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.

摘要