Overview
Targeting NO/IKK Signaling to Counteract Hemodynamic Flow-Dependent Endothelial Dysfunction and Vascular Damage after Space Radiation
Principal Investigator:
Mohan Natarajan, Ph.D.
Organization:
University of Texas Health Science Center, San Antonio
Technical Summary
The development of subclinical vascular abnormalities, which have been known to occur during space missions, is largely due to functional alterations of endothelial cells, the inner lining of the vessels. Endothelial dysfunction is regarded as a primary sub-clinical condition that could progress into cardiovascular diseases over the life of astronauts.
Hypothesis
Space radiation at low doses may impair the interplay between three key proteins -- eNOS, Hsp-90 and IKK-# -- and cause functional alterations of endothelial cells. This dysfunctional endothelium fails to regulate vascular healing processes and negates cell migration/motility. When unchecked, this may predispose the vascular bed to become a sustained pro-inflammatory milieu for the initiation of cardiovascular abnormalities.
Radiation exposure can simultaneously also have an impact on endothelial progenitor cells (EPCs) and thereby attenuate EPC-dependent repair and reendothelializqation.
Specific Aims
1) Investigate the significance of high Linear Energy Transfer (LET) radiation on causing endothelial dysfunction and associated damages on vascular bed, impairment of cell migration/motility and inhibition of vascular healing processes. Three different HZE ion beams (16O, 28Si and 56Fe) accelerated to the same velocity (600 MeV/amu) and having similar track structure dimensions, but different ionization densities will be compared;
2) Study how high LET radiation concurrently exploits eNOS, Hsp-90, and IKK# signaling to cause endothelial dysfunction, while impairing the repair capacity of bone-marrow derived endothelial progenitor cells (EPCs); and,
3) Examine whether the findings, whilst allowing the researchers to gain knowledge on the mechanism of cardiovascular alterations by high LET radiation exposure, would lead the group to develop and quantitatively assess biological countermeasures for cardiovascular risks.
This study emphasizes a multi-stage approach -- in vitro, ex vivo and in vivo -- to understand the underlying mechanism of functional alteration of flow-adapted endothelial cells in response to space radiation. This study fits in very well with HRP-Integrated Research Program road map.