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SOMATOMEDIN: AUTOLOGOUS REGULATOR OF BONE FORMATION

Award Number: R01DK042424
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: 08/01/1989
PERIOD OF PERFORMANCE END DATE: 06/30/2009

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SOMATOMEDIN: AUTOLOGOUS REGULATOR OF BONE FORMATION - DESCRIPTION (provided by applicant): Former investigations from our laboratory revealed that skeletal cells synthesize insulin-like growth factor (IGF) I, and its synthesis is regulated by CCAAT/enhancer binding proteins (C/EBP). Consequently, we explored the regulation and function of C/EBPs in osteoblastic cells and found that C/EBPs determine the cellular fate of undifferentiated stromal cells. We are particularly interested in the function of C/EBP homologous protein (CHOP) or C/EBP Zeta since its constitutive overexpression decreases adipogenesis and induces osteoblast differentiation in stromal cell cultures. This effect involves sensitization of the bone morphogenetic protein/Smad signaling pathway. The objective of this project is to understand the function of CHOP in bone in vivo and in vitro. For this purpose, we obtained chop null mice and are creating transgenic mouse lines overexpressing CHOP under the control of the type I collagen and of the osteocalcin promoters. Our initial studies demonstrated that chop null mice exhibit decreased bone formation. Furthermore, CHOP is required for normal osteoblastic function in vivo and in vitro, and chop null cells exhbit impaired collagen synthesis. Our specific aims are to extend these initial observations: 1) to determine the function of CHOP in vivo by transgenic overexpression of the nuclear protein under the control of the type I collagen or of the osteocalcin promoter so that expression occurs in differentiated cells and in osteoblasts in the bone microenvironment. The skeletal phenotype of transgenic mice will be compared to that of wild type mice and determined by histomorphometry, contact radiography, densitometry and micro CT scanning; 2) to determine the function of CHOP in vivo by defining the skeletal phenotype of chop null mice. This will be assessed with histomorphometric and radiological techniques, and if indicated, by examining structural and crystal properties of the skeleton; and 3) to determine the mechanism of action of CHOP in vitro, by overexpressing CHOP in cells of the osteoblastic lineage and by examining the phenotype of chop null cells. The impact of CHOP on the differentiation, function and apoptosis of cells of the osteoblastic lineage will be determined, and mechanisms involved and specific domains of the chop gene responsible for an effect will be defined. These investigations should clarify the role of CHOP in bone cell differentiation and function.


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: 2008 ( Subtotal = $194,159 )
2008	2008	ST FRANCIS HOSPITAL & MEDICAL CENTER	114 WOODLAND STREET	HARTFORD	CT	06105	CAPITOL	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	18	7/1/2008	NON-COMPETING CONTINUATION	$194,159
														Subtotal = $194,159

Issue Date FY: 2007 ( Subtotal = $198,122 )
2007	2007	ST FRANCIS HOSPITAL & MEDICAL CENTER	114 WOODLAND STREET	HARTFORD	CT	06105	CAPITOL	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	17	6/28/2007	NON-COMPETING CONTINUATION	$198,122
														Subtotal = $198,122

Issue Date FY: 2006 ( Subtotal = $204,039 )
2006	2006	ST FRANCIS HOSPITAL & MEDICAL CENTER	114 WOODLAND STREET	HARTFORD	CT	06105	CAPITOL	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	16	6/30/2006	NON-COMPETING CONTINUATION	$204,039
														Subtotal = $204,039

Issue Date FY: 2005 ( Subtotal = $208,950 )
2005	2005	ST FRANCIS HOSPITAL & MEDICAL CENTER	114 WOODLAND STREET	HARTFORD	CT	06105	CAPITOL	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	15	7/18/2005	COMPETING CONTINUATION	$208,950
														Subtotal = $208,950

Issue Date FY: 2003 ( Subtotal = $179,084 )
2003	2003	ST FRANCIS HOSPITAL & MEDICAL CENTER	114 WOODLAND STREET	HARTFORD	CT	06105	CAPITOL	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	14		NON-COMPETING CONTINUATION	$179,084
														Subtotal = $179,084

Issue Date FY: 2002 ( Subtotal = $179,084 )
2002	2002	ST FRANCIS HOSPITAL & MEDICAL CENTER	114 WOODLAND STREET	HARTFORD	CT	06105	CAPITOL	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	13	1/30/2002	NON-COMPETING CONTINUATION	$179,084
														Subtotal = $179,084

Issue Date FY: 2001 ( Subtotal = $179,084 )
2001	2001	ST FRANCIS HOSPITAL & MEDICAL CENTER	114 WOODLAND STREET	HARTFORD	CT	06105	CAPITOL	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	12	3/5/2001	NON-COMPETING CONTINUATION	$179,084
														Subtotal = $179,084

Issue Date FY: 2000 ( Subtotal = $179,084 )
2000	2000	ST FRANCIS HOSPITAL & MEDICAL CENTER	114 WOODLAND STREET	HARTFORD	CT	06105	CAPITOL	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	11	5/1/2000	COMPETING CONTINUATION	$179,084
														Subtotal = $179,084

Issue Date FY: 1998 ( Subtotal = $177,090 )
1998	1998	ST FRANCIS HOSPITAL & MEDICAL CENTER	114 WOODLAND STREET	HARTFORD	CT	06105	CAPITOL	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	10	9/16/1998	NON-COMPETING CONTINUATION	$177,090
														Subtotal = $177,090

Grand Total All Awards = $1,698,696

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SOMATOMEDIN: AUTOLOGOUS REGULATOR OF BONE FORMATION

Award Number: R01DK042424

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: 08/01/1989

PERIOD OF PERFORMANCE END DATE: 06/30/2009

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