Development of a novel site-and cell-selective mRNA therapeutic to treat atherosclerosis

开发一种新的位点和细胞选择性 mRNA 治疗剂来治疗动脉粥样硬化

• 批准号: 10679992
• 负责人: Isabella Hetherington
• 金额: $ 3.79万
• 依托单位: UNIVERSITY OF SOUTH FLORIDA
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-05-15 至 2026-05-14
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10679992
• 关键词: 5' Untranslated Regions; Adverse effects; Anti-Inflammatory Agents; Apolipoprotein E; Arterial Fatty Streak; Arteries; Atherosclerosis; Binding Sites; Cardiac; Cause of Death; Cell Cycle; Cell Proliferation; Cell Separation; Cell physiology; Cells; Chronic; Clinical Trials; Colchicine; Control Groups; Coronary artery; Deposition; Development; Disease; Dose; Effectiveness; Endothelial Cells; Endothelium; Environment; Event; Generations; Goals; Health; Heart; Human; Hypertension; In Vitro; Incidence; Infection; Inflammasome; Inflammation; Inflammatory; Inhibition of Cell Proliferation; Injury; Institution; Interleukin-1 beta; Lipids; Macrophage; Medicine; Mentors; Mentorship; Messenger RNA; Methods; MicroRNAs; Modeling; Mus; Outcome; Patients; Penetration; Peptides; Pharmaceutical Preparations; Postdoctoral Fellow; Principal Investigator; Procedures; Proliferating; Public Health; Reporting; Research; Research Proposals; Resolution; Resources; Risk Factors; Series; Site; Small Interfering RNA; Smooth Muscle Myocytes; Stenosis; Stents; Targeted Research; Technology; Testing; Therapeutic; Therapeutic Research; Thrombosis; Training; Transfection; United States; Vascular Endothelium; Vascular Smooth Muscle; Work; career; cell assembly; cell motility; cell type; clinically relevant; college; comparison control; cytokine; design; effectiveness testing; efficacy testing; experimental study; feasibility testing; healing; hypercholesterolemia; in vivo; inhibitor; innovation; migration; mortality risk; mouse model; nanoparticle; nanoparticle delivery; nanotherapy; neointima formation; novel; novel therapeutics; overexpression; percutaneous coronary intervention; preservation; selective expression; self assembly; stent thrombosis; targeted treatment; therapeutic RNA

PROJECT SUMMARY Atherosclerotic cardiovascular diseases (ASCVDs) are the leading cause of death in the United States and worldwide. Atherosclerosis of the arteries underlies these conditions and is characterized by chronic inflammation and inappropriate proliferation of disease contributing cells. Current medications available for the treatment of atherosclerosis merely target risk factors, not the disease-causing cells themselves. Additionally, invasive procedures such as percutaneous coronary intervention (PCI) treat arterial stenosis but can have adverse effects such as thrombosis. Therefore, despite progress in the field, site-specific and cell-selective therapies that target the cells that form atherosclerotic plaques while sparing the vascular endothelium are not available. Thus, the main objective of this research proposal is to test the feasibility of a novel messenger RNA (mRNA) therapeutic that is site-specific in targeting regions of atherosclerotic plaques only, while specifically targeting disease causing cells, reducing inflammation, and sparing the vascular endothelium. This research is highly significant to public health as ASCVDs represent a major public health issue and place an enormous burden on our Nation. I hypothesize that a combination of microRNA (miRNA) switch and small interfering RNA (siRNA) technology into a single mRNA construct will allow for a first of its kind RNA therapeutic strategy to cause atherosclerotic plaque regression and resolution. In order to test the efficacy of this new therapeutic, I will employ a series of rigorous experiments using in vitro, in vivo, and ex vivo models. Importantly, my ex vivo model uses freshly isolated coronary arteries from human hearts, giving more clinical relevance to my work and allowing me to test my therapeutic on human arteries burdened with atherosclerotic plaques. We aim to make a positive impact on the field by not only designing a novel mRNA therapeutic to treat atherosclerosis, but also, by providing evidence for the effectiveness of this unique therapeutic strategy that can be modified in order to treat other diseases. I will work towards this goal under the mentorship of my sponsor, Dr. Hana Totary-Jain, an expert in the field of CVD as well as RNA therapeutic research, at the supportive research environment of USF Health’s Morsani College of Medicine. My mentor, committee, additional advisors, and department will provide me with all the necessary training and resources needed to complete this very impactful research while also preparing me for my next career stage as a post-doctoral scholar and eventually a principal investigator.

项目概要 动脉粥样硬化性心血管疾病 (ASCVD) 是美国和美国的主要原因 在世界范围内，动脉粥样硬化是这些病症的基础，其特点是慢性。 目前可用的药物包括炎症和疾病细胞的不适当增殖。 动脉粥样硬化的治疗仅针对危险因素，而不是致病细胞本身。 经皮冠状动脉介入治疗 (PCI) 等侵入性手术可以治疗动脉狭窄，但可能会导致动脉狭窄。 因此，尽管该领域取得了进展，但位点特异性和细胞选择性。 以形成动脉粥样硬化斑块的细胞为目标同时不损伤血管内皮的疗法并不 因此，本研究计划的主要目的是测试新型信使RNA的可行性。 (mRNA) 治疗剂仅针对动脉粥样硬化斑块区域具有位点特异性，而特异性 这项研究旨在针对致病细胞、减少炎症并保护血管内皮。 ASCVD 是一个重大的公共卫生问题，并且对公众健康产生了巨大的影响，因此对公众健康非常重要。 我领导了 microRNA (miRNA) 开关和小干扰 RNA 的结合。 (siRNA) 技术融入单个 mRNA 构建体中，将成为首个此类 RNA 治疗策略 导致动脉粥样硬化斑块消退和消退 为了测试这种新疗法的功效，我 将使用体外、体内和离体模型进行一系列严格的实验。重要的是，我的离体模型。 模型使用从人类心脏中新鲜分离的冠状动脉，为我的工作提供更多的临床相关性 并允许我测试我对患有动脉粥样硬化斑块的人类动脉的治疗效果。 不仅设计了一种新的 mRNA 疗法来治疗动脉粥样硬化， 而且，通过提供证据证明这种独特的治疗策略的有效性，可以在 为了治疗其他疾病，我将在我的赞助商 Hana 博士的指导下努力实现这一目标。 Totaly-Jain 是 CVD 和 RNA 治疗研究领域的专家，参与支持性研究 我的导师、委员会、其他顾问和南佛罗里达大学健康学院莫萨尼医学院的环境。 部门将为我提供完成这项工作所需的所有必要的培训和资源 有影响力的研究，同时也为我作为博士后学者的下一个职业阶段做好准备，并最终 首席研究员。