Small molecule toxins have been found to be epidemiologically linked to a number of protein misfolding diseases. Using arsenite (As(lll)) as a model system, the potential role of environmental toxins on altering the global protein fold in vivo will be analyzed. The mechanism of As(lll)-induced protein misfolding will be evaluated by comparing the proteins found to be misfolded in As(lll)-treated cells and proteins that are found to bind As(lll) in situ. As(lll)-induced misfolding will be further characterized by comparisons between the misfolded proteins in As(lll) treated cells and misfolded proteins in cells treated with other stress- inducing agents, allowing the mechanism of As(lll)-induced misfolding to be elucidated. Using the methods outlined in this proposal, the role of the Integrated Stress Response and AIRAP in protecting cells against As(lll) toxicity will be also be examined. This work will not only identify potential therapeutic targets for the numerous human populations predisposed to human disease by As(lll) exposure, but it will also allow for a better understanding of the role environmental toxins play in predisposing populations to protein misfolding diseases of aging and neurodegeneration. ? ? ?

Agency
National Institute of Health (NIH)
Institute
National Institute of Environmental Health Sciences (NIEHS)
Type
Postdoctoral Individual National Research Service Award (F32)
Project #
5F32ES014775-03
Application #
7391586
Study Section
Special Emphasis Panel (ZRG1-F05-J (20))
Program Officer
Humble, Michael C
Project Start
2006-04-01
Project End
2009-03-31
Budget Start
2008-04-01
Budget End
2009-03-31
Support Year
3
Fiscal Year
2008
Total Cost
$48,796
Indirect Cost
Name
New York University
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
121911077
City
New York
State
NY
Country
United States
Zip Code
10016
Wiseman, R Luke; Zhang, Yuhong; Lee, Kenneth P K et al. (2010) Flavonol activation defines an unanticipated ligand-binding site in the kinase-RNase domain of IRE1. Mol Cell 38:291-304
Wiseman, R Luke; Chin, King-Tung; Haynes, Cole M et al. (2009) Thioredoxin-related Protein 32 is an arsenite-regulated Thiol Reductase of the proteasome 19 S particle. J Biol Chem 284:15233-45