The health of the proteome is of central importance to the cell and contributes significantly to the health and lifespan of the organism. The proteome is constantly challenged by external physiological and environmental stress, and places demands upon the protein quality control machinery and the proteostasis network, to sense and respond to the expression of misfolded and damaged proteins. It is increasingly clear that acute proteotoxicity, associated with the chronic expression of disease-associated aggregation-prone proteins, is daunting to the cell. When proteostatic capacity is exceeded, the consequence can be neurodegeneration, cancer, immunological disease, or metabolic diseases. Our studies have shown that expression of an aggregation-prone protein imbalances proteostasis and destabilize other conformationally challenged, metastable proteins. During ageing, the collapse of proteostasis leads to the disruption of multiple cellular activities leading to cell dysfunction and organismal failure. The studies proposed here are to understand how diverse stress signals are sensed by individual cells and tissues in the intact metazoan animal and the roles of stress-inducible transcription factors, HSF1 and Daf-16, to integrate stress biology to enhance cytoprotective networks that suppress the deleterious consequences of ageing and disease. We propose three integrated aims: (1) At the level of the organism, to understand how stress response's in the intact metazoan are regulated by specific neurons that sense and transmit environmental and physiological stress signals to control expression of chaperones in somatic cells. We will identify the signaling pathways that transmit the thermosensory signal from the AFD neurons to regulate the cell non-autonomous control of the heat shock response and HSF1 activity in somatic cells, (2) At the cellular level, to characterize the tissue-specific expression of the family of genes encoding molecular chaperones to elucidate the underlying strategy for chaperone networks in response to stress, during development, and ageing. These studies will provide a network-level understanding of the organizational properties of the eukaryotic chaperome, and (3) At the molecular level, to characterize the regulation of HSF1 by stress-inducible acetylation and deacetylation by the NAD-dependent sirtuin, SIRT1, and the role(s) of this post-translational regulatory pathway in metabolic control of cell stress and lifespan.

Public Health Relevance

Chaperone networks and cytoprotective stress responses regulate the stability of the proteome, and consequently the health of the cell, and lifespan of the organism. An understanding of how these networks are organized and regulated has relevance to a multitude of diseases associated with protein misfolding and aggregation. The studies proposed here are to understand how diverse stress signals are sensed by individual cells and tissues in the intact animal and the roles of stress-inducible transcription factors to integrate stress biology to enhance cytoprotective networks that suppress the deleterious consequences of ageing and disease.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Research Project (R01)
Project #
5R01GM038109-26
Application #
8248752
Study Section
Special Emphasis Panel (ZRG1-BST-S (90))
Program Officer
Reddy, Michael K
Project Start
1987-04-01
Project End
2014-03-31
Budget Start
2012-04-01
Budget End
2013-03-31
Support Year
26
Fiscal Year
2012
Total Cost
$553,005
Indirect Cost
$183,439
Name
Northwestern University at Chicago
Department
Biochemistry
Type
Schools of Arts and Sciences
DUNS #
160079455
City
Evanston
State
IL
Country
United States
Zip Code
60201
Morimoto, Richard I; Cuervo, Ana Maria (2014) Proteostasis and the aging proteome in health and disease. J Gerontol A Biol Sci Med Sci 69 Suppl 1:S33-8
Ryno, Lisa M; Genereux, Joseph C; Naito, Tadasuke et al. (2014) Characterizing the altered cellular proteome induced by the stress-independent activation of heat shock factor 1. ACS Chem Biol 9:1273-83
Shibata, Yoko; Morimoto, Richard I (2014) How the nucleus copes with proteotoxic stress. Curr Biol 24:R463-74
Kitamura, Akira; Inada, Noriko; Kubota, Hiroshi et al. (2014) Dysregulation of the proteasome increases the toxicity of ALS-linked mutant SOD1. Genes Cells 19:209-24
Roth, Daniela Martino; Hutt, Darren M; Tong, Jiansong et al. (2014) Modulation of the maladaptive stress response to manage diseases of protein folding. PLoS Biol 12:e1001998
van Oosten-Hawle, Patricija; Morimoto, Richard I (2014) Organismal proteostasis: role of cell-nonautonomous regulation and transcellular chaperone signaling. Genes Dev 28:1533-43
Brehme, Marc; Voisine, Cindy; Rolland, Thomas et al. (2014) A chaperome subnetwork safeguards proteostasis in aging and neurodegenerative disease. Cell Rep 9:1135-50
Yu, Anan; Shibata, Yoko; Shah, Bijal et al. (2014) Protein aggregation can inhibit clathrin-mediated endocytosis by chaperone competition. Proc Natl Acad Sci U S A 111:E1481-90
Labbadia, John; Morimoto, Richard I (2013) Huntington's disease: underlying molecular mechanisms and emerging concepts. Trends Biochem Sci 38:378-85
Ciryam, Prajwal; Tartaglia, Gian Gaetano; Morimoto, Richard I et al. (2013) Widespread aggregation and neurodegenerative diseases are associated with supersaturated proteins. Cell Rep 5:781-90

Showing the most recent 10 out of 55 publications