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

摘要： 本申请旨在实现RFA-AI-16-053的科学目标。使用新型和非侵入性的 光学成像与数学建模，我们将研究纵向变化血管后遗症高达70 辐射后30天内的数据，以涵盖对多个器官的急性和延迟影响。我们亦会研究 Notch-delta-like ligand 4（Dll 4）在辐射后调节血管变化中的作用。Notch途径是 是血管发育的关键，最近已显示可调节血管消退。辐射 已知会导致多个器官的血管退化。对于详细的机理分析，我们将 测量两个受照射器官的脉管系统中的Notch-Dll 4中间体，所述器官对所述Notch-Dll 4中间体最敏感。 辐射的后期影响，肺和肾我们将通过测量灌注来支持这些研究， 在辐射后相同时间点在相同模型中的回归。此外，我们将定义一个 在Notch-Dll中，急性辐射暴露（DEARE）延迟效应的成功缓解剂，药物赖诺普利， 介导的回归赖诺普利是一种血管紧张素转换酶（ACE）抑制剂，可提高生存率 在临床前和临床研究中，这些目标将在一个完整的动物模型中进行， 野生型和转基因大鼠品系。我们将使用全身放射治疗对多个器官进行放射治疗 分别以7.5戈伊或13戈伊的高剂量照射，不照射或单腿出照射野照射。 这些辐射模型在我们的实验室中建立得非常好，有助于获得可靠和可靠的数据 收藏.体内研究将得到离体和分子方法的支持， 血管我们还将使用辐照和对照大鼠和人类内皮细胞在培养中进行比较 Notch-Dll 4信号传导应答。在强有力的统计支持下，我们的战略将确保 approach.我们在应用中提出的尖端技术有可行的替代方案， 相关生物变量（雌性和雄性大鼠）和适当的定量里程碑。的强度 我们的应用依赖于放射生物学，工程学，数学建模， 血管生物学、动物护理、临床医学、辐射物理学和精确剂量测定。

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.