Telomerase, a ribo-nucleoprotein that counteracts telomere shortening, has recently been suggested as having a telomere independent survival function. A protective effect of telomerase on mitochondrial function under conditions of oxidative stress has been described, yet the exact mechanism and phenotype linked to mitochondrial or nuclear TERT (catalytic subunit of telomerase) is not clearly identified. We have shown that in the presence of coronary artery disease or acute vascular stressors, there is a shift in the mechanism of flow mediated dilation (FMD) from NO to H2O2. The current study aims to differentiate the role of nuclear TERT vs. mitochondrial TERT in the development of cardiovascular (CV) disease. In our central hypothesis, mitochondrial TERT plays a critical and previously undiscovered role in reducing mitochondrial reactive oxygen species (ROS) thus protecting against CV disease and other ROS associated disorders. This study will focus on CV health and use FMD and its mechanism and redox environment as physiological markers. The conceptual paradigm shift tested is that mitochondrial TERT decreases mitochondrial ROS production by improving mitochondrial respiratory chain activity. This contributes to maintaining normal NO levels, thereby preserving physiological regulation of FMD in the microvasculature. Conversely, we postulate that reduced mitochondrial TERT results in increased mitochondrial ROS, driving microvascular dysfunction by changing the mediator of FMD from NO to H2O2 thereby creating a pro-inflammatory milieu. We will be using state of the art methods to evaluate vascular reactivity alongside molecular evaluation of the redox environment to characterize the role of telomerase in regulating cellular and mitochondrial ROS levels. This novel hypothesis and the models generated have important translational potential and will be extremely useful for investigators studying varying diseases and in multiple fields.

Public Health Relevance

Telomerase, traditionally a protector of telomere length, has recently been linked to changes in levels of reactive oxygen species;however, it is not understood if this is via its nuclear or mitochondrial function. The overall goal of this applicatin is to differentiate and define the role of nuclear vs. mitochondrial TERT (catalytic subunit of telomerase) in the development of disease with a specific focus on cardiovascular events. This novel hypothesis and the models generated have important translational potential and will be extremely useful for investigators studying varying diseases and in multiple fields.

Agency
National Institute of Health (NIH)
Type
Exploratory/Developmental Grants (R21)
Project #
1R21OD018306-01
Application #
8681115
Study Section
Vascular Cell and Molecular Biology Study Section (VCMB)
Program Officer
Mirochnitchenko, Oleg
Project Start
Project End
Budget Start
Budget End
Support Year
1
Fiscal Year
2014
Total Cost
Indirect Cost
Name
Medical College of Wisconsin
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
City
Milwaukee
State
WI
Country
United States
Zip Code
53226