Autophagy, the process that mediates degradation of intracellular constituents in lysosomes, is an essential component of the cellular quality control systems and of the cellular response to very different stressors. This project focuses on this role of different autophagic pathways as part of the cellular response to stress and aims to elucidate the contribution that the age-dependent changes in autophagy have on the inadequate response to stress in old organisms. During the previous period, we have identified a novel role of autophagy in the cellular response against lipotoxicity (with P4) and genotoxicity (with P3) that we will now explore in more detail in the context of aging, a condition in which we have identified a malfunctioning of two types of autophagy, macroautophagy (MA) and chaperone-mediated autophagy (CMA). In addition, we will incorporate analysis of endosomal microautophagy (eMI), an autophagic pathway that we identified in collaboration with P2, to our study. The overall goal of this proposal is 1) to elucidate the contribution of the impairment in autophagy with age to the functional deterioration and inability to orchestrate an efficient stress response in aging, 2) to understand the molecular mechanisms behind compensation among different autophagic pathways and 3) to devise interventions that could help overcome the autophagic failure in aging. The three original specific aims will be continued/expanded to address: 1) What happens to autophagy during stress? In this period we will focus on three stressors: lipotoxicity, proteotoxicity, and genotoxicity;2) What happens if autophagy does not work under stress conditions? We will utilize the recently generated conditional mouse models with compromised CMA and the ones with compromised MA to study their response to the three stressors and analyze the molecular basis of possible compensatory mechanisms among autophagic pathways; 3) Can we improve the response to stress by repairing autophagy? We will analyze the possible beneficial effect in the organ-specific response to stress of upregulating CMA by using genetic interventions and by continuing the development of chemical modulators of CMA. Relevance: Alterations in the ability to orchestrate an efficient response to stress underlie the basis of important age-related diseases. The studies in this project may provide the conceptual basis and tools for future efforts aimed at manipulating autophagy to improve the response to stress in the elderly and delay the onset of age-related diseases.

Public Health Relevance

A common characteristic of old organisms is their inability to efficiently respond to stress, which renders them vulnerable to different stressors. In fact, inadequate stress-responses have been shown to underlie the basis and/or to aggravate the course of common age-related diseases. This project investigates the contribution of malfunctioning of autophagy, one of the cellular defense systems, to the higher susceptibility of old organism to stress, and explores the possibility of upregulating this defensive mechanism with anti-aging purposes.

Agency
National Institute of Health (NIH)
Type
Research Program Projects (P01)
Project #
2P01AG031782-06A1
Application #
8739817
Study Section
Special Emphasis Panel (ZAG1)
Project Start
Project End
Budget Start
Budget End
Support Year
6
Fiscal Year
2014
Total Cost
Indirect Cost
Name
Albert Einstein College of Medicine
Department
Type
DUNS #
City
Bronx
State
NY
Country
United States
Zip Code
10461
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Cuervo, Ana Maria; Macian, Fernando (2014) Autophagy and the immune function in aging. Curr Opin Immunol 29:97-104
Quintavalle, Cristina; Di Costanzo, Stefania; Zanca, Ciro et al. (2014) Phosphorylation-regulated degradation of the tumor-suppressor form of PED by chaperone-mediated autophagy in lung cancer cells. J Cell Physiol 229:1359-68
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
Bejarano, Eloy; Yuste, Andrea; Patel, Bindi et al. (2014) Connexins modulate autophagosome biogenesis. Nat Cell Biol 16:401-14
Schneider, Jaime L; Cuervo, Ana Maria (2014) Autophagy and human disease: emerging themes. Curr Opin Genet Dev 26:16-23
Schneider, Jaime L; Cuervo, Ana Maria (2014) Liver autophagy: much more than just taking out the trash. Nat Rev Gastroenterol Hepatol 11:187-200
Cuervo, Ana Maria; Wong, Esther (2014) Chaperone-mediated autophagy: roles in disease and aging. Cell Res 24:92-104
Balch, William E; Sznajder, Jacob I; Budinger, Scott et al. (2014) Malfolded protein structure and proteostasis in lung diseases. Am J Respir Crit Care Med 189:96-103
Schneider, Jaime L; Suh, Yousin; Cuervo, Ana Maria (2014) Deficient chaperone-mediated autophagy in liver leads to metabolic dysregulation. Cell Metab 20:417-32

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