Decreased protein degradation in aging

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Project Title: Decreased protein degradation in aging
Principal Investigators (PI): CUERVO ANA M
Project Number: 2R01AG021904-06
Organization: ALBERT EINSTEIN COL OF MED YESHIVA UNIV
 
Project Description:
[unreadable] (provided by applicant): All intracellular components are subjected to constant synthesis and degradation which guarantees their continuous renewal. This application focuses on a cellular pathway, known as chaperone-mediated autophagy (CMA), responsible for the selective removal of cytosolic proteins in lysosomes. We have previously identified that the activity of this pathway decreases with age and proposed that declined CMA activity could contribute to the intracellular accumulation of altered proteins characteristic of old organisms. The long-term goal of our study is to understand the cause(s) and consequences of the decrease in CMA activity with age and to restore normal CMA activity in old organisms and analyze the possible beneficial effects of this intervention. We will use in vitro systems with isolated lysosomes and in vivo mouse models with altered or improved CMA activity to: 1) determine the changes in the lysosomal compartment responsible for the observed instability of the receptor for CMA in old organisms; 2) identify the signaling mechanisms that regulate CMA activity; 3) analyze the systemic consequences of changes in CMA activity with age and the possible beneficial effect of multi-organ preservation of normal CMA activity until advanced ages in life-span and incidence of age-related diseases. The studies proposed in this project should provide the basis for new approaches to restore CMA in old organisms and in pathological conditions with altered activity of this catabolic pathway. RELEVANCE TO PUBLIC HEALTH: The gradual deterioration of the cellular quality control systems is in part responsible for the loss of function and the high incidence of disease as individuals age. Alteration of these systems is on the basis of detrimental metabolic and neurodegenerative disorders, highly prevalent in the aging population, such as diabetes or Alzheimer's disease. Understanding the contribution of alterations in CMA to the poor handling of altered proteins in old organisms is essential for any future efforts to improve functional performance in elders and to delay the onset of age-related diseases. [unreadable] [unreadable] [unreadable]
 
Project Terms:
20S Catalytic Proteasome 20S Core Proteasome 20S Proteasome 20S Proteosome APF-1 ATP-Dependent Proteolysis Factor 1 Abscission Age Aged 65 and Over Aging Alzheimer Alzheimer disease Alzheimer sclerosis Alzheimer syndrome Alzheimer's Alzheimer's Disease Alzheimers Dementia Alzheimers disease Autophagocytosis Body Tissues Cell Communication and Signaling Cell Function Cell Process Cell Signaling Cell physiology Cellular Function Cellular Physiology Cellular Process Chaperone Characteristics Condition Defect Degenerative Diseases, Nervous System Degenerative Neurologic Disorders Dementia, Alzheimer Type Dementia, Primary Senile Degenerative Dementia, Senile Deterioration Diabetes Mellitus Disease Disorder Effectiveness of Interventions Elderly Elderly, over 65 Excision Extirpation Future Goals HMG-20 High Mobility Protein 20 Image Impairment In Vitro Incidence Individual Intracellular Communication and Signaling Length of Life Lipid Rafts, Cell Membrane Liver Longevity Lysosomes Macropain Macroxyproteinase Mammalian Cell Mammals, Mice Mammals, Rodents Mediating Membrane Membrane Microdomains Metabolic Mice Molecular Molecular Chaperones Multicatalytic Proteinase Murine Mus Neurodegenerative Diseases Neurodegenerative Disorders Neurologic Degenerative Conditions Neurologic Diseases, Degenerative Organ Organ Preservation Organism Pathology Pathway interactions Performance Personal Satisfaction Post-Transcriptional Gene Silencing Post-Transcriptional Gene Silencings Posttranscriptional Gene Silencing Posttranscriptional Gene Silencings Primary Senile Degenerative Dementia Process Prosome Proteasome Proteasome Endopeptidase Complex Protein Degradation, Metabolic Protein Degradation, Regulatory Protein Turnover Proteins Proteosome Public Health Purpose Quality Control Quelling RNA Interference RNA Silencing RNA Silencings RNAi Receptor Protein Regulation Removal Reporter Rodent Rodentia Rodentias Screening procedure Senescence Sequence-Specific Posttranscriptional Gene Silencing Signal Transduction Signal Transduction Systems Signaling Sphingolipid Microdomains Sphingolipid-Cholesterol Rafts Stress Subcellular Process Surgical Removal System System, LOINC Axis 4 Tissues Transgenic Organisms Ubiquitin Whole Organism advanced age age dependent age related aging population autophagy base biological signal transduction body system, hepatic dementia of the Alzheimer type diabetes disease/disorder effect of intervention elders gene product geriatric imaging improved in vitro Assay in vivo late life later life life span lifespan lipid raft liver function living system loss of function membrane structure mouse model multicatalytic endopeptidase complex neurodegenerative illness new approaches novel novel approaches novel strategies novel strategy older adult older person organ system, hepatic pathway prevent preventing primary degenerative dementia protein degradation public health medicine (field) receptor resection response restoration screening screenings senescent senile dementia of the Alzheimer type senior citizen transgenic well-being
Project Title: Decreased protein degradation in aging
Principal Investigators (PI): CUERVO ANA M
Project Number: 2R01AG021904-06
Organization: ALBERT EINSTEIN COL OF MED YESHIVA UNIV
 
Project Categories:
• Natural Sciences > Aging-related markers and targets, Aging Diseases and Pathology > Biomarkers of diseases, Premature (accelerated) aging > Neurodegenerative disorders biomarkers, Aging-like consequences of smoking, hypothyroidism etc.
 
Other Information:
Fiscal Year: 2003
Project Start Date: 15 April 2003
Project End Date: 31 March 2013
Administering Institute Or Center: AG
 
Project Funding Information:
Total Funding: $340,300
Year Funding Organization Total Funding, $
2008 NATIONAL INSTITUTE ON AGING $340,300
Project Title: Decreased protein degradation in aging
Principal Investigators (PI): CUERVO ANA M
Project Number: 2R01AG021904-06
Organization: ALBERT EINSTEIN COL OF MED YESHIVA UNIV
 
Project_number Title Year FY Total Cost
There are no results for this project in database.
Project Title: Decreased protein degradation in aging
Principal Investigators (PI): CUERVO ANA M
Project Number: 2R01AG021904-06
Organization: ALBERT EINSTEIN COL OF MED YESHIVA UNIV
 
Project number Project title Organization FY Funding Organization FY Total Cost
1R21AG025355-01PROTEOMIC ANALYSIS OF DECREASED AUTOPHAGY IN AGINGALBERT EINSTEIN COL OF MED YESHIVA UNIV2004NATIONAL INSTITUTE ON AGING
$162,444
3R01AG021904-01S1DECREASED PROTEIN DEGRADATION IN AGINGALBERT EINSTEIN COL OF MED YESHIVA UNIV2004NATIONAL INSTITUTE ON AGING
$18,704
5R01AG021904-02DECREASED PROTEIN DEGRADATION IN AGINGALBERT EINSTEIN COL OF MED YESHIVA UNIV2004NATIONAL INSTITUTE ON AGING
$423,714
5R01AG021904-08DECREASED PROTEIN DEGRADATION IN AGINGALBERT EINSTEIN COL OF MED YESHIVA UNIV2010NATIONAL INSTITUTE ON AGING
$336,897
5P01AG031782-02Functional Consequences of Impaired Autophagy in AgingALBERT EINSTEIN COL OF MED YESHIVA UNIV2010NATIONAL INSTITUTE ON AGING
$2,023,075
3R01AG021904-02S1DECREASED PROTEIN DEGRADATION IN AGINGALBERT EINSTEIN COL OF MED YESHIVA UNIV2005NATIONAL INSTITUTE ON AGING
$19,083
5R01AG021904-03DECREASED PROTEIN DEGRADATION IN AGINGALBERT EINSTEIN COL OF MED YESHIVA UNIV2005NATIONAL INSTITUTE ON AGING
$393,721
5R21AG025355-02PROTEOMIC ANALYSIS OF DECREASED AUTOPHAGY IN AGINGALBERT EINSTEIN COL OF MED YESHIVA UNIV2005NATIONAL INSTITUTE ON AGING
$208,750
5R01AG021904-04DECREASED PROTEIN DEGRADATION IN AGINGALBERT EINSTEIN COL OF MED YESHIVA UNIV2006NATIONAL INSTITUTE ON AGING
$366,921
5R01AG021904-05DECREASED PROTEIN DEGRADATION IN AGINGALBERT EINSTEIN COL OF MED YESHIVA UNIV2007NATIONAL INSTITUTE ON AGING
$356,279
3R01AG021904-05S1DECREASED PROTEIN DEGRADATION IN AGINGALBERT EINSTEIN COL OF MED YESHIVA UNIV2007NATIONAL INSTITUTE ON AGING
$99,600
2R01AG021904-06DECREASED PROTEIN DEGRADATION IN AGINGALBERT EINSTEIN COL OF MED YESHIVA UNIV2008NATIONAL INSTITUTE ON AGING
$340,300
1P01AG031782-01A1Functional Consequences of Impaired Autophagy in AgingALBERT EINSTEIN COL OF MED YESHIVA UNIV2009NATIONAL INSTITUTE ON AGING
$2,017,110
5R01AG021904-07DECREASED PROTEIN DEGRADATION IN AGINGALBERT EINSTEIN COL OF MED YESHIVA UNIV2009NATIONAL INSTITUTE ON AGING
$340,300
5R01AG021904-09DECREASED PROTEIN DEGRADATION IN AGINGALBERT EINSTEIN COL OF MED YESHIVA UNIV2011NATIONAL INSTITUTE ON AGING
$303,207
5P01AG031782-03Functional Consequences of Impaired Autophagy in AgingALBERT EINSTEIN COL OF MED YESHIVA UNIV2011NATIONAL INSTITUTE ON AGING
$1,875,398
Project Title: Decreased protein degradation in aging
Principal Investigators (PI): CUERVO ANA M
Project Number: 2R01AG021904-06
Organization: ALBERT EINSTEIN COL OF MED YESHIVA UNIV
 
Project number Project title Principal investigator
There are no any related projects.
Project Title: Decreased protein degradation in aging
Principal Investigators (PI): CUERVO ANA M
Project Number: 2R01AG021904-06
Organization: ALBERT EINSTEIN COL OF MED YESHIVA UNIV
 
Title Abstract Authors Year Rel
Autophagy-mediated clearance of aggresomes is not a universal phenomenon. Human molecular genetics. 2008 Aug 15 17 (16) :2570-82 Wong, Esther S P; Tan, Jeanne M M; Soong, Wen-E; Hussein, Kamila; Nukina, Nobuyuki; Dawson, Valina L; Dawson, Ted M; Cuervo, Ana Maria; Lim, Kah-Leong 2008
Dopamine-modified alpha-synuclein blocks chaperone-mediated autophagy. The Journal of clinical investigation. 2008 Feb 118 (2) :777-88 Martinez-Vicente, Marta; Talloczy, Zsolt; Kaushik, Susmita; Massey, Ashish C; Mazzulli, Joseph; Mosharov, Eugene V; Hodara, Roberto; Fredenburg, Ross; Wu, Du-Chu; Follenzi, Antonia; Dauer, William; Przedborski, Serge; Ischiropoulos, Harry; Lansbury, Peter T; Sulzer, David; Cuervo, Ana Maria 2008
Early cellular changes after blockage of chaperone-mediated autophagy. Autophagy. 2008 May 16 4 (4) :442-56 Massey, Ashish C; Follenzi, Antonia; Kiffin, Roberta; Zhang, Cong; Cuervo, Ana Maria 2008
Chaperone-mediated autophagy. Methods in molecular biology (Clifton, N.J.). 2008 445 () :227-44 Kaushik, S; Cuervo, A M 2008
Entering the lysosome through a transient gate by chaperone-mediated autophagy. Autophagy. 2008 Nov 16 4 (8) :1101-3 Bandyopadhyay, Urmi; Cuervo, Ana Maria 2008
Constitutive activation of chaperone-mediated autophagy in cells with impaired macroautophagy. Molecular biology of the cell. 2008 May 19 (5) :2179-92 Kaushik, Susmita; Massey, Ashish C; Mizushima, Noboru; Cuervo, Ana Maria 2008
Autophagy fights disease through cellular self-digestion. Nature. 2008 Feb 28 451 (7182) :1069-75 Mizushima, Noboru; Levine, Beth; Cuervo, Ana Maria; Klionsky, Daniel J 2008
The chaperone-mediated autophagy receptor organizes in dynamic protein complexes at the lysosomal membrane. Molecular and cellular biology. 2008 Sep 28 (18) :5747-63 Bandyopadhyay, Urmi; Kaushik, Susmita; Varticovski, Lyuba; Cuervo, Ana Maria 2008
Restoration of chaperone-mediated autophagy in aging liver improves cellular maintenance and hepatic function. Nature medicine. 2008 Sep 14 (9) :959-65 Zhang, Cong; Cuervo, Ana Maria 2008
Loss of macroautophagy promotes or prevents fibroblast apoptosis depending on the death stimulus. The Journal of biological chemistry. 2008 Feb 22 283 (8) :4766-77 Wang, Yongjun; Singh, Rajat; Massey, Ashish C; Kane, Saul S; Kaushik, Susmita; Grant, Taneisha; Xiang, Youqing; Cuervo, Ana Maria; Czaja, Mark J 2008
Autophagy and aging: keeping that old broom working. Trends in genetics : TIG. 2008 Dec 24 (12) :604-12 Cuervo, Ana Maria 2008