Role of miR-222 in pathological hypertrophy and heart failure

miR-222在病理性肥厚和心力衰竭中的作用

• 批准号: 9250361
• 负责人: ANTHONY ROSENZWEIG
• 金额: $ 42.97万
• 依托单位: MASSACHUSETTS GENERAL HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-12-24 至 2020-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9250361
• 关键词: Animal Model; Aortic Valve Stenosis; Bioinformatics; Cardiac; Cardiac Myocytes; Clinical; Data; Evaluation; Exercise; Expression Library; Genetic; Genetic Transcription; Goals; Growth; Health; Heart; Heart Hypertrophy; Heart failure; Hypertension; Hypertrophy; In Vitro; Injury; Intervention; Investigation; Knowledge; Laboratories; Lead; Learning; Lentivirus Vector; MicroRNAs; Mission; Modeling; Molecular; Molecular Profiling; Nature; Nodal; Outcome; Pathologic; Pathology; Pathway interactions; Patients; Physiological; Public Health; Regulation; Research; Research Personnel; Risk; Role; Serum; Stress; System; Technology; Testing; Therapeutic; United States National Institutes of Health; Work; adverse outcome; base; combinatorial; constriction; genome-wide analysis; in vitro Model; in vivo; in vivo Model; innovation; insight; loss of function; new technology; new therapeutic target; overexpression; programs; response; synthetic biology; therapeutic target; transcription factor; transcription factor NF-AT c3

Pathological hypertrophy is a common predecessor to heart failure (HF). The heart also grows in response to exercise but this growth, termed physiological hypertrophy, does not generally lead to adverse consequences and can even protect the heart against pathological stress. There is a fundamental gap in our understanding of why cardiac hypertrophy can have such divergent outcomes. Our over-arching hypothesis is that there are distinct forms of hypertrophy, which may appear superficially similar but have dramatically different likelihoods of progressing to HF. Our long-term goal is to understand the pathways responsible for these differences and learn whether they can be exploited therapeutically. The objective of the current application is to understand the role of the microRNA (miRNA), miR-222, in pathological hypertrophy and HF. Prior work from the applicant's laboratory identified 16 cardiac miRNAs that were concordantly regulated in two distinct exercise models. Of these, miR-222, which is also increased in serum of HF patients after exercise, was necessary for exercise-induced physiological cardiac growth. While miR-222 was not sufficient to induce cardiac hypertrophy at baseline, it was sufficient to protect against adverse remodeling after ischemic injury. The role of miR-222 in pathological hypertrophy and HF remains unexplored. Based on preliminary data presented in this application, we hypothesize that miR-222 – despite being involved in physiological hypertrophy – paradoxically protects against pathological hypertrophy and the progression to HF. Moreover, we hypothesize that miR-222 acts as a nodal modulator of physiological versus pathological genetic programs at least in part through effects on two transcription factors: HMBOX1 and NFATc3. These central hypotheses will be tested in three integrated Specific Aims. In Aim 1, we will use specific and effective gain- and loss-of-function models to directly assess the role of miR-222 in pathological hypertrophy and HF. In Aim 2, a combination of expression profiling and bioinformatic analyses will be used to identify downstream targets of miR-222 and delineate the mechanisms responsible for its effects in pathological hypertrophy and HF. In Aim 3, a novel technology termed CombiGEM (Combinatorial Genetics En Masse), recently developed by our collaborator, Dr. Tim Lu of the MIT Synthetic Biology group, will be used to investigate the additive or synergistic effects of miRNAs altered in exercised hearts. In vivo studies will be supported by in vitro investigation of primary cardiomyocytes to elucidate the underlying mechanisms. Our approach combines innovative hypotheses, technologies, and unique animal models with the complementary expertise of an outstanding team of collaborating investigators. The proposed research is significant, because it is expected to advance our understanding of cardiac hypertrophy and HF as well as pathways with the potential to mitigate these clinically important conditions.

病理肥大是心力衰竭（HF）的常见前身。心脏也在进来 对运动的反应，但这种称为身体肥大的增长通常不会导致逆境 后果，甚至可以保护心脏免受病理压力。我们有根本的差距 了解为什么心脏肥大会产生这种不同的结果。我们的总体假设 是有不同形式的肥大形式，可能看起来超级相似，但具有巨大的 发展到HF的可能性不同。我们的长期目标是了解负责的途径 这些差异并了解是否可以热探索它们。电流的目的 应用是了解microRNA（miRNA），miR-222在病理肥大和HF中的作用。 申请人实验室的先前工作确定了16个受监管的心脏miRNA 两个不同的运动模型。其中，miR-222，在HF患者血清中也增加了 运动是运动引起的身体心脏生长所必需的。虽然mir-222不够 为了在基线诱导心脏肥大，足以防止不良重塑 缺血性损伤。 miR-222在病理肥大和HF中的作用仍然出乎意料。基于 在本应用程序中提供的初步数据，我们假设mir-222 - 愿望参与 物理肥大 - 自相矛盾地预防病理肥大和发展 HF。此外，我们假设miR-222充当生理与病理的淋巴结调节剂 遗传程序至少部分通过对两个转录因子的影响：HMBOX1和NFATC3。这些 中央假设将以三个集成的特定目的进行检验。在AIM 1中，我们将使用特定和 有效的功能丧失模型直接评估miR-222在病理肥大中的作用 和HF。在AIM 2中，将使用表达分析和生物信息学分析的组合来识别 miR-222的下游靶标，并描述了其在病理中影响的机制 肥大和HF。在AIM 3中，一种新颖的技术称为Combigem（Masse组合遗传学）， MIT合成生物学小组的合作者最近开发的 研究在运动心脏中改变的miRNA的累加或协同作用。体内研究将是 通过对原发性心肌细胞的体外研究支持，以阐明潜在的机制。我们的 方法结合了创新的假设，技术和独特的动物模型与完整性 杰出的合作调查员团队的专业知识。拟议的研究很重要， 因为期望它可以提高我们对心脏肥大和HF的理解以及与 减轻这些临床上重要条件的潜力。