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The Sir2-p53-IGF link in mammalian life-span control

Award Number: R01AG026094
ORGANIZATION: NATIONAL INSTITUTE ON AGING
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 03/15/2006
PERIOD OF PERFORMANCE END DATE: 02/28/2011

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The Sir2-p53-IGF link in mammalian life-span control - We have generated a transgenic mouse in which over-expression of the short isoform of the tumor suppressor p53 (p44) results in the premature loss of health and life. We intend to delineate the molecular mechanism by which increased p44 expression accelerates the process of normal aging in this animal model. In SPECIFIC AIM 1, we test the hypothesis that a change in the p44-to-p53 ratio can modulate mammalian longevity. In this Aim, we characterize the expression of p44 during normal aging in both mouse and human (Experiment 1.1) and determine its relevance in the context of full-length p53 to the rate of aging using RNAi in cells (Experiments 1.2) and a p44-deficient p53 allele in animals (Experiment 1.3) to manipulate p44 levels. In SPECIFIC AIM 2, we test the hypothesis thatp53 modulates life-span in the mouse by coupling the Sir2 and IGF-1 pathways. In this Aim, we propose a series of biochemical experiments to elucidate the molecular mechanism by which p44 might interfere with the interaction between p53 and Sir2, including altering the interaction of p53 with its known binding partners (Experiment 2.1); altering p53 post- translational modifications, including phosphorylation and acetylation/deacetylation (Experiment 2.2); altering p53 sub-cellular localization (Experiment 2.3); and, interfering with the assembly or function of p53- dependent transcription complexes (Experiment 2.4). If p53 is the link between Sir2a and IGF signaling in the mouse, then p44 uncouples the link, and the clues to how this link functions normally lie in why it is non- functional when p44 is in excess. Finally, in SPECIFIC AIM 3, we test the hypothesis that the Igf-1 receptor is theprincipal downstream effector by which p44 alters mammalian health- and life-span. In this aim, we exploit the power of mouse genetics to determine if the Igf-1 receptor, which is altered in cells and tissues ofp44 homozygous transgenic mice, is the key component mediating the loss of health and life in this mammalian system. Because this gene is the critical first step in IGF-1 signal transduction, this Aim focuses on the interactionof p53 and the signalingpathway that plays a major role in life-span determination in lower organisms, such as C. elegans and D. melanogaster.


Issue Date FY	Funding FY	Legal Entity Name	Legal Entity Address	Legal Entity City	Legal Entity State	Legal Entity Zip Code	Legal Entity COUNTY	Legal Entity COUNTRY	Assistance Listing	Award Code	Budget Year	Action Date	Action Type	Action Amount

Issue Date FY: 2018 ( Subtotal = -$10,321 )
2018	2016	MAYO CLINIC	200 1ST ST SW	ROCHESTER	MN	55905	OLMSTED	USA	Aging Research	000	11	9/25/2018	EXTENSION WITH OR WITHOUT FUNDS	-$10,321
														Subtotal = -$10,321

Issue Date FY: 2016 ( Subtotal = $348,062 )
2016	2016	MAYO CLINIC	200 FIRST STREET, S. W.	ROCHESTER	MN	55905	OLMSTED	USA	Aging Research	000	11	5/30/2016	EXTENSION WITH OR WITHOUT FUNDS	$348,062
														Subtotal = $348,062

Issue Date FY: 2015 ( Subtotal = $343,344 )
2015	2015	MAYO CLINIC	200 FIRST STREET, S. W.	ROCHESTER	MN	55905	OLMSTED	USA	Aging Research	000	10	5/18/2015	NON-COMPETING CONTINUATION	$343,344
														Subtotal = $343,344

Issue Date FY: 2014 ( Subtotal = $353,963 )
2014	2014	MAYO CLINIC	200 FIRST STREET, S. W.	ROCHESTER	MN	55905	OLMSTED	USA	Aging Research	000	9	6/14/2014	NON-COMPETING CONTINUATION	$353,963
														Subtotal = $353,963

Issue Date FY: 2013 ( Subtotal = $336,220 )
2013	2013	MAYO CLINIC	200 FIRST STREET, S. W.	ROCHESTER	MN	55905	OLMSTED	USA	Aging Research	000	8	7/29/2013	NON-COMPETING CONTINUATION	$336,220
														Subtotal = $336,220

Issue Date FY: 2012 ( Subtotal = $355,788 )
2012	2012	MAYO CLINIC	200 FIRST STREET, S. W.	ROCHESTER	MN	55905	OLMSTED	USA	Aging Research	000	7	8/13/2012	COMPETING CONTINUATION	$355,788
														Subtotal = $355,788

Issue Date FY: 2010 ( Subtotal = $291,809 )
2010	2010	MAYO CLINIC ROCHESTER	200 FIRST STREET, S. W.	ROCHESTER	MN	55905	OLMSTED	USA	Aging Research	002	6	3/30/2010	NON-COMPETING CONTINUATION	$291,809
2010	2009	MAYO CLINIC	200 FIRST STREET	ROCHESTER	MN	55905	OLMSTED	USA	Aging Research	001	5	2/18/2010	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$0
2010	2009	MAYO CLINIC	200 FIRST STREET	ROCHESTER	MN	55905	OLMSTED	USA	Aging Research	000	5	2/18/2010	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$0
														Subtotal = $291,809

Issue Date FY: 2009 ( Subtotal = $833,570 )
2009	2009	UNIVERSITY OF VIRGINIA	P.O. BOX 400195	CHARLOTTESVILLE	VA	22904	CHARLOTTESVILLE CITY	USA	Aging Research	000	4	3/25/2009	NON-COMPETING CONTINUATION	$295,537
2009	2009	MAYO CLINIC ROCHESTER	200 FIRST STREET, S. W.	ROCHESTER	MN	55905	OLMSTED	USA	Aging Research	002	5	8/31/2009	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$192,803
2009	2009	UNIVERSITY OF VIRGINIA	P.O. BOX 400195	CHARLOTTESVILLE	VA	22904	CHARLOTTESVILLE CITY	USA	Aging Research	001	4	8/31/2009	NON-COMPETING CONTINUATION	-$192,803
2009	2009	MAYO CLINIC ROCHESTER	200 FIRST STREET, S. W.	ROCHESTER	MN	55905	OLMSTED	USA	Trans-NIH Recovery Act Research Support	004	5	9/17/2009	SUPPLEMENT FOR EXPANSION	$538,033
2009	2009	MAYO CLINIC ROCHESTER	200 FIRST STREET, S. W.	ROCHESTER	MN	55901	OLMSTED	USA	Aging Research	003	5	9/11/2009	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$0
														Subtotal = $833,570

Issue Date FY: 2008 ( Subtotal = $295,537 )
2008	2008	UNIVERSITY OF VIRGINIA	PO BOX 400195	CHARLOTTESVILLE	VA	22904	CHARLOTTESVILLE CITY	USA	Aging Research	000	3	2/29/2008	NON-COMPETING CONTINUATION	$295,537
														Subtotal = $295,537

Issue Date FY: 2007 ( Subtotal = $301,568 )
2007	2007	UNIVERSITY OF VIRGINIA	PO BOX 400195	CHARLOTTESVILLE	VA	22904	CHARLOTTESVILLE CITY	USA	Aging Research	000	2	3/12/2007	NON-COMPETING CONTINUATION	$301,568
														Subtotal = $301,568

Issue Date FY: 2006 ( Subtotal = $311,259 )
2006	2006	UNIVERSITY OF VIRGINIA	PO BOX 400195	CHARLOTTESVILLE	VA	22904	CHARLOTTESVILLE CITY	USA	Aging Research	000	1	3/9/2006	NEW	$311,259
														Subtotal = $311,259

Grand Total All Awards = $3,760,799

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The Sir2-p53-IGF link in mammalian life-span control

Award Number: R01AG026094

ORGANIZATION: NATIONAL INSTITUTE ON AGING

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

PERIOD OF PERFORMANCE START DATE: 03/15/2006

PERIOD OF PERFORMANCE END DATE: 02/28/2011

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