Ultrasound-mediated modulation of microRNAs for treatment of cardiac hypertrophy

超声介导的 microRNA 调节治疗心脏肥大

• 批准号: 8835272
• 负责人: Jonathan Andrew Kopechek
• 金额: $ 5.82万
• 依托单位: UNIVERSITY OF PITTSBURGH AT PITTSBURGH
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-01-01 至 2017-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8835272
• 关键词: Abbreviations; Acoustics; Address; Adverse effects; Antihypertensive Agents; Aortic Valve Stenosis; Attenuated; Cardiac; Cardiac Myocytes; Cardiomyopathies; Cardiovascular Diseases; Cause of Death; Cell membrane; Cessation of life; Clinical; Clinical Treatment; Cytoplasm; Development; Dilated Cardiomyopathy; EFRAC; Endocytosis; Event; Foundations; Frequencies; Genes; Goals; Heart; Heart Hypertrophy; Heart failure; Human; Hypertension; Hypertrophy; Image; Immune response; In Vitro; Infusion procedures; Label; Lead; Left Ventricular Hypertrophy; Left Ventricular Mass; Left ventricular structure; Measures; Mechanics; Mediating; Methods; MicroRNAs; Microbubbles; Modeling; Molecular; Mus; Myocardial Infarction; Neonatal; Nucleic Acids; Nucleotides; Pathway interactions; Pharmaceutical Preparations; Phenylephrine; Rattus; Regimen; Regulation of Proteolysis; Research; Risk; Site; Small Interfering RNA; Speed; Stroke; Testing; Therapeutic; Transcriptional Regulation; Translations; Ubiquitin; Ultrasonography; United States; Ventricular Arrhythmia; Viral Vector; base; cardiovascular risk factor; heart function; hypertensive heart disease; imaging system; improved; in vivo; in vivo Model; indexing; inhibitor/antagonist; insight; interest; novel; programs; public health relevance; sudden cardiac death; targeted delivery; theranostics; therapeutic target; tool; ventricular hypertrophy

DESCRIPTION (provided by applicant): Left ventricular hypertrophy (LVH), such as occurs in hypertension, carries an increased risk for cardiovascular events. Clinical evidence indicates that inhibition and regression of LVH is associated with improved cardiac function and a reduced risk of cardiovascular complications. MicroRNAs (miRNAs) are short endogenous RNAs that can regulate multiple genes. miRNA levels have been shown to significantly change in diseased human hearts. Modulation of miRNAs to treat cardiovascular disease is seen as a potentially powerful clinical tool; e.g. knockdown of miR-23a, which promotes hypertrophy, was shown to blunt cardiac hypertrophy in a hypertensive murine model. However, the lack of effective, safe, non-immunogenic methods for delivery of miRNA mimics or inhibitors limits clinical translation. Ultrasound targeted microbubble destruction (UTMD) represents an attractive non-immunogenic, theranostic delivery strategy to locally modulate miRNA levels in the heart. UTMD has been shown to enhance endocytosis and can also induce transient pores to form in cell membranes as a result of microbubble oscillation and collapse, potentially allowing nucleotides to enter the cytoplasm directly. The objective of this proposal is to develop a platform utilizing ultrasound and microbubbles to regulate miRNA levels in the heart. This platform can potentially be used to deliver any miRNA mimic or inhibitor of interest. Accordingly, we hypothesize that UTMD-mediated delivery of an antagomir directed against pro-hypertrophic miR-23a will attenuate phenylephrine-induced cardiac hypertrophy. Our 3 Specific Aims are to determine: (1) if UTMD can deliver an antagomir against a prohypertrophic miRNA to cardiomyocytes in vitro; (2) if UTMD can deliver an antagomir against a pro-hypertrophic miRNA to a beating, hypertensive heart; and (3) the mechanism of action involved in UTMD-mediated antagomir release from microbubbles. The efficacy of UTMD under varying acoustic conditions will be evaluated with respect to expression levels of miR-23a and its downstream targets, cardiomyocyte and ventricular hypertrophy, and overall cardiac function. Novel ultra high speed imaging of antagomir release by microbubbles under the influence of ultrasound will provide insights into mechanisms underlying effective UTMD regimes. Ultimately, this research program will provide a foundation for a clinically translatable targeted delivery platform to therapeuticaly regulate miRNA levels in the heart.

描述（由申请人提供）：左心室肥厚（LVH），如高血压患者，会增加心血管事件的风险。临床证据表明，LVH的抑制和消退与心功能改善和心血管并发症风险降低有关。MicroRNAs （miRNAs）是一种可以调控多种基因的内源性短rna。miRNA水平已被证明在患病的人类心脏中发生显著变化。调节mirna治疗心血管疾病被视为一种潜在的强大临床工具；例如，在高血压小鼠模型中，敲低促进肥厚的miR-23a被证明可以钝化心脏肥厚。然而，缺乏有效、安全、非免疫原性的递送miRNA模拟物或抑制剂的方法限制了临床翻译。超声靶向微泡破坏（UTMD）代表了一种有吸引力的非免疫原性治疗递送策略，可以局部调节心脏中的miRNA水平。UTMD已被证明可以增强内吞作用，并且还可以诱导细胞膜上由于微泡振荡和崩溃而形成瞬时孔隙，从而可能使核苷酸直接进入细胞质。本提案的目的是开发一个利用超声和微泡调节心脏中miRNA水平的平台。该平台可以潜在地用于递送任何感兴趣的miRNA模拟物或抑制剂。因此，我们假设utmd介导的针对促肥厚性miR-23a的阿塔戈米递送将减轻苯肾上腺素诱导的心脏肥厚。我们的3个特定目标是确定：(1)UTMD是否可以在体外将抗肥厚性miRNA的抗他戈米递送到心肌细胞；(2) UTMD是否可以将抗促肥厚miRNA的抗他戈米送入跳动的高血压心脏；(3) utmd介导的安他哥莫微泡释放的作用机制。将根据miR-23a及其下游靶点、心肌细胞和心室肥厚以及整体心功能的表达水平来评估UTMD在不同声学条件下的疗效。超声影响下微泡释放安他哥莫的新型超高速成像将为有效UTMD制度的机制提供见解。最终，该研究计划将为临床可翻译的靶向递送平台提供基础，以治疗性地调节心脏中的miRNA水平。