Tremendous advances in our understanding of pathologic mechanisms have recently revealed that defective protein processing within the secretory pathway is an integral component of many genetic and environmental diseases. Diverse disease states ranging from diabetes, Alzheimer's disease, and Parkinson's disease, to hemophilia and lysosomal storage diseases have all been characterized by folding defects or impaired transport from the endoplasmic reticulum (ER). Very importantly, it has recently come to light that deregulation of protein synthesis is likely a key component in the pathogenic metastasis of a variety human cancers. When misfolded protein accumulates in the ER lumen, the cell activates the Unfolded Protein Response (UPR) to clear the malfolded proteins and restore homeostatic protein processing. When a stress is prolonged or robust, the UPR employs a genetic pathway that results in cell death. These proposed studies are focused to identify and characterize drug-like small molecule regulators of these two distinct arms of the UPR. We will investigate the hypotheses that: 1) Activation of the IRE1-XBP1 (adaptive) arm of the UPR will facilitate a prolonged recovery opportunity in pathologies where cells are burdened with an accumulation of mis-folded or poorly secreted proteins;and 2) Specific and robust activation of the PERK-eIF21-CHOP (apoptotic) arm will exacerbate the UPR and lead to cell death in malignant cells with hyper-active secretory machinery. In our preliminary studies, we have successfully screened a 66,000 compound library with Chinese Hamster Ovary (CHO) cell lines stably expressing luciferase constructs that report individually on the IRE1-XBP1 or PERK-eIF21-CHOP arms of the UPR. Having worked with a team of expert Medicinal, Organic/Synthetic and Computational Chemists we have identified some hits that productively modulate the UPR. We now propose to expand our probe database by repeating the screen with libraries of greater chemical diversity and complexity with the goal of identifying more specific and potent UPR-regulating probes.

Public Health Relevance

The long-term objective of the proposed studies is to identify novel small molecules that specifically activate adaptive or cell death arms of the unfolded protein response (UPR). We will characterize: 1) the potential of the adaptive activators as therapeutic agents for treating diseases caused by aberrant protein folding and/or trafficking;and 2) the ability of the apoptosis-inducing compounds to kill head and neck cancer cells. Small molecule UPR agonists/antagonists identified through the proposed studies will provide a convenient cost-effective means of treating patients suffering from diseases for which therapies are limited to minimally effective gene therapy or extensive costly enzyme replacement therapies.

National Institute of Health (NIH)
National Institute of Mental Health (NIMH)
Small Research Grants (R03)
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Special Emphasis Panel (ZRG1-BST-J (50))
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Yao, Yong
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University of Michigan Ann Arbor
Schools of Medicine
Ann Arbor
United States
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Cao, Stewart Siyan; Kaufman, Randal J (2011) iRhoms: ERADicating the messenger in growth control signaling. Dev Cell 20:414-6
Wu, Jun; Ruas, Jorge L; Estall, Jennifer L et al. (2011) The unfolded protein response mediates adaptation to exercise in skeletal muscle through a PGC-1?/ATF6? complex. Cell Metab 13:160-9
Zhang, Kezhong; Wang, Shiyu; Malhotra, Jyoti et al. (2011) The unfolded protein response transducer IRE1? prevents ER stress-induced hepatic steatosis. EMBO J 30:1357-75
Fribley, Andrew M; Miller, Justin R; Reist, Tyler E et al. (2011) Large-scale analysis of UPR-mediated apoptosis in human cells. Methods Enzymol 491:57-71
Fribley, Andrew M; Cruz, Patricia G; Miller, Justin R et al. (2011) Complementary cell-based high-throughput screens identify novel modulators of the unfolded protein response. J Biomol Screen 16:825-35
Malhi, Harmeet; Kaufman, Randal J (2011) Endoplasmic reticulum stress in liver disease. J Hepatol 54:795-809
Huang, Charlie C; Li, Yi; Lopez, Alex B et al. (2010) Temporal regulation of Cat-1 (cationic amino acid transporter-1) gene transcription during endoplasmic reticulum stress. Biochem J 429:215-24
Kaufman, R J; Back, S H; Song, B et al. (2010) The unfolded protein response is required to maintain the integrity of the endoplasmic reticulum, prevent oxidative stress and preserve differentiation in ýý-cells. Diabetes Obes Metab 12 Suppl 2:99-107
Greene, Teshell K; Wang, Cheng; Hirsch, Jessica D et al. (2010) In vivo efficacy of platelet-delivered, high specific activity factor VIII variants. Blood 116:6114-22
Vecchi, Chiara; Montosi, Giuliana; Zhang, Kezhong et al. (2009) ER stress controls iron metabolism through induction of hepcidin. Science 325:877-80