Non-cardiomyocyte miR-34a Mediates Susceptibility to Right Heart Failure

非心肌细胞 miR-34a 介导右心衰竭的易感性

• 批准号: 8870024
• 负责人: Sushma Reddy
• 金额: $ 13.17万
• 依托单位: STANFORD UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-03-05 至 2020-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8870024
• 关键词: Angiotensin-Converting Enzyme Inhibitors; Antioxidants; Attenuated; Binding; Biological Markers; Biology; Cardiac; Cardiac Myocytes; Cardiovascular system; Cell Aging; Cell Death; Child; Chronic; Coculture Techniques; Collaborations; Communication; Conditioned Culture Media; Critical Thinking; Data; Disease Progression; Down-Regulation; Endothelial Cells; Environment; Failure; Fibroblasts; Foundations; Future; Gene Expression Profile; Gene Targeting; Genes; Heart failure; Histopathology; Hypertrophy; In Vitro; Laboratories; Left ventricular structure; Link; Mediating; Mediator of activation protein; Medical; Mentors; Mentorship; MicroRNAs; Mitochondria; Modeling; Molecular; Mus; Myocardial; Operative Surgical Procedures; Oxidants; Pathway interactions; Patients; Phenotype; Physicians; Plasma; Predisposition; Production; RNA-Induced Silencing Complex; Reactive Oxygen Species; Research; Right Ventricular Hypertrophy; Role; Scientist; Site; Stress; Testing; Training; Training Programs; Untranslated RNA; Vascular Endothelial Growth Factors; Work; angiogenesis; base; career; career development; cohort; congenital heart disorder; in vivo; interest; novel; overexpression; oxidant stress; paracrine; pressure; programs; public health relevance; research study; response; senescence; skills; small molecule; therapeutic target; transcriptome sequencing; vector

 DESCRIPTION (provided by applicant): This proposal describes a five-year career development program to prepare the candidate, Dr. Sushma Reddy, for a career as an independent scientist evaluating the mechanisms of right heart failure. This program will expand Dr. Reddy's scientific background in cardiovascular research by providing technical training and expertise in myocardial, mitochondrial and endothelial biology through focused course work, technical training and targeted externships. In addition, Dr. Reddy's successful transition from a mentored clinician scientist to an independent scientist will be accomplished by strengthening skills in critical thinking, communication, collaboration, mentorship and laboratory management. MicroRNAs (miRs) are small non-coding RNAs that have emerged as crucial regulators of cardiac remodeling. However, there is minimal data on their role in right ventricular hypertrophy (RVH) and failure (RVF). Understanding the mechanisms of RV remodeling is a critical question for many patients with congenital heart disease, given that the afterload stressed RV is more likely to fail compared to the left ventricle (LV), and that standard heart failure therapies fail o work in patients with RVF. Although the molecular responses of the RV and LV to pressure overload are largely similar, there are key differences in regulators of oxidant stress and angiogenesis which could explain the enhanced vulnerability of the RV. Dr. Reddy's objective is to elucidate the role of miRs as a mechanism for these RV-LV differences. Using a murine model, she has identified miRs 34a, 28, 93 and 148a as unique to RVH/RVF. Of interest, all four miRs are expressed only in non-cardiomyocytes yet may have their greatest effects in cardiomyocytes. She hypothesizes that RV-specific non-cardiomyocyte miR-34a, through crosstalk with cardiomyocytes, is responsible for the early failure of antioxidant defenses and the attenuated angiogenic response in RVF. Aim 1 will evaluate the mechanisms by which miR-34a regulates the transition from RVH to RVF. Overexpression of miR-34a in fibroblasts, endothelial cells and cardiomyocytes will evaluate effects on ROS production, antioxidant defenses, and mediators of cell death and angiogenesis, as well as the mechanism of miR-34a crosstalk with cardiomyocytes and the paracrine role of exosomes. Aim 2 will evaluate the in vivo functional significance of miR-34a using LNA antimiRs to rescue RVF in her murine model, identify novel target genes using transcriptome and RISCome sequencing, and identify plasma biomarkers of disease progression in children with RVH/RVF. Future studies will evaluate (i) the mechanism of action of miRs 28, 93 and 148a, either singly or in concert in the RV susceptibility to heart failure; (ii) the role of these miRs in a model of chronic pressure overload and (iii) validate plasma biomarkers in a larger cohort of children. In summary, these studies will aid in developing RV-specific heart failure therapies and identify biomarkers of RV failure, allowing earlier medical or surgical intervention.

 描述（由应用程序提供）：该提案描述了一项为期五年的职业发展计划，以准备候选人Sushma Reddy博士，作为一名独立科学家的职业，评估了正确的心力衰竭机制。该计划将通过针对心肌，线粒体和内皮生物学的技术培训和专业知识，通过专注的课程工作，技术培训和针对性的实质性提供技术培训和专业知识，扩大Reddy博士的心血管研究科学背景。此外，雷迪博士从精神临床科学家到独立科学家的成功过渡将通过增强批判性思维，沟通，协作，心态和实验室管理方面的技能来实现。 microRNA（miR）是小型非编码RNA，已成为心脏重塑的关键调节剂。但是，关于它们在右心肥大（RVH）和失败（RVF）中的作用的数据最少。对于许多先天性心脏病患者来说，了解RV重塑的机制是一个关键问题，鉴于与左心室（LV）相比，载荷后的RV更有可能失败，并且标准的心力衰竭疗法失败了RVF患者的工作。尽管RV和LV对压力超负荷的分子反应在很大程度上相似，但在氧化应激和血管生成的调节剂中存在关键差异，这可以解释RV的增强脆弱性。 Reddy博士的目标是阐明MIR作为这些RV-LV差异的机制的作用。她使用鼠模型，将mirs 34a，28、93和148A确定为RVH/RVF独有的。有趣的是，所有四个miR仅在非脑膜菌细胞中表达，但在心肌细胞中可能具有最大的作用。她假设通过与心肌细胞串扰，RV特异性非齿状细胞miR-34a是抗氧化剂防御剂的早期失败和RVF中的血管生成反应的早期失败。 AIM 1将评估miR-34a调节从RVH到RVF的过渡的机制。 MiR-34a在成纤维细胞，内皮细胞和心肌细胞中的过表达将评估对ROS产生的影响，抗氧化剂防御剂，细胞死亡和血管生成的介质以及MiR-34a Crosstalk的机制，以及具有心肌细胞和副型副介质的机制。 AIM 2将使用LNA抗杀菌剂在其鼠模型中拯救RVF，使用转录组和RISCome测序鉴定新的靶基因，并鉴定RVH/RVF儿童疾病进展的血浆生物标志物，从而评估miR-34a的体内功能意义。未来的研究将评估（i）mir 28、93和148a的作用机理，无论是在RV易感性的心力衰竭易感性中，还是共同进行的； （ii）这些miR在慢性压力超负荷模型中的作用和（iii）在较大的儿童队列中验证血浆生物标志物。总而言之，这些研究将有助于开发RV特异性的心力衰竭疗法并确定RV衰竭的生物标志物，从而允许早期的医学或外科干预。