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INTERSTITIAL FLUID FLOW IN BONE REMODELING

Award Number: R01AR046797
ORGANIZATION: NATIONAL INSTITUTE OF ARTHRITIS & MUSCULOSKELETAL & SKIN DISEASES
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 04/01/2000
PERIOD OF PERFORMANCE END DATE: 03/31/2013

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INTERSTITIAL FLUID FLOW IN BONE REMODELING - DESCRIPTION (provided by applicant): Over the past two decades, there has been an accumulation of evidence demonstrating the critical role of skeletal interstitial fluid flow in the viability, maintenance, and response to loading and unloading of bone. Our objective is to elucidate the mechanisms by which interstitial fluid flow (IFF) stimulates bone cells, using molecular, cell, and in vivo knockout and transgenic models. IFF is characterized by both steady and dynamic components driven by vascular pressure and mechanical loading. Even though bone cells respond to both flow components, we have demonstrated that the mechanotransduction pathways and the subsequent cellular and in vivo responses to these two mechanical stimuli differ. The overarching hypothesis is that dynamic or pulsatile flows result in an osteoblast mitogenic response while steady flow induces both an anti-resorptive skeletal response as well as osteoblast differentiation. To investigate this hypothesis, we propose the following the specific aims: 1) Test the hypothesis that oscillatory flow in vitro induces an osteoblast growth (mitogenic) response, while ramped steady flow induces osteoblast differentiation. Mitogenic indices (BrdU incorporation) and transcriptional activators (egr-1 and c-fos) and differentiation indices (bone sialoprotein, Cbfa-1, and p57Kip2) will be measured in osteoblasts and osteocytes. 2) Determine the mechanisms for the nitric oxide-related mechanochemical signal transduction pathways of pulsatile flow and ramped steady flow in osteoblasts and osteocytes. We will characterize which nitric oxide synthase (NOS) isoforms mediate the flow responses, and determine the mechanism of regulation of NOS activity. 3) Using our novel implantable microfluidic oscillatory pressure device, we will determine if oscillatory flow induces an anabolic response, while increased steady flow is anti-resorptive in the hindlimb suspended rat. And 4) using osteoblast-specific conditional knockout mice, determine the roles of NOS and caveolin in mediating the skeletal cellular responses to dynamic interstitial fluid flow. The proposed research will elucidate the basic mechanisms by which interstitial fluid flow acts on bone, and provide the basis for treatments based on the modulation of interstitial fluid flow to counter osteopenia of disuse. PUBLIC HEALTH RELEVANCE. There is mounting evidence that interstitial fluid flow (IFF) mediates the skeletal response to loading and unloading. The overarching hypothesis is that dynamic IFF results in an osteoblast mitogenic response while steady flow induces osteoblast differentiation. Using both in vitro and in vivo models, the proposed research will elucidate the basic mechanisms by which IFF acts on bone, and provide the basis for treatments based on the modulation of IFF to counter osteopenia of disuse.


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: 2012 ( Subtotal = $396,013 )
2012	2012	LA JOLLA BIOENGINEERING INSTITUTE	505 COAST BOULEVARD SOUTH	LA JOLLA	CA	92037	SAN DIEGO	USA	Arthritis, Musculoskeletal and Skin Diseases Research	000	9	4/4/2012	NON-COMPETING CONTINUATION	$396,013
														Subtotal = $396,013

Issue Date FY: 2011 ( Subtotal = $396,013 )
2011	2011	LA JOLLA BIOENGINEERING INSTITUTE	505 COAST BOULEVARD SOUTH	LA JOLLA	CA	92037	SAN DIEGO	USA	Arthritis, Musculoskeletal and Skin Diseases Research	000	8	3/11/2011	NON-COMPETING CONTINUATION	$371,262
2011	2011	LA JOLLA BIOENGINEERING INSTITUTE	505 COAST BOULEVARD SOUTH	LA JOLLA	CA	92037	SAN DIEGO	USA	Arthritis, Musculoskeletal and Skin Diseases Research	001	8	6/4/2011	NON-COMPETING CONTINUATION	$24,751
														Subtotal = $396,013

Issue Date FY: 2010 ( Subtotal = $412,513 )
2010	2010	LA JOLLA BIOENGINEERING INSTITUTE	505 COAST BOULEVARD SOUTH	LA JOLLA	CA	92037	SAN DIEGO	USA	Arthritis, Musculoskeletal and Skin Diseases Research	000	7	4/12/2010	NON-COMPETING CONTINUATION	$412,513
														Subtotal = $412,513

Issue Date FY: 2009 ( Subtotal = $416,680 )
2009	2009	LA JOLLA BIOENGINEERING INSTITUTE	505 COAST BOULEVARD SOUTH	LA JOLLA	CA	92037	SAN DIEGO	USA	Arthritis, Musculoskeletal and Skin Diseases Research	000	6	3/30/2009	NON-COMPETING CONTINUATION	$416,680
														Subtotal = $416,680

Issue Date FY: 2008 ( Subtotal = $416,680 )
2008	2008	LA JOLLA BIOENGINEERING INSTITUTE	505 COAST BOULEVARD SOUTH	LA JOLLA	CA	92037	SAN DIEGO	USA	Arthritis, Musculoskeletal and Skin Diseases Research	000	5	7/5/2008	COMPETING CONTINUATION	$416,680
														Subtotal = $416,680

Issue Date FY: 2004 ( Subtotal = $453,750 )
2004	2004	LA JOLLA BIOENGINEERING INSTITUTE	505 COAST BOULEVARD SOUTH	LA JOLLA	CA	92037	SAN DIEGO	USA	Arthritis, Musculoskeletal and Skin Diseases Research	000	4	5/20/2004	NON-COMPETING CONTINUATION	$453,750
														Subtotal = $453,750

Issue Date FY: 2003 ( Subtotal = $453,854 )
2003	2003	LA JOLLA BIOENGINEERING INSTITUTE	505 COAST BOULEVARD SOUTH	LA JOLLA	CA	92037	SAN DIEGO	USA	Arthritis, Musculoskeletal and Skin Diseases Research	000	3	9/1/2003	NON-COMPETING CONTINUATION	$453,854
														Subtotal = $453,854

Issue Date FY: 2002 ( Subtotal = $455,000 )
2002	2002	LA JOLLA BIOENGINEERING INSTITUTE	505 COAST BOULEVARD SOUTH	LA JOLLA	CA	92037	SAN DIEGO	USA	Arthritis, Musculoskeletal and Skin Diseases Research	000	2	8/26/2002	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$455,000
														Subtotal = $455,000

Issue Date FY: 2001 ( Subtotal = $354,000 )
2001	2001	UNIVERSITY OF CALIFORNIA-SAN DIEGO	Q027	LA JOLLA	CA	92093	SAN DIEGO	USA	Arthritis, Musculoskeletal and Skin Diseases Research	000	1	8/15/2001	NEW	$354,000
														Subtotal = $354,000

Grand Total All Awards = $3,754,503

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INTERSTITIAL FLUID FLOW IN BONE REMODELING

Award Number: R01AR046797

ORGANIZATION: NATIONAL INSTITUTE OF ARTHRITIS & MUSCULOSKELETAL & SKIN DISEASES

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 04/01/2000

PERIOD OF PERFORMANCE END DATE: 03/31/2013

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