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INHIBITION OF OSTEOCLAST ACTIVITY BY OIP-1/HSCAL

Award Number: R01DE012603
ORGANIZATION: NATIONAL INSTITUTE OF DENTAL AND CRANIOFACIAL RESEARCH
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 04/10/1999
PERIOD OF PERFORMANCE END DATE: 06/30/2009

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INHIBITION OF OSTEOCLAST ACTIVITY BY OIP-1/HSCAL - DESCRIPTION (provided by applicant): The present application is an ongoing project that will identify the molecular mechanisms responsible for osteoclast (OCL) inhibition by OCL inhibitory peptide-1 (OIP-1/hSca 1). During the previous proposal period, we have identified the OCL Inhibitory Peptide-1 (OIP-1/hSca), a local factor produced in the bone microenvironment as a novel inhibitor of OCL formation and bone resorption that is produced by OCLs. OIP-1 is a glycosylphosphatidyl-inositol (GPI) linked membrane protein (17 kDa) related to the Ly-6 family of hematopoietic proteins. We have determined that the OIP-1 c-peptide region (32 amino acids) of OIP-1 is critical for OIP-1's inhibition of OCL formation. Synthetic OIP-1 c-peptide inhibits OCL formation through suppression of TRAF-2 and p-c-Jun kinase activity, but has no effect on TRAF-6 and NF-kappaB activation. We also found that cytokines such as IFN-gamma, and IL-1beta significantly enhance OIP-1 mRNA expression in OCL precursors, CFU-GM. It is our hypothesis that OIP-1 plays a critical role in the physiologic regulation of OCL development by cellular signaling through unique transmembrane protein interactions and that OIP-1 expression in OCL precursors is controlled by specific transcriptional regulatory mechanisms. To test this hypothesis, we will pursue the following Specific Aims: Aim (1) Identify and clone the osteoclast transmembrane proteins which interacts with the OIP-1 c-peptide: (i) Clone and characterize the osteoclast membrane receptor for OIP-1; (ii) Identify OIP-1 interacting proteins using yeast two-hybrid system; (iii) Determine the effects of over-expression or blocking the expression of OIP-1 interacting proteins on OIP-1 capacity to inhibit OCL formation (iv) Determine the participation of OIP-1 interacting proteins in OIP-1 signaling to inhibit OCL formation; Aim (2) Determine if over-expression of OIP-1 in cells of OCL lineage inhibit osteoclast formation: (a) Develop TRAP-OIP-1 transgenic mice targeting OIP-1 expression in cells of OCL lineage to assess OCL development in vivo; (b) Determine if overexpression of OIP-1 in OCL precursor cells affects OCL differentiation and the status of RANKL signaling molecules during OCL differentiation in vitro; Aim (3) Isolate and characterize the OIP-1 gene promoter sequence for cytokine regulatory regions and potential transcription factors that module OIP-1 gene expression in osteoclasts. These studies should provide important insights into the regulatory mechanisms responsible for OIP-1 inhibition of OCL formation in the bone microenvironment and allow development of novel rational approaches and therapeutic agents to control enhanced osteoclast activity in Paget's disease and other bone diseases such as osteoporosis and multiple myeloma.


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 = $194,637 )
2008	2008	MEDICAL UNIVERSITY OF SOUTH CAROLINA	19 HAGOOD AVE, SUITE 608	CHARLESTON	SC	29425	CHARLESTON	USA	Oral Diseases and Disorders Research	000	10	5/29/2008	NON-COMPETING CONTINUATION	$194,637
														Subtotal = $194,637

Issue Date FY: 2007 ( Subtotal = $196,816 )
2007	2007	MEDICAL UNIVERSITY OF SOUTH CAROLINA	19 HAGOOD AVE, SUITE 608	CHARLESTON	SC	29425	CHARLESTON	USA	Oral Diseases and Disorders Research	000	9	6/27/2007	NON-COMPETING CONTINUATION	$196,816
														Subtotal = $196,816

Issue Date FY: 2006 ( Subtotal = $202,708 )
2006	2006	MEDICAL UNIVERSITY OF SOUTH CAROLINA	19 HAGOOD AVE, SUITE 608	CHARLESTON	SC	29425	CHARLESTON	USA	Oral Diseases and Disorders Research	000	8	6/15/2006	NON-COMPETING CONTINUATION	$202,708
														Subtotal = $202,708

Issue Date FY: 2005 ( Subtotal = $207,600 )
2005	2005	MEDICAL UNIVERSITY OF SOUTH CAROLINA	19 HAGOOD AVE, SUITE 608	CHARLESTON	SC	29425	CHARLESTON	USA	Oral Diseases and Disorders Research	000	7	6/10/2005	NON-COMPETING CONTINUATION	$207,600
														Subtotal = $207,600

Issue Date FY: 2004 ( Subtotal = $204,554 )
2004	2004	MEDICAL UNIVERSITY OF SOUTH CAROLINA	19 HAGOOD AVE, SUITE 608	CHARLESTON	SC	29425	CHARLESTON	USA	Oral Diseases and Disorders Research	000	6	9/24/2004	COMPETING CONTINUATION	$204,554
														Subtotal = $204,554

Issue Date FY: 2002 ( Subtotal = $147,237 )
2002	2002	UNIVERSITY OF PITTSBURGH	FIFTH & BIGELOW BOULEVARD	PITTSBURGH	PA	15213	ALLEGHENY	USA	Oral Diseases and Disorders Research	000	5	2/20/2002	NON-COMPETING CONTINUATION	$147,237
														Subtotal = $147,237

Issue Date FY: 2001 ( Subtotal = $142,757 )
2001	2001	UNIVERSITY OF TEXAS HEALTH SCIENCE CTR AT SAN ANTONIO	7703 FLOYD CURL DRIVE	SAN ANTONIO	TX	78284	BEXAR	USA	Oral Diseases and Disorders Research	000	3	3/27/2001	NON-COMPETING CONTINUATION	$142,757
														Subtotal = $142,757

Issue Date FY: 2000 ( Subtotal = $138,917 )
2000	2000	UNIVERSITY OF TEXAS HEALTH SCIENCE CTR AT SAN ANTONIO	7703 FLOYD CURL DRIVE	SAN ANTONIO	TX	78284	BEXAR	USA	Oral Diseases and Disorders Research	000	2	3/9/2000	NON-COMPETING CONTINUATION	$138,917
														Subtotal = $138,917

Issue Date FY: 1999 ( Subtotal = $135,304 )
1999	1999	UNIVERSITY OF TEXAS HEALTH SCIENCE CTR AT SAN ANTONIO	7703 FLOYD CURL DRIVE	SAN ANTONIO	TX	78284	BEXAR	USA	Oral Diseases and Disorders Research	000	1	4/10/1999	NEW	$135,304
														Subtotal = $135,304

Grand Total All Awards = $1,570,530

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INHIBITION OF OSTEOCLAST ACTIVITY BY OIP-1/HSCAL

Award Number: R01DE012603

ORGANIZATION: NATIONAL INSTITUTE OF DENTAL AND CRANIOFACIAL RESEARCH

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 04/10/1999

PERIOD OF PERFORMANCE END DATE: 06/30/2009

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