This is a new Program Project to investigate the role that age-related changes in autophagy play in the functional alterations and inefficient response to immunological challenges and to stress of old organisms. Four Projects involving 4 faculty members from 3 academic departments are proposed. These projects will share ideas, techniques and experimental models. Completion of most specific aims requires the participation of members from several of the projects. Degradation of intracellular components in lysosomes, or autophagy, is essential for cellular homeostasis, as an energy source when nutrients are sparse and in response to stress. The activity of the two best characterized types of autophagy, macroautophagy and chaperone-mediated autophagy, is altered in old organisms. We hypothesize that this impairment in autophagy could be behind the functional deterioration and the inability to respond to immunological challenges and to stress in old organism. To test this hypothesis we will: 1) characterize the involvement of different autophagic pathways in liver (Project 1 and 4), brain (P1) and the immune system (P2 and 3), under basal or stress conditions;2) analyze the changes with age in the autophagic system in these organs (P1-4);and 3) determine the contribution of these changes to the metabolic syndrome of aging (P4), the gradual deterioration of cognitive function (P1) and to the failure with age of two essential immune functions, antigen processing and presentation (P2) and T helper cell activation and tolerance (P3). These studies will require the synergistic cooperation of groups with expertise in autophagy, dendritic cell function, T cell biology, steatotic liver disease, lipid metabolism and oxidative cellular injury. This Program includes three Cores: the Administrative Core (Core A) provides the necessary secretarial and bookkeeping functions;the Analytical Imaging Core (Core B) provides state-of-the-art microscopy and imaging services, and the Aging and Transgenic Animal Core (Core C) provides maintenance, breeding and genotyping of the transgenic and aging mouse colonies required for this project. All four Projects are concerned with interrelated areas of cellular metabolism, molecular and cellular immunology and the biology of aging. Each proposed project represents collaborative efforts between independent investigators that will extend their individual expertise into areas that could not otherwise be effectively investigated. The four groups have been working together and will interact synergistically. Significance: These studies may ultimately lead to fundamental insights for understanding, treating or preventing the metabolic alterations and declined cognitive and immune function characteristic of elders.

Agency
National Institute of Health (NIH)
Institute
National Institute on Aging (NIA)
Type
Research Program Projects (P01)
Project #
5P01AG031782-05
Application #
8423009
Study Section
Special Emphasis Panel (ZAG1-ZIJ-2 (O3))
Program Officer
Velazquez, Jose M
Project Start
2009-02-15
Project End
2014-01-31
Budget Start
2013-02-01
Budget End
2014-01-31
Support Year
5
Fiscal Year
2013
Total Cost
$1,892,687
Indirect Cost
$752,514
Name
Albert Einstein College of Medicine
Department
Anatomy/Cell Biology
Type
Schools of Medicine
DUNS #
110521739
City
Bronx
State
NY
Country
United States
Zip Code
10461
Valdor, Rut; Mocholi, Enric; Botbol, Yair et al. (2014) Chaperone-mediated autophagy regulates T cell responses through targeted degradation of negative regulators of T cell activation. Nat Immunol 15:1046-54
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

Showing the most recent 10 out of 60 publications