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: 10544729
• 负责人: Saraswati Pokharel
• 金额: $ 40.34万
• 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/10544729
• 关键词: Achievement; Address; Birth; Blood Vessels; Blood flow; Bypass; Cancer Patient; Cancer Survivor; Cardiac; 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; Functional disorder; Genes; Genetic; Genetic Transcription; Genetically Engineered Mouse; Goals; Half-Life; Heart; Heart failure; Hodgkin Disease; Impairment; Incidence; Injury; Intervention; Ionizing radiation; Ions; Knowledge; Lead; Liposomes; Malignant Neoplasms; Malignant neoplasm of lung; Malignant neoplasm of thorax; Mediating; Microvascular Dysfunction; Modeling; Molecular; Molecular Biology; Mus; Muscle Cells; Myocardial; Myocardial Ischemia; Myocardial perfusion; Operative Surgical Procedures; Organ; Pathologic; Peptides; Permeability; Pharmacotherapy; Porosity; Predisposition; Process; Property; Protocols documentation; Radiation; Radiation exposure; Radiation therapy; Resistance; Rodent; Role; Serum; Site; Small Interfering RNA; Stents; Structure; Technology; Testing; Therapeutic; Tight Junctions; Tissues; Vascular Endothelial Cell; Vascular Permeabilities; Xenograft Model; 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; radiation mitigation; reconstitution; restoration; seal; siRNA delivery; small molecule; solute; testing uptake; therapeutic evaluation; thymosin beta(4); tumor; uptake; vascular injury; 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 此应用程序旨在实现 FOA-PA-19-112 的科学目标。冠状动脉微血管 疾病（CMD）是癌症幸存者胸部放射治疗的主要后遗症。阻断较大的冠状动脉 动脉可以通过支架或外科搭桥手术进行治疗；然而，目前尚无有效的治疗方法 以 CMD 为目标。该项目旨在研究新颖且以前未探索过的电离机制 辐射 (IR) 引起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)，以抵消这些影响。该提议的科学前提是基于我们 最近的研究表明，内皮细胞严重损伤，冠状动脉血管损伤明显增加 啮齿动物胸部辐射暴露后的渗透性和纤维化。我们还发现辐射引起的 CMD 与claudin-1 (cldn1) 表达的转录抑制呈剂量依赖性相关。重要的是， 给予 Ac-SDKP（一种胸腺肽 β4 衍生的内源性肽），使内皮细胞正常化 通透性、重建 cldn1 并减少心脏纤维化。 尽管具有心脏保护潜力，但 Ac-SDKP 的治疗应用一直具有挑战性，因为 其在血清中的半衰期较短（T1/2 为 4.5 分钟）。因此，我们开发了一种稳定的脂质体 Ac-SDKP（Lip- Ac-SDKP）配方，我们打算测试其持续的系统效应。我们假设 Ac-SDKP 减轻辐射引起的冠状动脉内皮损伤，并通过以下方式防止微血管渗漏 抑制 IR 介导的 cldn1 丢失。在目标 I 中，我们将检查 Lip-Ac- 的吸收效率和生物活性 SDKP 在心脏和冠状动脉微血管内皮细胞中。在目标 II 中，我们将检查 Ac- 的影响 SDKP 对辐射后内皮屏障完整性的影响并研究 cldn1 在此过程中的作用。在目标 III 中，我们 将确定 Ac-SDKP 治疗对辐射引起的冠状动脉血流以及局部和区域的影响 整体心脏功能。 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 开发了一种内皮细胞特异性 cldn1 增益的新型基因工程小鼠模型 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，我们将利用携带肿瘤的同基因和异种移植模型来检查 Ac-SDKP 多剂量胸部照射后的效果。该项目将提供有关机制的见解 Ac-SDKP 对辐射引起的 CMD 的保护作用，并将具有重要的治疗意义 对易受放疗引起的 CMD 和心脏病的癌症患者进行及时和有针对性的干预 缺血。