Our laboratory is interested in the mechanisms of aging. Aging is a chronic process associated with deteriorating physiological functions and increased risk for multiple diseases, such as cancer, cardiovascular diseases, neurodegeneration, and metabolic disorders. Our goals are to understand the biology of aging and to develop new approaches to intervene in diseases of aging. Research topics in the laboratory include autophagy, chromatin and epigenetics, immunology, and metabolism, in the broad scenarios of aging and cancer.
NUCLEAR DEGENERATION IN AGING AND CANCER
The nucleus is a central cellular entity. Our study suggests that the nucleus undergoes profound degeneration during aging and tumorigenesis. Nuclear components, including nuclear lamina and chromatin, can be degraded by autophagy (Dou et al, Nature, 2015). While autophagy is generally viewed as a cytoplasmic recycling mechanism, the degradation of nuclear materials is beginning to unravel. We are particularly interested in asking:
What are nuclear and chromatin substrates of autophagy?
How is nuclear autophagy regulated?
How does nuclear autophagy impact chromatin and the epigenome?
What are the functional roles of nuclear degeneration in aging and cancer?
THE BIOLOGY OF CELLULAR SENESCENCE
Cellular senescence, also referred to as the Hayflick limit, is a stable form of cell cycle arrest. Senescence restricts proliferation of damaged cells, and hence is a tumor suppressive mechanism. However, senescent cells accumulate in aged tissues, contributing to many age-associated diseases. Our study shows that senescent cells generate chromatin fragment in the cytoplasm, which is interpreted by the cell as a “danger signal” and activates the cytosolic DNA sensing cGAS-STING pathway, leading to inflammation (Dou et al, Nature, 2017). The pro-inflammatory feature of senescence triggers immuno-surveillance of oncogenic cells, but contributes to age-associated diseases. We aim to address several fundamental questions of senescence:
How is cytoplasmic chromatin generated and regulated?
What is the interaction between senescent cells and the immune system?
How can we target this pro-inflammatory pathway to treat diseases?
IHC of NRas in liver, immune cells are highlighted
MECHANISMS OF MAMMALIAN AGING
We are broadly interested in the biology of aging at the molecular, cellular, and organismal levels. The laboratory employs multiple mouse models to study alterations of metabolism and the immune system during aging. Our long-term goal is to develop novel approaches to treat age-related diseases and to promote “healthy aging without diseases”.