Research

As the resident immune cells in the brain, microglia serve as liaisons between the immune system and CNS and are strategically located to participate in the onset and progression of CNS inflammatory responses in neurodegenerative diseases. Identifying protective and toxic pathways in microglia in neurodegeneration could lead to new therapeutic targets. Our laboratory research has identified pivotal pathways in microglia that play significant roles in neurodegenerative diseases. We have explored their contribution to inflammatory responses, including NF-kB, Akt, and cGAS-STING-IFN-I in progression of disease pathology and cognitive resilience. We have extended our novel mechanistic insights to small molecule microglial modulators that specifically target the toxic aspects of microglia responses in neurodegeneration. Future endeavors will focus on how microglia interact with other brain cells in the CNS, with the goal of establishing new, effective microglia-targeted therapeutic strategies.

Pathogenic tau accumulation plays a central role in cognitive decline in Alzheimer’s disease, and taupathies. Over the past decade, most studies have been focused on how hyperphosphorylation affects tau accumulation and aggregation. Strategies focused on inhibiting tau phosphorylation have met few successes and have serious side effects. We have unveiled the significance of tau acetylation, a departure from the traditional focus on tau phosphorylation, in the pathogenesis of Alzheimer’s disease. Our systematic approach has expanded our understanding of tau’s interactions and potential therapeutic targets. Our platform also allows for investigation of tau aggregation and spread in human iPSC-derived neurons, and to study tauopathy in organoids integrated with microglia, to further elucidate tau’s role in Alzheimer’s disease and develop novel therapeutic strategies.

Our laboratory concentrates on employing human stem cell-based technologies to discover novel mechanisms and therapeutic strategies. We have identified an aberrant neuronal network as a fundamental mechanism in abnormal development and have discovered compounds that effectively reduce endogenous tau levels. Our advanced iPSC-derived neuronal and microglial platforms are powerful tools to identify novel disease modifiers with CRISPRi/CRISPRa screening, and screen for disease-modifying compounds. The overarching objective is to continue advancing our understanding of neurodegenerative diseases and contribute to the development of innovative treatment methods.