Extended longevity is often correlated with increased resistance against the deleterious effects of environmental and physiological stresses, including heat and oxidative stresses. Our previous results suggested that the C. elegans heat-shock transcription factor (HSF-1), a master regulator of the cellular response to heat stress, is under direct regulation of the insulin/IGF-1-like signaling (IIS) networks to modulate the rate of aging and the onset of age-related diseases associated with proteotoxicity. The ultimate goal of our research is to develop new therapeutic strategies for combating age-related disease by understanding how HSF-1 influences the aging process. We have previously demonstrated that the rate of aging can be influenced by the level of HSF-1 activity in C. elegans, and that HSF-1 activity is required for daf-2 mutations to extend lifespan. Our recent findings suggest that IIS may control HSF-1 activity by regulating the formation of an inhibitory protein heterocomplex (DHIC) containing HSF-1, HSB-1, and two novel HSF-1 regulators, DDL-1 and -2. We found that the formation of DHIC is largely inhibited when IIS is reduced or when DDL-1 is phosphorylated at the T182 residue. We also found that the phosphorylation status of DDL-1 is regulated by IIS. Based on these observations, this proposal will focus on: 1) Further defining the role of DHIC complex in HSF-1 regulation. In this aim, we will develop a BiFC reporting system to verify the formation of DHIC in vivo and use it as a read-out to identify additional regulators of DHIC formation. We will also determine the structural requirements for the DHIC complex formation. 2) Determining the mechanism by which IIS regulates DDL-1 phosphorylation and DHIC formation. In the proposed studies, we will determine how the IIS pathway regulates DDL-1 phosphorylation and the formation of DHIC. 3) Identifying and characterizing additional regulators and effectors of HSF-1. Both heat-shock and reduction of IIS promotes an increase in the post- translational modifications (PTM) of HSF-1. In this aim, we will investigate the impacts of these PTMs on HSF- 1 activity. In addition, we will further characterize a number of novel HSF-1 regulators previously identified from a genetic screen.

Public Health Relevance

Studies in a variety of organisms have revealed that extended longevity is often correlated with increased resistance against the deleterious effects of environmental and physiological stresses. Our previous results suggested that heat-shock transcription factor (HSF-1), a master regulator of the cellular response to heat stress, acts in concert with the insulin-like signaling networks to modulate the rate of aging and the onset of age-related disease. Understanding the role of HSF-1 in regulating longevity and aging can help us achieve the ultimate goal of our research, which is to develop new therapeutic strategies for combating age-related diseases, such as cancer and neurodegenerative diseases.

Agency
National Institute of Health (NIH)
Institute
National Institute on Aging (NIA)
Type
Research Project (R01)
Project #
5R01AG028516-07
Application #
8669895
Study Section
Cellular Mechanisms in Aging and Development Study Section (CMAD)
Program Officer
Finkelstein, David B
Project Start
2006-07-01
Project End
2018-05-31
Budget Start
2014-06-01
Budget End
2015-05-31
Support Year
7
Fiscal Year
2014
Total Cost
$318,775
Indirect Cost
$113,775
Name
University of Michigan Ann Arbor
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
073133571
City
Ann Arbor
State
MI
Country
United States
Zip Code
48109
Yuan, Yiyuan; Hakimi, Parvin; Kao, Clara et al. (2016) Reciprocal Changes in Phosphoenolpyruvate Carboxykinase and Pyruvate Kinase with Age Are a Determinant of Aging in Caenorhabditis elegans. J Biol Chem 291:1307-19
Vukoti, Krishna; Yu, Xiaokun; Sheng, Quanhu et al. (2015) Monitoring newly synthesized proteins over the adult life span of Caenorhabditis elegans. J Proteome Res 14:1483-94
Zhang, Bi; Xiao, Rui; Ronan, Elizabeth A et al. (2015) Environmental Temperature Differentially Modulates C. elegans Longevity through a Thermosensitive TRP Channel. Cell Rep 11:1414-24
Horikawa, Makoto; Sural, Surojit; Hsu, Ao-Lin et al. (2015) Co-chaperone p23 regulates C. elegans Lifespan in Response to Temperature. PLoS Genet 11:e1005023
Kumsta, Caroline; Ching, Tsui-Ting; Nishimura, Mayuko et al. (2014) Integrin-linked kinase modulates longevity and thermotolerance in C. elegans through neuronal control of HSF-1. Aging Cell 13:419-30
Chiang, Wei-Chung; Tishkoff, Daniel X; Yang, Bo et al. (2012) C. elegans SIRT6/7 homolog SIR-2.4 promotes DAF-16 relocalization and function during stress. PLoS Genet 8:e1002948
Chiang, Wei-Chung; Ching, Tsui-Ting; Lee, Hee Chul et al. (2012) HSF-1 regulators DDL-1/2 link insulin-like signaling to heat-shock responses and modulation of longevity. Cell 148:322-34
Yuan, Yiyuan; Kadiyala, Chandra S; Ching, Tsui-Ting et al. (2012) Enhanced energy metabolism contributes to the extended life span of calorie-restricted Caenorhabditis elegans. J Biol Chem 287:31414-26
Ching, Tsui-Ting; Hsu, Ao-Lin (2011) Solid plate-based dietary restriction in Caenorhabditis elegans. J Vis Exp :
Ching, Tsui-Ting; Chiang, Wei-Chung; Chen, Ching-Shih et al. (2011) Celecoxib extends C. elegans lifespan via inhibition of insulin-like signaling but not cyclooxygenase-2 activity. Aging Cell 10:506-19

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