The biology system is complicated in many senses, in particular regarding to the multiple pathways involved in initiating and regulating pathophysiological processes. We are interested in how different signaling events could interact with the cell death machinery important to these processes. In earlier studies, we defined the critical role of Bid, a pro-death Bcl-2 family protein, in the cross-talk between the death receptor pathway and the mitochondria pathway in a murine model of liver injury and hepatocyte apoptosis. We have since then found that novel signaling events are involved in the pathways, particularly when TNF-R1 is engaged. Based on our preliminary studies, we hypothesize that JNK and reactive oxygen species (ROS) are two important mechanisms that could integrate with the mitochondrial activation independently of Bid. We will address the function of JNK in promoting TNFa-induced hepatocyte apoptosis and liver injury (Aim 1) and how JNK may activate the mitochondria in a Bid-independent way (Aim 2).
In Aim 3, we will investigate the role of ROS in TNFa induced liver injury and hepatocyte apoptosis, their regulation by the NF-KB pathway and how they may activate the mitochondria in a Bid-independent manner. A variety of approaches will be taken, including the in vivo models that utilize gene knockout mice and in vivo gene knockdown by RNAi, in vitro primary cell cultures and biochemistry analysis. While the focus of this proposal is at the integration of some of the key signaling processes at the mitochondria level following TNFa stimulation, our long-term goal is to understand how different signal pathways can be integrated to determine the final outcome of a pathological process, which would be important to the development of novel therapeutics.
|Liao, Yong; Li, Min; Chen, Xiaoyun et al. (2018) Interaction of TBC1D9B with Mammalian ATG8 Homologues Regulates Autophagic Flux. Sci Rep 8:13496|
|Li, M; Fu, Y; Yang, Z et al. (2017) Measurement of the Activity of the Atg4 Cysteine Proteases. Methods Enzymol 587:207-225|
|Li, Min; Yang, Zuolong; Vollmer, Laura L et al. (2015) AMDE-1 is a dual function chemical for autophagy activation and inhibition. PLoS One 10:e0122083|
|Gallo, Luciana I; Liao, Yong; Ruiz, Wily G et al. (2014) TBC1D9B functions as a GTPase-activating protein for Rab11a in polarized MDCK cells. Mol Biol Cell 25:3779-97|
|Chen, Xi; Khambu, Bilon; Zhang, Hao et al. (2014) Autophagy induced by calcium phosphate precipitates targets damaged endosomes. J Biol Chem 289:11162-74|
|Li, Min; Khambu, Bilon; Zhang, Hao et al. (2013) Suppression of lysosome function induces autophagy via a feedback down-regulation of MTOR complex 1 (MTORC1) activity. J Biol Chem 288:35769-80|
|Lin, Chih-Wen; Zhang, Hao; Li, Min et al. (2013) Pharmacological promotion of autophagy alleviates steatosis and injury in alcoholic and non-alcoholic fatty liver conditions in mice. J Hepatol 58:993-9|
|Czaja, Mark J; Ding, Wen-Xing; Donohue Jr, Terrence M et al. (2013) Functions of autophagy in normal and diseased liver. Autophagy 9:1131-58|
|Ding, Wen-Xing; Guo, Fengli; Ni, Hong-Min et al. (2012) Parkin and mitofusins reciprocally regulate mitophagy and mitochondrial spheroid formation. J Biol Chem 287:42379-88|
|Ding, Wen-Xing; Li, Min; Biazik, Joanna M et al. (2012) Electron microscopic analysis of a spherical mitochondrial structure. J Biol Chem 287:42373-8|
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