1. ER Stress Signal Transduction
The endoplasmic reticulum (ER) responds to the accumulation of unfolded proteins in its lumen (ER stress) by activating intracellular signal transduction pathways : the unfolded protein response (UPR). The well known three mechanistically distinct arms of the UPR regulate the expression of numerous genes that function within the secretory pathway but also affect metabolism of proteins, amino acids and lipids. Upon severe or prolonged ER stress the UPR induces apoptosis to eliminate unhealthy cells from a population. In our Lab, I will focus the study about ER stress signal transduction pathways involved in transducing the unfolded protein signal from the ER to other cellular organelles-mitochondria, nucleus or the cytosol. Through BAX inhibitor-I-an ER stress-associated protective protein, we are studing the ER stress signal transduction.
2. The Communication between cellular organelles
There are two common signal transduction pathways between ER and mitochondria. Electron uncoupling-associated ROS accumulation and Ca2+ influx and efflux system. In addition, there is a direct relation between oxidative stress and Ca2+ influx. Oxidative stress causes Ca2+ influx into the cytoplasm from the extracellular environment and from the endoplasmic reticulum or sarcoplasmic reticulum (ER/SR) through the cell membrane and the ER/SR channels, respectively. Rising Ca2+ concentration in ER causes Ca2+ influx into mitochondria and nuclei. In mitochondria Ca2+ accelerates and disrupts normal metabolism leading to cell death. In nuclei Ca2+ modulates gene transcription and nucleases that control cell apoptosis. Ca2+ can regulate phosphorylation/dephosphorylation of proteins and can modulate signal transduction pathways as a result. Since oxidative stress is associated with cardiac ischemia/reperfusion, neurodegenerative disease, inflammation-associated diseases and physiologic aging process, understanding how oxidants alter Ca2+ signaling can help to understand process of the (patho)physiologic status, and may lead to development of new drug and establishment of new strategy and basic concept. Based upon the hypothesis -ROS/Ca2+ initiated from ER can be extrapolated to mitochondria as well as nucleus, we are studying the communication between orgalleles.
3. Mitochondrial & ER associated apoptosis
BAX inhibitor-1 (BI-1) has been described both as an inhibitor of programmed cell death and as an inhibitor of ER stress-associated ER dysfunction during apoptosis. It is still not clear what biochemical activity of BI-1 is responsible for its function, but increasing evidence indicates that a functional activity of BI-1 on the endoplasmic reticulum (ER) protects mitochondria under diverse circumstances. In our lab, we recently published that, during ER stress, the BI-1 regulates ER stress-induced ROS accumulation by the expression of Heme oxygenase-1 ( Bax Inhibitor-1 Regulates Endoplasmic Reticulum Stress-associated Reactive Oxygen Species and Heme Oxygenase-1 Expression. J Biol Chem . 2007 Jul 27;282(30):21618-28 ). Based upon the starting point that ER stress can accumulate ROS, possibly linking to mitochondrial ROS spike as well as Ca2+ loading, our lab is studying about the mechanism of ER stress-associated apoptosis different from mitohcondrial cell death.
In addition, mitochondria-cell death pathway is studied now. Adriamycin can be on example for this study. Through ROS stimulator -adriamycin-related apoptosis, especially in cardiac cells, we are understanig the mitohcondria-associated cell death pathway, different from another organelle-ER-associated apoptosis.
Our lab has established the Cardiac ischemia system and Ca2+ measuring system. Using Langendorff system- classical ischemia tool, we can screen the protective medicine against cardiac ischemia/reperfusion and phsiologically study about the mechanism.
4. The development of new medicine & herbal products
Our original goal is to develop new medicine and herbal products through the above-mentioned researches. Understanding the (patho)physiology of Ca2+ and ROS in organelles and its role can lead to provide new strategy to develop drug. Half of ER stress lab members are focusing on the projects.