Genetic studies have clearly shown that the rate of aging, like many other biological processes, is subject to regulation. Our previous results suggested that the C. elegans heat-shock transcription factor (HSF-1), a master regulator of the cellular response to heat stress, acts in concert with the insulin/IGF-1-like signaling networks to regulate the rate of aging and the onset of age-related disease. By understanding how HSF-1 influences the aging process, the ultimate goal of our research is to develop new therapeutic strategies for combating age-related disease. We believe that HSF-1 plays a crucial role in the DAF-2 insulin/IGF-1-like signaling network to influence longevity. 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 the activity of HSF-1, like DAF-16, can be regulated directly by the DAF-2 insulin/IGF-1-like signaling. In addition, we have identified two novel genes, ddl-1 and ddl-2, that might influence longevity by negatively regulating the HSF-1 activity. Based on these observations, this proposal will focus on: 1) Determining the role of HSF-1 in the insulin/IGF-1-like signaling network to influence aging. In the proposed studies, we will determine how the DAF-2 pathway regulates the activity of HSF-1, and how HSF-1 interacts with other components of the DAF-2 pathway. 2) Characterizing two novel longevity genes, ddl-1 and ddl-2, that might function in the HSF-1 pathway to determine longevity. We will examine whether HSF-1 activity is regulated by ddl-1 and ddl-2, and whether these two genes exert their function by physically interacting with HSF-1. We will also investigate when and where ddl-1 and ddl-2 function to regulate longevity. 3) Identifying proteins that can regulate the activity of HSF-1 via protein-protein interactions. Previous studies in vertebrates suggest that the activity of HSF is often regulated by the interaction of HSF and its binding proteins. We will identify the proteins that may interact with HSF-1 by immuno-precipitation and mass spectrometry and confirm their role in determining lifespan. 4) Identifying additional genes in the HSF-1 pathway to regulate the rate of aging and stress resistance. We will perform genetic screens to identify mutations that can either suppress or enhance the phenotypes observed in hsf-1 over-expressing animals.

Agency
National Institute of Health (NIH)
Institute
National Institute on Aging (NIA)
Type
Research Project (R01)
Project #
5R01AG028516-05
Application #
8230617
Study Section
Cellular Mechanisms in Aging and Development Study Section (CMAD)
Program Officer
Finkelstein, David B
Project Start
2008-03-01
Project End
2013-02-28
Budget Start
2012-03-01
Budget End
2013-02-28
Support Year
5
Fiscal Year
2012
Total Cost
$237,211
Indirect Cost
$81,151
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
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; 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
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
Ching, Tsui-Ting; Paal, Alisha B; Mehta, Avni et al. (2010) drr-2 encodes an eIF4H that acts downstream of TOR in diet-restriction-induced longevity of C. elegans. Aging Cell 9:545-57