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

通过Notch-Dll4途径辐射引起的血管内损伤和缓解机制

• 批准号: 10305680
• 负责人: Heather A Himburg
• 金额: $ 50.14万
• 依托单位: MEDICAL COLLEGE OF WISCONSIN
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-12-11 至 2023-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10305680
• 关键词: Acute; Address; Angiotensin II; Angiotensin-Converting Enzyme Inhibitors; Animal Model; Animals; Biological; Biology; Blood Vessels; Chemicals; Clinical Medicine; Clinical Research; Computer Models; Data; Data Collection; Development; Dose; Drug Kinetics; Endothelial Cells; Engineering; Ensure; Female; Genetic; Goals; Human; Image; Imaging Techniques; In Situ; Injury; Investigation; Kidney; Laboratories; Late Effects; Leg; Ligands; Lisinopril; Longitudinal Studies; Lung; Magnetic Resonance Imaging; Measures; Mediating; Mediator of activation protein; Methods; MicroRNAs; Modeling; Molecular; Notch Signaling Pathway; Organ; Pathway interactions; Perfusion; Permeability; Pharmaceutical Preparations; Pharmacology; Proteins; RNA; Radiation; Radiation Injuries; Radiation Physics; Radiation Pneumonitis; Radiation Tolerance; Radiation exposure; Radiation induced damage; Radiobiology; Radiology Specialty; Rat Strains; Rattus; Reproducibility; Resources; Retina; Role; Signal Transduction; Supervision; Technology; Text; Time; Tissues; Vascular System; Whole-Body Irradiation; angiogenesis; animal care; base; contrast enhanced; density; design; dosimetry; improved; in vivo; inhibitor; innovation; male; mathematical model; new therapeutic target; non-invasive optical imaging; notch protein; novel; optical imaging; preclinical study; radiation effect; radiation response; radiation-induced injury; response; vascular injury; vessel regression

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.

抽象的： 该应用程序旨在实现 RFA-AI-16-053 的科学目标。使用新颖且非侵入性的 光学成像与数学模型，我们将研究血管后遗症的纵向变化高达70 辐射后几天，以涵盖多个器官的急性和延迟影响。我们还将检查 Notch-delta 样配体 4 (Dll4) 在调节辐射后血管变化中的作用。 Notch途径是 血管发育的关键，最近被证明可以调节血管退化。辐射是 已知可引起多个器官的血管退化。对于详细的机制分析，我们将 测量对最敏感的两个受辐射器官的脉管系统中的 Notch-Dll4 中间体 辐射、肺和肾脏的后期影响。我们将通过测量灌注和 辐射后同一时间点的同一模型中的回归。此外，我们将定义一个角色 Notch-Dll4-中的药物赖诺普利成功缓解了急性辐射暴露（DEARE）的延迟效应 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 临床前和临床研究中放疗后。这些目标将在整个动物模型中使用 野生型和转基因大鼠品系。我们将利用全身向多个器官提供辐射 单独或单腿离开照射区域的照射，分别采用 7.5 Gy 或 13 Gy 的高剂量。 这些辐射模型在我们的实验室中非常完善，可提供可靠且可靠的数据 收藏。体内研究将得到离体和分子方法的支持，使用分离的器官和 血管。我们还将在培养物中使用经过辐照的大鼠和对照大鼠和人内皮细胞来进行比较 Notch-Dll4 信号响应。凭借强大的统计支持，我们的战略将确保稳健且公正的 方法。我们在应用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）和适当的定量里程碑。实力 我们的应用在于放射生物学、工程学、数学建模、 血管生物学、动物护理、临床医学、放射物理学和精确剂量测定。