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.

Agency
National Institute of Health (NIH)
Institute
National Institute of Mental Health (NIMH)
Type
Small Research Grants (R03)
Project #
5R03MH089782-02
Application #
7940976
Study Section
Special Emphasis Panel (ZRG1-BST-J (50))
Program Officer
Yao, Yong
Project Start
2009-09-30
Project End
2011-05-31
Budget Start
2010-06-01
Budget End
2011-05-31
Support Year
2
Fiscal Year
2010
Total Cost
$38,239
Indirect Cost
Name
University of Michigan Ann Arbor
Department
Biochemistry
Type
Schools of Medicine
DUNS #
073133571
City
Ann Arbor
State
MI
Country
United States
Zip Code
48109
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