This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. Primary support for the subproject and the subproject's principal investigator may have been provided by other sources, including other NIH sources. The Total Cost listed for the subproject likely represents the estimated amount of Center infrastructure utilized by the subproject, not direct funding provided by the NCRR grant to the subproject or subproject staff. Introduction: Osteoporosis is a multifactorial disease characterized by reduced bone strength and increased susceptibility to low trauma fracture. Although a strong genetic contribution to osteoporosis and fracture is well documented, the genes and allelic variants conferring risk remain largely undefined. There is now an ongoing effort using modern genetic analyses to map the chromosomal loci of genes responsible for heritable differences in osteoporosis risk. While recent clinical reports show promise, unraveling the genetic influences on a complex disease like osteoporosis is a formidable challenge in humans because of the genetic and cultural heterogeneity of patient populations. Through the support of NIAMS, we have employed a congenic breeding strategy to develop different strains of laboratory mice with improved bone strength. Hypothesis: When applied to congenic mouse models with uniform genetic and environmental backgrounds, the high sensitivity, high dynamic range capillary LC-FTICR proteomic techniques developed at the PNNL NCRR Resource Center will identify biologically relevant molecular signatures and provide new insights into the pathophysiology of osteoporosis. Methods and Results: 1. Develop a database for the normal mouse plasma proteome, using fasting samples obtained from 10 female C57BL/6 inbred control mice. 2. Develop a database for the plasma proteome of two mice with improved bone strength, using fasting plasma samples from 10 female mice from two different congenic strains (both of which share the C57BL/6 background genome). 3. Perform quantitative analysis of protein abundances in the blood plasma in the two improved bone strength strains relative to the control mouse strain and each other. Discussion: Comparison of the proteome data from the background (C57BL/6) low bone mass mice and the two congenic high bone mass strains along with the knowledge of the different introgressed chromosomal regions in each of the congenic strains will allow for identification of biochemical pathways, networks and signaling nodes involved in the attainment and maintenance of skeletal integrity. These initial findings will be used as preliminary data for a subsequent grant application that will employ targetted proteomic, genomic and functional analyses of our murine models to further characterize the pathogenetic underpinnings of skeletal fragility and perhaps even identify biomarkers for early diagnosis of increased osteoporosis risk.

Agency
National Institute of Health (NIH)
Institute
National Center for Research Resources (NCRR)
Type
Biotechnology Resource Grants (P41)
Project #
5P41RR018522-09
Application #
8365488
Study Section
Special Emphasis Panel (ZRG1-BCMB-H (40))
Project Start
2011-07-01
Project End
2012-06-30
Budget Start
2011-07-01
Budget End
2012-06-30
Support Year
9
Fiscal Year
2011
Total Cost
$28,669
Indirect Cost
Name
Battelle Pacific Northwest Laboratories
Department
Type
DUNS #
032987476
City
Richland
State
WA
Country
United States
Zip Code
99352
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