Research in Yuan Lab
The research of Professor Yuan focuses on the molecular mechanisms that regulate cell death. Regulation of cell death is critical for human health. Defects in the cell death mechanisms play critical roles in the etiology of major human diseases such as cancer and neurodegeneration. Over the past two decades, the research in Yuan lab has provided major insights into the molecular mechanisms that control multiple forms of regulated cell death, including apoptosis and necroptosis. Their discoveries on apoptosis include the first demonstration of mammalian caspases as functional homologues in mediating apoptosis of mammalian cells and neurons (Gagliardini et al., 1994; Miura et al., 1993), the role of Bid as a critical signal transducer between the death receptor and mitochondrial pathway of apoptosis (Li et al., 1998), the role of caspase-11 as a critical mediator of caspase-1 activation in response to LPS stimulation (Wang et al., 1998), the role of caspases in mediating acute neurological injury (Friedlander et al., 1997) and chronic neurodegeneration (Nakagawa et al., 2000; Sanchez et al., 1999). Using tools of chemical biology, Yuan lab discovered a novel regulated necrotic cell death pathway termed necroptosis (Degterev et al., 2008; Degterev et al., 2005). This discovery disapproved the traditional belief that necrosis is a form of passive cell death caused by overwhelming stress and demonstrated a RIP1 kinase-regulated necroptosis pathway that controls this regulated form of necrotic cell death (Hitomi et al., 2008). Yuan and colleagues continue to use a creative combination of cell biology, molecular biology and chemical biology approaches to investigate multiple cellular mechanisms and pathways, including apoptosis, necroptosis and autophagy, that regulate cell death.
The discoveries of Yuan lab had initiated the transformation of apoptosis from a descriptive phenomenon to molecular understandings of cellular suicide in the past decade. With small molecules as a tool, the Yuan lab is now embarking on a journey to understand the molecular mechanisms of necrotic cell death and to explore methods to reduce the accumulation of misfolded proteins. All of these works were started from a wish to ameliorate the pain and suffering of patients with chronic neurodegenerative diseases.
Fig 1. The three fates of TNF signaling.