Cardiac regeneration in situ: Is it possible?

心脏原位再生：可能吗？

基本信息

批准号：
8244983
负责人：
Thomas Force
金额：
$ 1.94万
依托单位：
THOMAS JEFFERSON UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2011
资助国家：
美国
起止时间：
2011-04-01 至 2012-01-27
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8244983
关键词：
Address Adult Apoptosis Automobile Driving Biological Preservation Biology Bromodeoxyuridine Cardiac Cardiac Myocytes Chest Clinical Dependovirus Destinations Disease Etiology Exploratory/Developmental Grant Future Gene Expression Gene Transfer Glycogen Synthase Kinase 3 Glycogen Synthase Kinases Goals Heart Heart Diseases Heart Transplantation Heart failure Histone H3 Hypertrophy In Situ Infusion procedures Injection of therapeutic agent Knowledge Lead Left Left Ventricular Function Marketing Mediating Mus Muscle Cells Myocardial Myocardial Infarction Natural regeneration Neonatal Outcome Pathway interactions Patients Physiological Play Publishing Rattus Reporting Research Role Signal Pathway Staging Stem cells Stress System Systolic Pressure Tamoxifen Testing Therapeutic Time Transplantation Ventricular Work base cell type constriction embryonic stem cell experience improved in vivo inhibitor/antagonist injured mouse model public health relevance repaired response small molecule stem virus core

项目摘要

DESCRIPTION (provided by applicant): Strategies to repair injured hearts have predominantly focused on infusion, direct injection, or transplantation of any of a variety of types of stem/progenitor cells. We have recently reported that conditional deletion of GSK-3b specifically in cardiomyocytes leads to proliferation of cardiomyocytes. Furthermore, we find that the degree of proliferation is amplified in the setting of stress induced by thoracic aortic constriction (producing marked increases in left ventricular systolic pressure) or myocardial infarction (MI). In fact, we have found that deletion (or inhibition) of GSK-3b leads to proliferation of cardiomyocytes in mouse embryonic stem cell-derived embryoid bodies, in neonatal rat ventricular myocytes in culture, in cardiomyocytes in the developing heart, in cardiomyocytes in the normal heart, and, as noted above, particularly in cardiomyocytes in the stressed heart. If this proliferation is sufficiently robust, one could induce meaningful regeneration without the need for transplantation (i.e. regeneration in situ). We will address this hypothesis with three Specific Aims. We will first determine how robust is the cardiomyocyte proliferation resulting from deletion of GSK-3b by quantifying proliferation rates and cardiomyocyte mass in both the normal heart and in the stressed heart. We will then examine the physiologic consequences of this proliferation by determining whether there is a beneficial effect on left ventricular function. Finally, we will determine whether deletion of GSK-3b can lead to beneficial effects in mice with moderately advanced heart failure- recapitulating the clinical scenario of patients with advanced heart failure for whom there are very few treatment options besides heart transplant or destination LVAD therapy. In a "future directions" section, we also discuss the critical role played by GSK-3b in driving differentiation of immature cardiomyocytes into mature cardiomyocytes. We propose studies to restore expression of GSK-3b via adeno-associated virus gene transfer to the heart after the proliferative response has created new myocytes. Thus any immature myocytes formed in response to the deletion of GSK-3b will be differentiated into mature, fully functional myocytes, maximizing the chances of improving LV function. We believe that this application perfectly matches the goals of the R21 mechanism of supporting groundbreaking research with the potential to significantly advance therapeutic options for heart failure patients- a disease that has had no new important classes of agents come to market in many years. PUBLIC HEALTH RELEVANCE: Herein we propose to determine whether it is possible to drive cardiomyocyte proliferation sufficiently to result in cardiac regeneration in situ (i.e. without the need to utilize exogenous stem/progenitor cells). Based on our extensive studies in mouse models, we hypothesize that by manipulating a single signaling pathway- the glycogen synthase kinase-3b (GSK-3b) signaling pathway- in vivo, we will indeed be able to achieve regeneration. If we can achieve this, it would be a significant step forward in the treatment of patients with end- stage heart diseases of many etiologies.

描述（由申请人提供）：修复受损心脏的策略主要集中于输注、直接注射或移植多种类型的干/祖细胞中的任何一种。我们最近报道，心肌细胞中特异的 GSK-3b 条件性缺失会导致心肌细胞增殖。此外，我们发现，在胸主动脉缩窄（左心室收缩压显着增加）或心肌梗塞（MI）引起的应激环境下，增殖程度会放大。事实上，我们发现GSK-3b的缺失（或抑制）会导致小鼠胚胎干细胞衍生的胚状体、培养的新生大鼠心室肌细胞、发育中的心脏的心肌细胞、心脏中的心肌细胞的心肌细胞增殖。正常心脏，并且如上所述，特别是在应激心脏的心肌细胞中。如果这种增殖足够强大，则可以诱导有意义的再生，而无需移植（即原位再生）。我们将通过三个具体目标来解决这一假设。我们将首先通过量化正常心脏和应激心脏中的增殖率和心肌细胞质量来确定 GSK-3b 缺失导致的心肌细胞增殖有多强。然后，我们将通过确定是否对左心室功能产生有益影响来检查这种增殖的生理后果。最后，我们将确定 GSK-3b 的缺失是否会对中度晚期心力衰竭小鼠产生有益的影响——概括晚期心力衰竭患者的临床情况，除了心脏移植或目标 LVAD 治疗之外，这些患者几乎没有其他治疗选择。在“未来方向”部分，我们还讨论了 GSK-3b 在驱动未成熟心肌细胞分化为成熟心肌细胞中发挥的关键作用。我们建议进行研究，在增殖反应产生新的心肌细胞后，通过将腺相关病毒基因转移到心脏来恢复 GSK-3b 的表达。因此，因 GSK-3b 缺失而形成的任何未成熟的肌细胞都将分化为成熟、功能齐全的肌细胞，从而最大限度地提高改善左室功能的机会。我们相信，该应用完全符合 R21 机制的目标，即支持突破性研究，并有可能显着推进心力衰竭患者的治疗选择，心力衰竭患者是一种多年来没有新的重要药物类别上市的疾病。公共健康相关性：在此，我们建议确定是否有可能充分驱动心肌细胞增殖以导致心脏原位再生（即无需利用外源干/祖细胞）。基于我们对小鼠模型的广泛研究，我们假设通过在体内操纵单一信号通路——糖原合酶激酶-3b (GSK-3b) 信号通路，我们确实能够实现再生。如果我们能够实现这一目标，这将是治疗多种病因的终末期心脏病患者的重要一步。