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HOXB4 IS AN ACTIVATOR OF HSC SELF-RENEWAL

Award Number: R01HL065430
ORGANIZATION: NATIONAL HEART, LUNG, & BLOOD INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 07/01/2000
PERIOD OF PERFORMANCE END DATE: 04/30/2010

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HOXB4 IS AN ACTIVATOR OF HSC SELF-RENEWAL - DESCRIPTION (provided by applicant): The capacity for sustained self-renewal is one of the defining features of hematopoietic stem cells (HSCs). However, the molecular bases for HSC self-renewal remain obscure. We have previously reported that HSC expansion is profoundly affected by Hoxb4 overexpression and more recently developed HOXB4- based reagents and strategies which provide tools for deepening our knowledge of self-renewal mechanisms, and for achievement of clinically useful levels of HSC expansion. Four aims are proposed in this first renewal application: 1-To enhance the potential of HSCs to expand in vitro. This will be investigated first by varying Hoxb4 and Pbxl levels in HSCs as recently reported with our in vivo studies and by testing novel Hox-containing fusion genes with enhanced potential for HSC expansion. The contribution of growth factors and precursor differentiation stage (e.g., HSC vs MPP, etc) to HOXB4-driven HSC expansion will also be assessed. 2-To develop and test clinically-relevant strategies aimed at achieving a maximal expansion of HSCs in vitro. This includes the generation of soluble reagents that will interfere with the function of PBX1 and by testing the function of stabilized HOXB4 proteins. Studies with human HSCs will be conducted and effects of the manipulation evaluated by xenotransplantation using NOD/SCID mice and fetal sheep as recipients. 3-To identify a HOXB4-containing "HSC-self-renewal protein complex" and determine the role of the newly identified proteins in HSC self-renewal. Strategies include the utilization of a functional tandem affinity purification (TAP)-tagged HOXB4 and isolation of the complex in relevant cells. Identified proteins will be functionally validated using RNA interference. 4-To identify target genes to HOXB4 in purified mouse HSCs. This aim combines cell purification of newly characterized HSC populations with microarray analysis from small cell numbers and preliminary target gene validation.


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 = $359,303 )
2009	2009	UNIVERSITY OF MONTREAL	3850 RUE SAINT-URBAIN	MONTREAL, QUEBEC				CAN	Blood Diseases and Resources Research	000	10	6/12/2009	NON-COMPETING CONTINUATION	$359,303
														Subtotal = $359,303

Issue Date FY: 2007 ( Subtotal = $346,874 )
2007	2007	UNIVERSITY OF MONTREAL	3850 RUE SAINT-URBAIN	MONTREAL, QUEBEC		00000		CAN	Blood Diseases and Resources Research	000	8	4/10/2007	NON-COMPETING CONTINUATION	$346,874
														Subtotal = $346,874

Issue Date FY: 2006 ( Subtotal = $351,455 )
2006	2006	UNIVERSITY OF MONTREAL	3850 RUE SAINT-URBAIN	MONTREAL, QUEBEC		00000		CAN	Blood Diseases and Resources Research	000	7	3/31/2006	NON-COMPETING CONTINUATION	$351,455
														Subtotal = $351,455

Issue Date FY: 2005 ( Subtotal = $357,462 )
2005	2005	UNIVERSITY OF MONTREAL	3850 RUE SAINT-URBAIN	MONTREAL, QUEBEC		00000		CAN	Blood Diseases and Resources Research	000	6	5/6/2005	COMPETING CONTINUATION	$357,462
														Subtotal = $357,462

Issue Date FY: 2004 ( Subtotal = $200,000 )
2004	2004	UNIVERSITY OF MONTREAL	3850 RUE SAINT-URBAIN	MONTREAL, QUEBEC		00000		CAN	Blood Diseases and Resources Research	000	4	8/25/2004	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$200,000
														Subtotal = $200,000

Issue Date FY: 2003 ( Subtotal = $200,000 )
2003	2003	CLINICAL RESEARCH INSTITUTE OF MONTREAL	110 Pine Ave. W.	MONTREAL				CAN	Blood Diseases and Resources Research	000	3		NON-COMPETING CONTINUATION	$200,000
														Subtotal = $200,000

Issue Date FY: 2002 ( Subtotal = $200,000 )
2002	2002	UNIVERSITY OF MONTREAL	NIH (98)					USA	Blood Diseases and Resources Research	000	2	4/28/2002	NON-COMPETING CONTINUATION	$200,000
														Subtotal = $200,000

Issue Date FY: 2001 ( Subtotal = $200,000 )
2001	2001	UNIVERSITY OF MONTREAL	NIH (98)					USA	Blood Diseases and Resources Research	000	1	5/14/2001	NEW	$200,000
														Subtotal = $200,000

Grand Total All Awards = $2,215,094

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HOXB4 IS AN ACTIVATOR OF HSC SELF-RENEWAL

Award Number: R01HL065430

ORGANIZATION: NATIONAL HEART, LUNG, & BLOOD INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 07/01/2000

PERIOD OF PERFORMANCE END DATE: 04/30/2010

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