Role of miR-222 in pathological hypertrophy and heart failure

病理性肥大是心力衰竭（HF）的常见前驱。心也长在 但是这种生长，称为生理性肥大，通常不会导致不良的运动反应。 甚至可以保护心脏免受病理性压力。在我们的社会中， 了解为什么心脏肥大会有如此不同的结果。我们的过度假设 有不同形式的肥大，表面上看起来相似，但 发展成心力衰竭的可能性不同我们的长期目标是了解 这些差异，并了解它们是否可以用于治疗。当前的目标 应用是了解微小RNA（miRNA），miR-222在病理性肥大和HF中的作用。 申请人实验室先前的工作鉴定了16种心脏miRNAs，它们在心肌细胞中一致调节。 两种不同的锻炼模式。其中，miR-222在HF患者的血清中也增加， 运动，是必要的运动诱导的生理心脏生长。虽然miR-222不足以 在基线时诱导心脏肥大，足以防止 缺血性损伤miR-222在病理性肥大和HF中的作用尚未探索。基于 本申请中提供的初步数据，我们假设miR-222 -尽管参与了 生理性肥大-矛盾的是防止病理性肥大和进展， HF。此外，我们假设miR-222作为生理与病理的节点调节剂， 遗传程序至少部分通过影响两个转录因子：HMBOX 1和NFATc 3。这些 将在三个综合具体目标中检验中心假设。在目标1中，我们将使用特定的和 直接评估miR-222在病理性肥大中作用的有效功能获得和丧失模型 和HF。在目标2中，将使用表达谱分析和生物信息学分析的组合来鉴定 miR-222的下游靶点，并描述其在病理学中作用的机制。 肥大和HF。在目标3中，一种称为CombiGEM（组合遗传学混合）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Tim Lu博士开发的，将用于 研究运动心脏中改变的miRNAs的累加或协同效应。体内研究将是 通过对原代心肌细胞的体外研究来阐明潜在的机制。我们 方法结合了创新的假设，技术和独特的动物模型， 一个优秀的合作调查员团队的专业知识。拟议的研究意义重大， 因为它有望促进我们对心脏肥大和HF以及与HF相关的通路的理解。 缓解这些临床重要状况的潜力。

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.