Certain inherited modes of heart failure and several neurodegenerative diseases are characterized by protein misfolding states whose underlying mechanism(s) and pathophysiology are poorly understood. Effective therapies exist primarily as goals, not as clinical implementations. Macromolecular damage induced by oxidative stress is the sine qua non for thinking about many diseases. Our laboratory has challenged this paradigm by demonstrating that mouse hearts exhibiting protein-folding cardiomyopathy found in humans are under 'reductive stress'from an over-active antioxidative system. Decreasing the function of glucose-6-phosphate dehydrogenase (G6PD), which generates the reductant NADPH, """"""""cures"""""""" the disease in mice by ameliorating reductive stress, aggresome formation, hypertrophy, heart failure and death. This experiment defines a novel causal mechanism and implicates G6PD as a potential therapeutic target. We hypothesize that stress response and anti-oxidative pathways undergo a pathogenic transition, and become dysregulated by macromolecular stresses (e.g., misfolded proteins). We further propose that other cardiac and neurodegenerative diseases result from similar pathogenic transition. Our Pioneer Award proposal is designed to develop a robust experimental platform for exploring the mechanisms of reductive stress disease. Our work will extend from studies that model reductive stress in the genetically amenable fruit fly Drosophila melanogaster, through cultured mouse and human cells, to whole mice, and finally into patients as we work to develop diagnostic tools. Cuttingedge imaging techniques will be developed for monitoring redox couples and toxicities in living cells and tissues. Genetic screens in Drosophila will guide the identification of new genes and determine the effects of potentially therapeutic compounds that prevent reductive stress disease. Validation in mice of interacting genes and pathways will provide us target candidates for pharmacolog

Agency
National Institute of Health (NIH)
Institute
Office of The Director, National Institutes of Health (OD)
Type
NIH Director’s Pioneer Award (NDPA) (DP1)
Project #
5DP1OD006438-03
Application #
8143267
Study Section
Special Emphasis Panel (ZGM1-NDPA-B (02))
Program Officer
Wehrle, Janna P
Project Start
2009-09-30
Project End
2012-07-31
Budget Start
2011-08-01
Budget End
2012-07-31
Support Year
3
Fiscal Year
2011
Total Cost
$740,025
Indirect Cost
Name
University of Utah
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
009095365
City
Salt Lake City
State
UT
Country
United States
Zip Code
84112
Su, Kuo-Hui; Cao, Junyue; Tang, Zijian et al. (2016) HSF1 critically attunes proteotoxic stress sensing by mTORC1 to combat stress and promote growth. Nat Cell Biol 18:527-39
Grose, Julianne H; Langston, Kelsey; Wang, Xiaohui et al. (2015) Characterization of the Cardiac Overexpression of HSPB2 Reveals Mitochondrial and Myogenic Roles Supported by a Cardiac HspB2 Interactome. PLoS One 10:e0133994
Hussein, Rasha M; Benjamin, Ivor J; Kampinga, Harm H (2015) Rescue of ?B Crystallin (HSPB5) Mutants Associated Protein Aggregation by Co-Expression of HSPB5 Partners. PLoS One 10:e0126761
Banerjee Mustafi, Soumyajit; Grose, Julianne H; Zhang, Huali et al. (2014) Aggregate-prone R120GCRYAB triggers multifaceted modifications of the thioredoxin system. Antioxid Redox Signal 20:2891-906
Christians, Elisabeth S; Mustafi, Soumyajit B; Benjamin, Ivor J (2014) Chaperones and cardiac misfolding protein diseases. Curr Protein Pept Sci 15:189-204
Xie, Heng B; Cammarato, Anthony; Rajasekaran, Namakkal S et al. (2013) The NADPH metabolic network regulates human ?B-crystallin cardiomyopathy and reductive stress in Drosophila melanogaster. PLoS Genet 9:e1003544
Brewer, Alison C; Mustafi, Soumyajit Banerjee; Murray, Thomas V A et al. (2013) Reductive stress linked to small HSPs, G6PD, and Nrf2 pathways in heart disease. Antioxid Redox Signal 18:1114-27
Zhang, Huali; Limphong, Pattraranee; Pieper, Joel et al. (2012) Glutathione-dependent reductive stress triggers mitochondrial oxidation and cytotoxicity. FASEB J 26:1442-51
Benjamin, Ivor J (2012) Targeting endoglin, an auxiliary transforming growth factor ? coreceptor, to prevent fibrosis and heart failure. Circulation 125:2689-91
Christians, Elisabeth S; Benjamin, Ivor J (2012) Proteostasis and REDOX state in the heart. Am J Physiol Heart Circ Physiol 302:H24-37

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