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Characterization of the first HSCs during mouse ontogeny

Award Number: R37DK054077
ORGANIZATION: NATIONAL INSTITUTE OF DIABETES & DIGESTIVE & KIDNEY DISEASES
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 06/01/1998
PERIOD OF PERFORMANCE END DATE: 03/31/2016

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Characterization of the first HSCs during mouse ontogeny - DESCRIPTION (provided by applicant): The continuous life-long production of all mature blood cells in the circulation and hematopoietic tissues is contingent on hematopoietic stem cells (HSC). These rare cells reside in the bone marrow of the adult and are the clinically important cells in transplantation therapies for blood-related diseases and leukemias. The manipulation of limited numbers of adult HSCs has been difficult, since ex vivo expansion of these cells has not yet been achieved. Despite the identification and use of many hematopoietic growth factors, HSCs can at best be maintained, not expanded. We hypothesized that at some early stage in ontogeny HSCs are generated and expanded in a unique embryonic microenvironment. An understanding of the developmental processes leading to HSC emergence in the embryo should provide novel insights and improved methods for the ex vivo expansion of HSCs for clinical use. To this end, our long-term research objective has been to determine the cellular and molecular mechanisms by which HSCs are generated/expanded within the mammalian embryo. We have shown that the mouse aorta-gonad-mesonephros (AGM) region autonomously generates the first fully potent HSCs in close association with the aortic endothelium. We have demonstrated that Runxl and GATA-2 transcription factors are required for the generation and expansion of these HSCs. However, more factors have yet to be identified. In various preliminary studies of the AGM microenvironment, IL-3, BMP-4 and hedgehog factors have been implicated as effectors of AGM HSC emergence, but these factors must be further characterized. Thus, we will examine each factor for its role in the induction and expansion of HSCs in the midgestation mouse aorta. Using classical embryologic methods, we will deliver factors to whole cultured mouse embryos by bead/cell pellet implantation and transgenesis, to determine their effect on AGM HSCs. In similar factor manipulation experiments, we aim to establish the lineage relationships of precursors to AGM HSCs by dye marking of aortic endothelium. We will also investigate the long-term fate of the HSCs generated in the mouse AGM by Cre-lox recombination technology. If indeed embryonic aorta-derived HSCs migrate and colonize the adult bone marrow, our insights into their generation and expansion should lead to novel methods for clinical HSC expansion and thus, improve transplantation therapies.


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 = -$136,692 )
2018	2013	ERASMUS UNIVERSITAIR MEDISCH CENTRUM ROTTERDAM	'S-GRAVENDIJKWAL 230	ROTTERDAM	ZUID-HOLLAND	3015 CE		NLD	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	16	9/30/2018	EXTENSION WITH OR WITHOUT FUNDS	-$136,692
														Subtotal = -$136,692

Issue Date FY: 2015 ( Subtotal = $303,761 )
2015	2015	UNIVERSITY OF EDINBURGH	1-7 ROXBURGH STREET	EDINBURGH				GBR	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	19	3/31/2015	NON-COMPETING CONTINUATION	$303,761
														Subtotal = $303,761

Issue Date FY: 2014 ( Subtotal = $303,761 )
2014	2014	UNIVERSITY OF EDINBURGH	1-7 ROXBURGH STREET	EDINBURGH				GBR	Diabetes, Digestive, and Kidney Diseases Extramural Research	002	18	3/4/2014	NON-COMPETING CONTINUATION	$303,761
2014	2013	UNIVERSITY OF EDINBURGH	1-7 ROXBURGH STREET	EDINBURGH				GBR	Diabetes, Digestive, and Kidney Diseases Extramural Research	003	17	9/26/2014	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	-$136,693
2014	2013	ERASMUS MC	POST OFFICE BOX 1738	ROTTERDAM				NLD	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	16	12/4/2013	EXTENSION WITH OR WITHOUT FUNDS	-$136,693
2014	2013	UNIVERSITY OF EDINBURGH	1-7 ROXBURGH STREET	EDINBURGH				GBR	Diabetes, Digestive, and Kidney Diseases Extramural Research	001	17	12/5/2013	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$136,693
2014	2013	UNIVERSITY OF EDINBURGH	1-7 ROXBURGH STREET	EDINBURGH				GBR	Diabetes, Digestive, and Kidney Diseases Extramural Research	004	17	9/27/2014	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$136,693
														Subtotal = $303,761

Issue Date FY: 2013 ( Subtotal = $136,692 )
2013	2013	ERASMUS MC	POST OFFICE BOX 1738	ROTTERDAM				NLD	Diabetes, Digestive, and Kidney Diseases Extramural Research	001	16	12/4/2013	EXTENSION WITH OR WITHOUT FUNDS	-$136,693
2013	2013	ERASMUS MC	POST OFFICE BOX 1738	ROTTERDAM				NLD	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	16	3/19/2013	EXTENSION WITH OR WITHOUT FUNDS	$273,385
														Subtotal = $136,692

Issue Date FY: 2012 ( Subtotal = $303,760 )
2012	2012	ERASMUS MC	POST OFFICE BOX 1738	ROTTERDAM				NLD	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	15	3/29/2012	NON-COMPETING CONTINUATION	$303,760
														Subtotal = $303,760

Issue Date FY: 2011 ( Subtotal = $291,846 )
2011	2011	ERASMUS MC	POST OFFICE BOX 1738	ROTTERDAM		00000		NLD	Diabetes, Digestive, and Kidney Diseases Extramural Research	001	14	7/1/2011	EXTENSION WITH OR WITHOUT FUNDS	$0
2011	2011	ERASMUS MC	POST OFFICE BOX 1738	ROTTERDAM				NLD	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	14	4/18/2011	EXTENSION WITH OR WITHOUT FUNDS	$291,846
														Subtotal = $291,846

Issue Date FY: 2010 ( Subtotal = $245,662 )
2010	2010	ERASMUS MC	POST OFFICE BOX 1738	ROTTERDAM				NLD	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	13	4/8/2010	NON-COMPETING CONTINUATION	$245,662
														Subtotal = $245,662

Issue Date FY: 2009 ( Subtotal = $243,021 )
2009	2009	ERASMUS MC	POST OFFICE BOX 1738	ROTTERDAM				NLD	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	12	7/15/2009	NON-COMPETING CONTINUATION	$243,021
														Subtotal = $243,021

Issue Date FY: 2007 ( Subtotal = $237,927 )
2007	2007	ERASMUS MC	POST OFFICE BOX 1738	ROTTERDAM		00000		NLD	Kidney Diseases, Urology and Hematology Research	000	10	5/9/2007	NON-COMPETING CONTINUATION	$237,927
														Subtotal = $237,927

Issue Date FY: 2006 ( Subtotal = $207,236 )
2006	2006	ERASMUS MC	POST OFFICE BOX 1738	ROTTERDAM		00000		NLD	Kidney Diseases, Urology and Hematology Research	000	9	7/18/2006	COMPETING CONTINUATION	$207,236
														Subtotal = $207,236

Grand Total All Awards = $2,136,974

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Characterization of the first HSCs during mouse ontogeny

Award Number: R37DK054077

ORGANIZATION: NATIONAL INSTITUTE OF DIABETES & DIGESTIVE & KIDNEY DISEASES

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 06/01/1998

PERIOD OF PERFORMANCE END DATE: 03/31/2016

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