MicroRNAs (miRNA) play important roles in regulating the plasticity and functions of stem and progenitor cells. MiRNA expression pattern undergoes dynamic changes during aging in a tissue and gene specific manner, implicating a putative role of specific miRNA and their target genes in mediating senescent changes and functional impairment of endothelial progenitor cells (EPC)/lineage negative bone marrow cells (linBMC). We and others have shown that EPC are actively involved in vascular repair. Senescent EPC, such as those from aged animals, have impaired repair capacity, which is coupled with atherosclerosis development. Therefore, EPC senescence may partially mediate the strong predisposing effects of aging and other cardiovascular risk factors on atherosclerosis. To determine the molecular underpinnings for age associated EPC senescence in the presence and absence of percholesterolemia, we have performed miRNA and mRNA profiling in EPC/linBMC from young and aged apoE/ and wild type mice. We have identified miR10A*/ miR21, miR29c and miR126, as well as their target genes, to be differentially expressed in young and aged linBMC. These miRNA control distinct aspects of linBMC competency. Specifically, the miR10a*/ miR21hmga2?p16Ink4a/p19Arf axis mainly regulates linBMC self renewal potential, whereas miR29cklf2a'miR126 spred1 VEGF signaling predominantly governs linBMC differentiation capacity. We have generated evidence supporting the role of miRNA in regulating linBMC activities in vivo. With this proposal, we have developed a comprehensive set of experiments to characterize the combined effects of these two candidate pathways in regulating linBMC senescence in vitro. We will also study additional miRNA/mRNA candidates derived from analysis of our genome wide profiling data and published reports. Then, we will determine the functional significance of miR10a*/miR21hmga2-?p16Ink4a/p19Arf axis and miR29c-'klf2a-'miR126spred1 VEGF signaling as well as additional candidate miRNA and their target genes (validated in vitro) in affecting the effectiveness of linBMC in vascular repair and atherosclerosis development in apoE/mice in vivo. This integrated and innovative approach will allow us to thoroughly characterize the molecular mechanisms underlying linBMC senescence and functional impairment, which will facilitate the design of novel strategies to slow down/reverse the senescent process of EPC/linBMC (therefore to reduce atherosclerosis risk) and to enhance the therapeutic efficacy of bone marrow based cellular treatments for atherosclerosis using genetic modifications.

Public Health Relevance

We propose to study the microRNA regulation of age-associated endothelial progenitor cell competency, which impairs vascular repair and promotes atherosclerosis. We will focus on two pathways that regulate distinct function of EPC competency-self-renewal potential and differentiation capacity, respectively. We will test whether correcting these microRNA/target gene changes represents feasible and effective approaches for rejuvenating senescent progenitor cells. This knowledge is instrumental to design novel strategy to reduce atherosclerosis burden.

Agency
National Institute of Health (NIH)
Institute
National Institute on Aging (NIA)
Type
Research Project (R01)
Project #
5R01AG041754-02
Application #
8663151
Study Section
Atherosclerosis and Inflammation of the Cardiovascular System Study Section (AICS)
Program Officer
Velazquez, Jose M
Project Start
2013-06-01
Project End
2018-05-31
Budget Start
2014-06-15
Budget End
2015-05-31
Support Year
2
Fiscal Year
2014
Total Cost
$314,675
Indirect Cost
$109,675
Name
University of Miami School of Medicine
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
052780918
City
Coral Gables
State
FL
Country
United States
Zip Code
33146