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

摘要： 此应用程序旨在满足RFA-AI-16-053的科学目标。使用新颖且非侵入性的 光学成像与数学建模，我们将研究血管后遗症的纵向变化高达70 辐射后数天，以涵盖多个器官的急性和延迟性影响。我们还将研究 Notch-Delta样配体4(DLL4)在调节辐射后血管变化中的作用Notch路径是 它是血管发育的关键，最近被证明可以调节血管退行性变。辐射是 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 测量两个受照器官血管系统中的Notch-DLL4中间体，这两个器官对 辐射、肺和肾的晚期效应。我们将通过测量血流灌注量和 在同一模型相同时间点进行辐射后回归。此外，我们还将定义 在Notch-DLL4中成功缓解急性辐射暴露(DEARE)的延迟效应，药物赖诺普利 中介回归。赖诺普利是一种血管紧张素转换酶(ACE)抑制剂，可提高存活率 放射治疗后的临床前和临床研究。这些目标将在整个动物模型中实现，使用 野生型和转基因大鼠品系。我们将通过全身向多个器官提供辐射 照射野外无照射或单侧照射，大剂量分别为7.5GY和13GY。 这些辐射模型在我们的实验室中得到了很好的建立，从而提供了可靠和可靠的数据 收集。体内研究将由体外和分子方法支持，使用分离的器官和 血管。我们还将在培养中使用辐照和对照的大鼠和人内皮细胞来比较 Noch-DLL4信号响应。在强有力的统计支持下，我们的战略将确保稳健和公正 接近。我们在申请中提出的尖端技术有可行的替代方案， 相关的生物变量(雌性和雄性大鼠)和适当的量化里程碑。力量的力量 我们的应用在于一支由放射生物学、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学。

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.