Protein misfolding occurs in numerous human diseases including cancer, Alzheimer’s Disease, neurodegeneration, diabetes, Cystic Fibrosis, viral infections, and blindness associated with retinitis pigmentosa due to expression of misfolded P23H rhodopsin in the eye. Human cells respond to protein misfolding by activating a set of intracellular signaling pathways collectively termed the Unfolded Protein Response (UPR). UPR signaling promotes cell survival by reducing misfolded protein levels in the cell. If protein misfolding persists, UPR signaling switches to promote cell death. Our group studies the role of the UPR in the pathogenesis of these diseases that arise from protein misfolding. We characterize which molecules of the UPR are activated at different stages of disease progression. We develop genetic and chemical ways to artificially control the UPR in mammalian cells. We test if artificial manipulation of the UPR can prevent these diseases. We pursue these experiments in tissue culture or in transgenic animal models.
Our group also studies how the UPR signaling pathways determine whether to protect cells or promote cell death. Protein misfolding initially triggers protective actions by the UPR. But, if protein misfolding persists, the UPR switches to promoting cell death. What is the molecular basis for this switch in UPR activity? We examine transcriptional, translational, and post-translational mechanisms that could determine whether UPR signaling pathways are protective or proapoptotic. We pursue these experiments using mammalian cell lines.
Lin JH, Li H, Yasumura D, Cohen HR, Zhang C, Panning B, Shokat KM, LaVail MM, Walter P. IRE1 signaling affects life/death cell fate during the unfolded protein response. Science. 2007; 318: 944-949.
Lin JH, Walter P, Yen, TSB. Endoplasmic reticulum stress in disease pathogenesis. Ann Rev Pathol. 2008. 3: 399-425.
Arber S, Ladel DR, Lin JH, Frank E, Jessell TM. ETS gene Er81 controls the formation of functional connections between group Ia sensory afferents and motor neurons. Cell. 2000; 101: 485-498.
Lin JH, Saito T, Anderson DJ, Lance-Jones C, Jessell TM, Arber S. Functionally related motor neuron pool and muscle sensory afferent subtypes defined by coordinate expression ETS gene expression. Cell. 1998; 95: 393-407.
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