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Research Projects

Targeting neuroinflammation and neurodegeneration

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Role of tumor necrosis factor (TNF) receptors in neuroinflammation and neurodegeneration

TNF receptor 1 and 2 (TNFR1 and TNFR2) play distinct roles in the brain. While TNFR1 activation is associated with inflammation, TNFR2 protects the brain from inflammation and damages by activating the immune system. However, it is unclear how the brain controls the expression of these two receptors and how they communicate to give rise to the biological functions in the cells.

(A) We will use highly multiplexed immunofluorescence imaging for single-cell spatial proteomics analysis to identify cell-type specific phenotypes associated with varying levels of TNFR1 and TNFR2 expression as well as to elucidate their distribution and interaction in the tissue microenvironment that contribute to Alzheimer's disease (AD) and multiple sclerosis (MS) pathogenesis and progression.

(B) We also aim to dissect the TNFR1 and TNFR2 associated signaling pathways (survival, apoptosis, necroptosis) in neurodegeneration and neuroprotection. Specifically, we investigate how TNF-TNFR1 activation and the presence of TNFR1 mutations impair autophagic and lysosomal functions and lead to neuronal cell death. 

(C) Our long-term goal is to conduct high-throughput screening and engineer brain-targeting nanoparticles to develop TNFR1 specific inhibitors (small molecules, peptides, and nanomedicine) to target neuroinflammation and neurodegeneration.

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Role of metabolic dysfunction in brain-body interaction

(A) In obesity associated metabolic disorders, lipid accumulation results in impairment of autolysosomal function, reduction in mitochondrial activity, and increased inflammation. We have demonstrated in type 2 diabetes (T2D) and non-alcoholic fatty liver disease (NAFLD) models that lysosome-targeted acidic nanoparticles (AcNPs) can restore lysosomal pH and function, thereby increasing the turnover of dysfunctional mitochondria, eventually restoring metabolic function and reducing inflammation in vitro and in vivo.

(B) There is an increasing association between obesity-related metabolic disorders with neurodegeneration pathogenesis. We aim to investigate how lipid accumulation contributes to changes in key signaling pathways such as insulin signaling and insulin resistance, as well as how it modulates the release of inflammatory cytokines and toxic lipid species that propagate to the brain.  

(C) Defective lysosomal acidification has been implicated as an early indicator and key driving factor in the pathogenesis of neurodegenerative diseases, including Alzheimer's disease (AD) and Parkinson's disease (PD). We aim to develop nanoparticles and small molecules to modulate lysosomal and autophagic functions to promote toxic protein degradation and reduce their spreading in mouse models of AD and PD.

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