Role of miR-222 in pathological hypertrophy and heart failure

病理性肥厚是心力衰竭(HF)的常见前身。心脏也会在 对运动的反应，但这种生长，称为生理性肥大，通常不会导致不良反应 甚至可以保护心脏免受病理性压力的侵袭。我们有一个根本性的差距 了解为什么心肌肥厚会有如此不同的结果。我们的总体假设 肥大有不同的形式，它们可能表面上看起来相似，但却戏剧性地 进展为心衰的可能性不同。我们的长期目标是了解负责 并了解这些差异是否可以用于治疗。当前的目标是 应用目的是了解microRNA(MiRNA)miR-222在病理性肥大和心衰中的作用。 申请人实验室之前的工作确定了16个心脏miRNAs，它们在 两种截然不同的锻炼模式。其中miR-222，心衰患者治疗后血清中miR-222也升高。 运动对于运动诱导的生理性心脏生长是必要的。而miR-222还不够 在基线水平诱导心肌肥厚，足以保护心脏免受不良重构的影响 缺血性损伤。MiR-222在病理性肥大和心衰中的作用尚不清楚。基于 本申请中提供的初步数据，我们假设miR-222-尽管参与了 生理性肥厚--矛盾地防止病理性肥厚和进展为 高频。此外，我们假设miR-222作为生理和病理的结节调节器。 遗传程序至少部分通过影响两个转录因子：HMBOX1和NFATc3。这些 中心假设将在三个综合的具体目标中得到检验。在目标1中，我们将使用特定和 直接评估miR-222在病理性肥厚中作用的有效功能获得和丧失模型 和高频。在目标2中，将结合表达谱和生物信息学分析来识别 MiR-222下游靶点及其致病机制的研究进展 肥大和心力衰竭。在目标3中，一种名为组合GEM(组合遗传学集体)的新技术， 最近由我们的合作者，麻省理工学院合成生物学小组的蒂姆·卢博士开发的，将用于 研究运动心脏中改变的miRNAs的相加或协同效应。体内研究将是 支持对原代心肌细胞的体外研究，以阐明其潜在的机制。我们的 方法将创新的假设、技术和独特的动物模型与互补的 一支出色的合作调查团队的专业知识。这项拟议的研究意义重大， 因为它有望促进我们对心肌肥厚和心力衰竭以及心力衰竭途径的理解 缓解这些临床重要病症的潜力。

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.