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. The endothelium lines the lumen of blood vessels and is a key regulator of vascular homeostasis. A loss of this homeostasis, or endothelial dysfunction, is recognized as a key process in the development and progression of chronic kidney disease (CKD). Endothelial dysfunction is a primary event in the development of atherosclerosis and it is now recognized that cardiovascular disease (CVD) and its complications are the most important cause of morbidity and mortality in CKD. Therefore, an understanding of the mechanisms responsible for endothelial dysfunction in CKD is important for improving renal and cardiovascular outcomes. Endothelial progenitor cells are stem cells that are mobilized into the circulation from the bone marrow and can help maintain endothelial function by contributing to the replacement of damaged endothelial cells. Endothelial progenitor cell function has been shown to be dependent on the ability of EPCs to release nitric oxide. Nitric oxide activity may be impaired in CKD as a result of increased production of the free radical superoxide and elevated levels of asymmetric dimethylarginine, an endogenous inhibitor of nitric oxide synthesis. Studies of endothelial progenitor cells in renal disease have been limited to end stage renal disease (ESRD) and have not investigated the mechanisms of functional impairment. Due to the progressive nature of CKD and the fact that the risk for CVD is elevated early in the progression of CKD, it is important to understand the mechanisms of endothelial dysfunction in CKD to develop early interventions that slow the progression of disease and reduce the risk of CVD. Our global hypothesis is that EPC function is impaired in CKD prior to the development of ESRD contributing to endothelial dysfunction and cardiovascular risk. We have developed in vitro techniques for the study of EPCs and will begin assessing EPC function in human CKD. In this INBRE application we propose to develop the 5/6 ablation-infarction (A/I) rat model of CKD and study in vitro function (migration and incorporation into tube structures) of EPCs isolated from the peripheral blood of these rats. To gain further insight into EPC function we propose to study the ability of EPCs to participate in vascular repair following carotid artery injury in 5/6 A/I rats. These studies are novel in that they would be the first to study EPC function in an animal model of CKD. Further, we would be in the unique position of being able to translate our findings in the 5/6 A/I animal model of CKD to our ongoing human work. Consistent with the goals of INBRE, these studies will provide preliminary data for an R01 proposal (end of year 2) to continue to elucidate the mechanisms of EPC dysfunction in our animal model. Therefore, the successful completion of this project would be expected to have a potentially important impact on maintaining renal function and reducing cardiovascular risk in CKD patients. Our research team is made up of faculty in the Department of Health, Nutrition, and Exercise Sciences and the Department of Biology at the University of Delaware. We will utilize the Bioimaging Core Lab at the Delaware Biotechnology Institute and the Center for Translational Cancer Research. Additionally, this work will provide both graduate and undergraduate students with hands on research training.

Agency
National Institute of Health (NIH)
Institute
National Center for Research Resources (NCRR)
Type
Exploratory Grants (P20)
Project #
5P20RR016472-11
Application #
8359622
Study Section
Special Emphasis Panel (ZRR1-RI-4 (01))
Project Start
2011-03-01
Project End
2012-02-29
Budget Start
2011-03-01
Budget End
2012-02-29
Support Year
11
Fiscal Year
2011
Total Cost
$98,821
Indirect Cost
Name
University of Delaware
Department
Type
Organized Research Units
DUNS #
059007500
City
Newark
State
DE
Country
United States
Zip Code
19716
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