Many aging-related diseases are characterized by protein malfolding, accumulation, and aggregation in the endoplasmic reticulum (ER). This proposal addresses the basis for cellular toxicity of protein malfolding in the ER. The eIF2a kinase PERK coordinates transcription and translational control and promotes cell survival under conditions of ER stress. Humans and mice with mutations in PERK develop Wolcott Rallison syndrome of infantile diabetes mellitus. To identify molecular mechanisms involved in PERK's ability to protect cells from ER stress consequences, Caenorhabditis elegans will serve as a genetic model system to identify mutations that render pek-1 (the orthologue of PERK) essential (a synthetic lethal screen). The diversity of mammalian ER stress response is conserved in this model organism and genetics is a powerful means to address complex physiological processes. This screen will identify genes involved in adaptation and survival during ER stress.
The specific aims of this proposal are: 1) To screen for mutations that elicit a constitutive unfolded protein response (UPR), by identifying mutant animals that activate Green Fluorescent Protein reporter genes responsive to the UPR. 2) To stratify the mutants by the degree to which their viability or health are compromised by inactivation of either the translational or transcriptional components of UPR signaling. 3) To map and characterize mutants that display specific synthetic phenotypes with loss of PERK function and compare those with mutations that require IRE1 function.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Postdoctoral Individual National Research Service Award (F32)
Project #
1F32DK061179-01A1
Application #
6552611
Study Section
Special Emphasis Panel (ZRG1-F05 (20))
Program Officer
Hyde, James F
Project Start
2003-04-01
Project End
Budget Start
2003-02-01
Budget End
2004-01-31
Support Year
1
Fiscal Year
2002
Total Cost
$38,320
Indirect Cost
Name
New York University
Department
Anatomy/Cell Biology
Type
Schools of Medicine
DUNS #
City
New York
State
NY
Country
United States
Zip Code
10016
Yun, Chi; Stanhill, Ariel; Yang, Yun et al. (2008) Proteasomal adaptation to environmental stress links resistance to proteotoxicity with longevity in Caenorhabditis elegans. Proc Natl Acad Sci U S A 105:7094-9