The overall goal of these studies is to define the mechano-induction and function of the endothelial KLF2 transcription factor in vascular biology. Our laboratory has performed numerous studies that have contributed significantly to understanding KLF2. These include the original cloning of the KLF2 gene, the development and examination of animals lacking KLF2 expression, and the initiation of studies on the regulation of the endothelial KLF2 gene by fluid shear stress. KLF2 plays an important role in endothelial cell (EC) biology. In vitro and in vivo experiments with human and mouse vascular ECs indicate that KLF2 exhibits sustained induction under pulsatile laminar shear stress, a biomechanical stimulus with recognized vaso-protective properties. Furthermore, numerous in vitro studies have demonstrated that KLF2 gene expression has the potential to reduce the susceptibility of the endothelium to atherosclerosis. We hypothesize that KLF2 mediates athero-protective endothelial phenotypes and, as such, that the mechanisms leading to KLF2 expression represent important therapeutic targets. These studies will expand upon our previous work on the mechano-transduction pathways responsible for the upregulation of KLF2 expression in response to fluid flow. They will also be the first to test whether KLF2 expression is sufficient to decrease the severity of lesions in murine models of atherosclerosis. Additionally, they will define the contribution of KLF2 to vasodilation in vivo using conditional knockout and transgenic over-expressing murine animal models. Importantly, they will serve as a prerequisite for further investigation of KLF2 as a vaso-protective therapeutic target.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL078806-04
Application #
7743732
Study Section
Vascular Cell and Molecular Biology Study Section (VCMB)
Program Officer
Gao, Yunling
Project Start
2007-01-19
Project End
2012-06-30
Budget Start
2010-01-01
Budget End
2012-06-30
Support Year
4
Fiscal Year
2010
Total Cost
$390,000
Indirect Cost
Name
University of Cincinnati
Department
Genetics
Type
Schools of Medicine
DUNS #
041064767
City
Cincinnati
State
OH
Country
United States
Zip Code
45221
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Lingrel, Jerry B; Pilcher-Roberts, Robyn; Basford, Joshua E et al. (2012) Myeloid-specific Krüppel-like factor 2 inactivation increases macrophage and neutrophil adhesion and promotes atherosclerosis. Circ Res 110:1294-302
Mahabeleshwar, Ganapati H; Kawanami, Daiji; Sharma, Nikunj et al. (2011) The myeloid transcription factor KLF2 regulates the host response to polymicrobial infection and endotoxic shock. Immunity 34:715-28