals, 2024)

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