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April 10th Seminar-Does palmitate interact directly with kinases to activate signaling of ER stress



Time:       Apr. 10th (Wednesday) 9:30-10:30 am

Venue:     New Biology Building 143, Tsinghua University

Speaker:   Christina Chan, Ph.D.

                George W. Bissell Professor

                Department of Biochemistry & Molecular Biology

                Department of Chemical Engineering & Materials Science

Host:       Xuerui Yang



Dr. Christina Chan is a Professor of Chemical Engineering at Michigan State University and holds the George W. Bissell Chair. She currently is a fellow of the American Institute of Medical and Biological Engineering (AIMBE) and serves on editorial and advisory boards as well as being section and associate editor of several journals. Prior to joining MSU in 2002, Dr. Chan was a post-doctoral fellow at the Center for Engineering in Medicine at the Harvard Medical School with Professor Martin L. Yarmush. There, her research focused on applying metabolic engineering in combination with biochemical and cellular measurements to uncover the major pathways involved in the control and regulation of lipid metabolism of primary rat hepatocytes. She earned her B.S. in Chemical Engineering from Columbia University and her M.S. and Ph.D. in Chemical and Biochemical Engineering from University of Pennsylvania with Professor Stuart Churchill. Currently, her laboratory studies signaling networks using a computational and systems biology approaches in combination with biochemical and molecular biology measurements. Their goal is to elucidate pathways involved in the induction of diseases, such as obesity, Alzheimer’s disease and cancer. The group also is developing drug delivery and tissue engineering platforms to modulate the pathways for treating these diseases.


Title: Does palmitate interact directly with kinases to activate signaling of ER stress?



Improved understanding of the mechanisms of diseases (e.g., lipotoxicity, steatosis, cancer, etc.) and the identification of effective drug targets require better understanding of how environmental factors (i.e. chemicals, lipids, etc.) modulate cellular processes. Our group had developed an integrative framework that reconstructs networks of active pathways from high throughput data, which helped to identify potential pathways perturbed by saturated fatty acids. Elevated levels of fatty acids have been implicated in numerous diseases, including diabetes, cancer, etc. However, the mechanisms by which elevated levels of saturated fatty acids, namely palmitate, contribute to these diseases are unclear. Our group identified that saturated fatty acids, well studied for their roles in metabolism, can also activate signaling pathways. More recently, we found that palmitate can directly bind to kinase proteins to modulate signaling in cells.


Along those lines, our laboratory has focused on understanding how palmitate is involved in activating endoplasmic reticulum (ER) stress. The ER is a major compartment within the eukaryotic cell responsible for folding of secretory and transmembrane proteins. Research in our laboratory suggests that palmitate could modulate the ER stress response and signaling. A malfunction of the ER stress response caused by aging, genetic mutations, or environmental factors can result in diseases such as diabetes, inflammation, cancer and neurodegenerative disorders including Alzheimer's disease.

This ER stress is sensed by the cells through three ER transmembrane proteins, IRE1α (inositol-requiring enzyme 1 α), PERK (protein kinase RNA (PKR)-like ER kinase), and ATF6α (activating transcription factor 6α). They activate signaling processes to restore ER homeostasis, and are collectively termed the unfolded protein response (UPR). UPR signaling coordinate the cellular response by down-regulating protein translation, enhancing expression of ER chaperone proteins that promote protein refolding, and activating proteases involved in the degradation of misfolded proteins. Through biochemical and biophysical methods (i.e. molecular dynamics simulation, binding, and mutation studies) we found that palmitate binds directly to IRE1α to modulate the activity of this kinase protein. Finally, I will touch upon polymeric delivery platform our laboratory is developing to eventually target these pathways.


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