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CLONAL ANALYSIS OF AGED HEMATOPOIETIC STEM CELLS

Award Number: R01AG023197
ORGANIZATION: NATIONAL INSTITUTE ON AGING
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 05/01/2004
PERIOD OF PERFORMANCE END DATE: 04/30/2010

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CLONAL ANALYSIS OF AGED HEMATOPOIETIC STEM CELLS - DESCRIPTION (provided by applicant): Published studies and our preliminary data indicate that hematopoietic stem cells (HSCs) from aged animals generate less lymphoid progeny than young HSCs. This results in an overrepresentation of myeloid cells in the periphery. Understanding the mechanisms that cause HSCs from aged animals to generate progeny skewed to the myeloid lineage would open avenues to correct or prevent the age-related decline in lymphopoiesis. All important functions of HSCs, including self-renewal and commitment, are determined on the level of a single HSC. Thus, a mechanistic understanding of the function and composition of the aged HSC compartment requires an examination on the clonal level. We developed an efficient method for isolating clonally derived HSCs. The analysis of young HSC clones led to the discovery of a new type of HSC, called lineage dominant HSC. We found that lineage dominant HSCs: 1) contribute to all hematopoietic lineages, albeit with a noticeably skewed ratio; 2) can have extensive self-renewal capacity; 3) maintain lineage dominance stably through multiple rounds of transplantation; 4) can be either myeloid or lymphoid dominant. The data indicate that lineage dominant HSCs are a new type of HSC with distinct development potential. We now hypothesize that the increased production of myeloid cells from the aged HSC compartment is caused by an accumulation of myeloid dominant HSCs. The central hypothesis of this application is that "aging does not change the behavior of individual HSCs, rather aging changes the composition of the HSC compartment." To test this, we propose to extend the clonal approach to the analysis of the aged HSC compartment. We propose three specific aims: 1) Is dysregulation of lymphoid and myeloid cells in aging due to loss of heterogeneity in the aged HSC compartment? 2) Is the microenvironment or are HSC-intrinsic effects responsible for the aged behavior of HSC? 3) Do HSCs from aged animals and myeloid dominant HSCs generate reduced levels of T cell precursors.


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: 2009 ( Subtotal = $0 )
2009	2008	SIDNEY KIMMEL CANCER CENTER	10905 Road To The Cure	San Diego	CA	92121	SAN DIEGO	USA	Aging Research	000	5	8/24/2009	NON-COMPETING CONTINUATION	-$47,660
2009	2008	BURNHAM INSTITUTE FOR MEDICAL RESEARCH	10901 NORTH TORREY PINES ROAD	LA JOLLA	CA	92037	SAN DIEGO	USA	Aging Research	001	6	8/24/2009	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$47,660
														Subtotal = $0

Issue Date FY: 2008 ( Subtotal = $337,570 )
2008	2008	SIDNEY KIMMEL CANCER CENTER	10835 ALTMAN ROW	SAN DIEGO	CA	92121	SAN DIEGO	USA	Aging Research	000	5	4/25/2008	NON-COMPETING CONTINUATION	$337,570
														Subtotal = $337,570

Issue Date FY: 2007 ( Subtotal = $344,459 )
2007	2007	SIDNEY KIMMEL CANCER CENTER	10835 ALTMAN ROW	SAN DIEGO	CA	92121	SAN DIEGO	USA	Aging Research	000	4	4/30/2007	NON-COMPETING CONTINUATION	$344,459
														Subtotal = $344,459

Issue Date FY: 2006 ( Subtotal = $354,747 )
2006	2006	SIDNEY KIMMEL CANCER CENTER	10835 ALTMAN ROW	SAN DIEGO	CA	92121	SAN DIEGO	USA	Aging Research	000	3	3/15/2006	NON-COMPETING CONTINUATION	$354,747
														Subtotal = $354,747

Issue Date FY: 2005 ( Subtotal = $363,285 )
2005	2005	SIDNEY KIMMEL CANCER CENTER	10835 ALTMAN ROW	SAN DIEGO	CA	92121	SAN DIEGO	USA	Aging Research	000	2	5/9/2005	NON-COMPETING CONTINUATION	$363,285
														Subtotal = $363,285

Issue Date FY: 2004 ( Subtotal = $363,285 )
2004	2004	SIDNEY KIMMEL CANCER CENTER	10835 ALTMAN ROW	SAN DIEGO	CA	92121	SAN DIEGO	USA	Aging Research	000	1	4/19/2004	NEW	$363,285
														Subtotal = $363,285

Grand Total All Awards = $1,763,346

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CLONAL ANALYSIS OF AGED HEMATOPOIETIC STEM CELLS

Award Number: R01AG023197

ORGANIZATION: NATIONAL INSTITUTE ON AGING

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 05/01/2004

PERIOD OF PERFORMANCE END DATE: 04/30/2010

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