The Tan lab studies molecular and biochemical mechanisms of cellular quality control in aging and age-related disease. We search for essential, unifying molecular principles behind complex stress responses, and dissect the underlying mechanisms using multidisciplinary methods including molecular biology, biochemistry, cell biology, and genetics. We are actively working on two broad directions. (1) Lysosomal quality control mechanisms in response to cellular stress stimuli: Lysosomes are known as the longevity-promoting organelles, the dysfunction of which is commonly found in aging and age-related diseases including all kinds of dementia. We are searching for universal mechanisms underlying lysosomal quality control in response to diverse age-related cellular stresses, with the goal of discovering new strategies to promote longevity through lysosomal rejuvenation. Our recent discoveries in this direction include an essential rapid lysosomal repair pathway (the PITT pathway). (2) Innate immune signaling in aging and neurodegeneration. Abnormal exposure of DNA fragments in the cytosol is a common condition during microbial infection, cell damage, organismal aging, cellular senescence, and degenerative diseases (Parkinson’s & Alzheimer’s, etc.). Such DNA exposure triggers the cGAS/STING DNA-sensing innate immune pathway to protect cells from infection but causes pathological consequences in other contexts. Our research focuses on elucidating the molecular mechanisms that underlie the detrimental functions of this pathway, including examining its interactions with lysosomes. The goal is to develop targeted interventions that can inhibit its pathogenic effects while preserving its antimicrobial activity. Our recent progress in this direction includes a conserved ion channel function of STING that mediates noncanonical autophagy and STING-dependent cell death.
Rotation projects include: 1) biochemical screening of lysosomal stress response pathways using established LysoTurboID cells; 2) CRISPR screens searching for molecular mechanisms underlying STING-dependent cell death; and 3) examine the impact of the PITT pathway on the aggregate clearance activity of microglia.
More information can be found at JayTanLab.org