Inhibition of Radiation-Induced Coronary Microvascular Disease

抑制辐射引起的冠状动脉微血管疾病

• 批准号: 10329997
• 负责人: Saraswati Pokharel
• 金额: $ 41.25万
• 依托单位: ROSWELL PARK CANCER INSTITUTE CORP
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-01-15 至 2025-12-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10329997
• 关键词: Achievement; Address; Birth; Blood flow; Bypass; Cancer Patient; Cancer Survivor; Cells; Cessation of life; Chest; Clinical; Coronary; Coronary Vessels; Coronary artery; Data; Development; Dose; Drug or chemical Tissue Distribution; Endothelial Cells; Endothelium; Engineering; Event; Extravasation; Fibrosis; Formulation; Genes; Genetic; Genetic Transcription; Genetically Engineered Mouse; Goals; Half-Life; Heart; Heart failure; Hodgkin Disease; Impairment; Incidence; Injury; Intervention; Ionizing radiation; Ions; Knowledge; Lead; Lip structure; Liposomes; Lys-Asp; Malignant Neoplasms; Malignant neoplasm of lung; Malignant neoplasm of thorax; Mediating; Microvascular Dysfunction; Modeling; Molecular; Molecular Biology; Mus; Muscle Cells; Myocardial; Myocardial Ischemia; Myocardial dysfunction; Myocardial perfusion; Operative Surgical Procedures; Organ; Pathologic; Peptides; Permeability; Pharmacotherapy; Porosity; Process; Property; Protocols documentation; Radiation; Radiation exposure; Radiation therapy; Resistance; Rodent; Role; Serum; Site; Small Interfering RNA; Stents; Structure; Technology; Testing; Therapeutic; Tight Junctions; Time; Tissues; Vascular Endothelial Cell; Vascular Permeabilities; Xenograft Model; base; cancer radiation therapy; cardiac magnetic resonance imaging; cardioprotection; cell injury; claudin-1 protein; cohort; coronary fibrosis; cytotoxic; design; effective therapy; fluorescence imaging; gain of function; heart function; hypoperfusion; imaging approach; improved; in vivo; insight; irradiation; knock-down; loss of function; lysylproline; malignant breast neoplasm; molecular imaging; mouse model; nanoparticle; next generation; novel; novel therapeutics; overexpression; preservation; prevent; protective effect; radiation effect; reconstitution; restoration; seal; siRNA delivery; small molecule; solute; testing uptake; therapeutic evaluation; thymosin beta(4); tumor; uptake; water diffusion

ABSTRACT This application is designed to address the scientific goals of FOA-PA-19-112. Coronary microvascular disease (CMD) is major sequelae of chest radiotherapy in cancer survivors. Blockade of the larger coronary arteries can be treated by stents or surgical bypass; however, there are no effective therapies currently available to target CMD. This project aims to investigate the novel and previously unexplored mechanisms of ionizing radiation (IR)-induced coronary microvascular injury, and test the beneficial effects of a small molecule, N-acetyl- ser-asp-lys-pro (Ac-SDKP), to counteract these effects. The scientific premise of this proposal is based on our recent studies demonstrating profound endothelial cell injury with marked increase in coronary vascular permeability, and fibrosis, after thoracic radiation exposure in rodents. We also found that radiation-induced CMD was dose-dependently associated with the transcriptional inhibition of claudin-1 (cldn1) expression. Importantly, administration of Ac-SDKP, a thymosin β4-derived endogenous peptide, normalized endothelial cell permeability, reconstituted cldn1, and reduced cardiac fibrosis. Despite its cardioprotective potential, therapeutic application of Ac-SDKP has been challenging due to its short half-life (T1/2 of 4.5 mins) in serum. Therefore, we have developed a stable, liposomal Ac-SDKP (Lip- Ac-SDKP) formulation, which we intend to test for sustained systemic effects. We hypothesize that Ac-SDKP mitigates radiation-induced coronary endothelial damage, and prevents microvascular leakage by inhibiting IR-mediated cldn1 loss. In Aim I, we will examine the uptake efficiency and bioactivity of Lip-Ac- SDKP in the heart and in coronary microvascular endothelial cells. In Aim II, we will examine the effects of Ac- SDKP on endothelial barrier integrity after radiation and study the role of cldn1 in this process. In Aim III, we will determine the effects of Ac-SDKP treatment on radiation-induced coronary blood flow and regional and global cardiac function. We will accomplish these aims by using advanced molecular biology and imaging approaches. We have developed a novel genetically engineered mouse model of endothelial cell-specific cldn1 gain-of- function. We have also developed a cldn1 loss-of-function model using a next generation in vivo siRNA delivery technology. Additionally, we will utilize tumor-bearing syngeneic and xenograft models to examine Ac-SDKP effects after multi-dose thoracic irradiation. This project will provide mechanistic insight on the protective effects of Ac-SDKP against radiation-induced CMD, and will have important therapeutic implications for timely and targeted interventions in cancer patients susceptible to radiotherapy-induced CMD and cardiac ischemia.

抽象的 该应用程序旨在解决FOA-PA-19-112的科学目标。冠状动脉微血管 疾病（CMD）是癌症存活中胸部放疗的主要后遗症。较大冠状动脉的封锁 动脉可以通过支架或手术旁路治疗；但是，目前尚无有效的疗法 靶向CMD。该项目旨在调查电离的新颖和以前出乎意料的机制 辐射（IR）诱导的冠状动脉微血管损伤，并测试小分子N-乙酰基的有益作用 Ser-Asp-Lys-Pro（AC-SDKP），以抵消这些效果。该提议的科学前提是基于我们的 最近的研究表明，冠状动脉血管的明显增加，表现出严重的内皮细胞损伤 啮齿动物胸腔辐射暴露后的渗透性和纤维化。我们还发现辐射诱导的CMD 剂量与Claudin-1（CLDN1）表达的转录抑制作用依赖性相关。重要的是， 给药AC-SDKP，一种胸腺素β4衍生的内源性肽，归一化的内皮细胞 渗透性，重建的CLDN1和降低心脏纤维化。 尽管具有心脏保护潜力，但AC-SDKP的治疗应用已受到挑战 它的半衰期短（4.5分钟的T1/2）在血清中。因此，我们已经开发了稳定的脂质体AC-SDKP（唇 - AC-SDKP）公式，我们打算测试持续的全身效应。我们假设AC-SDKP 减轻辐射引起的冠状动脉内皮损害，并防止微血管泄漏 抑制IR介导的CLDN1损失。在目标I中，我们将检查唇部AC-的吸收效率和生物活性 心脏和冠状动脉微血管内皮细胞中的SDKP。在AIM II中，我们将研究AC-的影响 辐射后的内皮屏障完整性上的SDKP并研究CLDN1在此过程中的作用。在AIM III中，我们 将确定AC-SDKP治疗对辐射诱导的冠状动脉血流和区域的影响 全球心脏功能。 我们将通过使用先进的分子生物学和成像方法来实现这些目标。我们有 开发了一种新颖的内皮细胞特异性CLDN1的通用小鼠模型 功能。我们还使用下一代体内siRNA开发了CLDN1功能丧失模型 交付技术。此外，我们将利用含有肿瘤的同步和异种移植模型来检查 多剂量胸腔照射后的AC-SDKP作用。该项目将提供有关机械的见解 AC-SDKP对辐射诱导的CMD的保护作用，并具有重要的治疗意义 及时且有针对性的干预措施，易受放射疗法诱导的CMD和心脏的干预措施 缺血。