Mechanism of radiation induced endovascular injury and mitigation via the Notch-Dll4 pathway

文摘:

ABSTRACT: This application is designed to address the scientific goals of RFA-AI-16-053. Using novel and non-invasive optical imaging with mathematical modeling, we will study longitudinal changes in vascular sequalae up to 70 days after radiation, in order to cover acute and delayed effects in multiple organs. We will also examine the role of the Notch-delta-like ligand 4 (Dll4) in regulating vascular changes after radiation. The Notch pathway is key to vascular development and has recently been shown to regulate vascular regression. Radiation is known to induce regression of blood vessels in multiple organs. For detailed mechanistic analyses, we will measure Notch-Dll4 intermediates in the vasculature of two irradiated organs that are the most sensitive to the late effects of radiation, the lungs and kidneys. We will support these studies by measuring perfusion and regression in the same models at the same time points after radiation. Further, we will define the role of a successful mitigator of delayed effects of acute radiation exposure (DEARE), the drug lisinopril, in Notch-Dll4- mediated regression. Lisinopril is an angiotensin-converting enzyme (ACE) inhibitor that improves survival after radiation in pre-clinical and clinical studies. These aims will be carried out in a whole animal model using wild type and genetically modified rat strains. We will deliver radiation to multiple organs using total body irradiation without or with one leg out of the field of exposure with high doses of 7.5 Gy or 13 Gy respectively. These radiation models are very well established in our laboratory facilitating reliable and robust data collection. The in vivo studies will be supported by ex vivo and molecular methods using isolated organs and blood vessels. We will also use irradiated and control rat and human endothelial cells in culture to compare Notch-Dll4 signaling responses. With strong statistical support, our strategy will ensure a robust and unbiased approach. The cutting-edge technology we have proposed in the application have feasible alternatives, relevant biological variables (female and male rats) and appropriate, quantitative milestones. The strength of our application lies in an integrated team of experts in radiobiology, engineering, mathematical modeling, vascular biology, animal care, clinical medicine, radiation physics and accurate dosimetry.