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.

项目摘要 动脉粥样硬化性心血管疾病（ASCVD）是美国的主要死亡原因， 国际吧动脉粥样硬化是这些病症的基础，其特征在于慢性动脉粥样硬化。 炎症和疾病贡献细胞的不适当增殖。目前可用的药物 动脉粥样硬化的治疗仅仅针对危险因素，而不是致病细胞本身。此外，本发明还 诸如经皮冠状动脉介入（PCI）侵入性手术治疗动脉狭窄，但可能 不良反应如血栓形成。因此，尽管在该领域取得了进展，但位点特异性和细胞选择性 靶向形成动脉粥样硬化斑块的细胞而不影响血管内皮的疗法 available.因此，这项研究计划的主要目的是测试一种新型信使RNA的可行性。 在一些实施方案中，本发明涉及一种仅在靶向动脉粥样硬化斑块的区域中具有位点特异性的mRNA（mRNA）治疗剂，而特异性地 靶向致病细胞，减少炎症，保护血管内皮。本研究是 ASCVD对公共卫生非常重要，因为ASCVD代表了一个主要的公共卫生问题， 我们国家的负担。我推测，微RNA（miRNA）开关和小干扰RNA的组合 将siRNA技术引入单个mRNA构建体将允许第一种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疗效，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，我的体外 这个模型使用的是从人体心脏中新鲜分离出来的冠状动脉，这使我的工作更具有临床意义 并允许我在患有动脉粥样硬化斑块的人类动脉上测试我的治疗方法。我们的目标是 对该领域产生了积极的影响，不仅设计了一种新的mRNA治疗剂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， 为了治疗其他疾病。我将在我的赞助人哈纳博士的指导下朝着这个目标努力 Totary-Jain是CVD和RNA治疗研究领域的专家， USF Health's Morsani College of Medicine附近的景点我的导师，委员会，其他顾问， 部门将为我提供所有必要的培训和资源，以完成这一非常 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， 首席调查员