- Morimoto Aging leads to proteostasis failure at the organismal level and is associated with the increased risk for misfolding, aggregation, and neurodegenerative disease. The emphasis of this Project is on organismal proteostasis, to understand how intertissue regulation of the proteostasis network (PN) between neurons and non-neuronal tissues of C. elegans. Our goals are to establish how communication between tissues ensures healthy proteostasis, to identify the basis for failure in quality control in aging, and how expression of Tau, SOD1, and polyglutamine causes amplification of proteotoxicity directly relevant to neurodegenerative disease. C. elegans has the advantages of transparency, detailed lineage relationships, and powerful genetic and molecular tools that are ideal to assess synthesis, folding, the ubiquitin-proteasome and autophagy lysosome pathway in tissues of wild type animals during normal aging. These results will be compared to short-and-long lived animals, and exposure to acute (heat shock) and chronic (Tau, SOD1, and polyglutamine) proteotoxic stress to identify the critical components of the PN that are essential for rapid response and protection. In C. elegans and other metazoans, the PN is regulated by cell non-autonomous control; for example, the organismal heat shock response (HSR) is regulated by sensory neurons that control induction of the HSR and properties of the PN in distal somatic tissues, moreover inducibility of the HSR declines in early adulthood by signal(s) from germ line stem cells that results in reduced tissue resilience post fecundity.
The Aims are to: (1): Examine the effects of aging and proteotoxic stress on PN composition and properties. We will use proteostasis reporters (Core B) to assess and quantify folding, transport, and degradation in different tissues during development and aging, and upon exposure to physiological and proteotoxic stress, relate PN functionality to PN composition in tissues using cell type-specific transcriptomic profiling and proteomics (Cores B, C), and establish how the PN adjusts in short-and long-lived animals, (2): Examine how intertissue stress signaling in aging is affected by Tau, SOD1, and polyglutamine proteins. We will use genetic approaches to perturb the PN in neurons, muscle, intestine to identify tissue circuits and directionality of stress signaling across tissues, determine the effects of aging and expression of Tau, SOD1, and polyglutamine proteins on intertissue communication, and whether PN modulation in sending or receiving tissues can restore proteostasis against proteotoxicity, and (3): Deploy proteostasis regulators to restore organismal proteostasis in aging and neurodegeneration. With Core D, we will develop strategies for PN modulation by small molecule Proteostasis Regulators to prevent proteostasis failure during aging and proteotoxicity of Tau, SOD1, and polyglutamine. The targets will be validated using genetic approaches (RNAi and CRISPR) and proteostasis sensors (Core B). We will establish chemical strategies to reset the PN, restore stress resilience, counteract the age-dependent decline in proteostasis, and prevent proteotoxicity.

Agency
National Institute of Health (NIH)
Institute
National Institute on Aging (NIA)
Type
Research Program Projects (P01)
Project #
1P01AG054407-01A1
Application #
9491467
Study Section
Special Emphasis Panel (ZAG1)
Project Start
Project End
Budget Start
2018-09-15
Budget End
2019-05-31
Support Year
1
Fiscal Year
2018
Total Cost
Indirect Cost
Name
Northwestern University at Chicago
Department
Type
DUNS #
160079455
City
Evanston
State
IL
Country
United States
Zip Code
60201