Cardiac regeneration in situ: Is it possible?

心脏原位再生：可能吗？

• 批准号: 8463728
• 负责人: Thomas Force
• 金额: $ 17.44万
• 依托单位: TEMPLE UNIV OF THE COMMONWEALTH
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-04-01 至 2013-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8463728
• 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; repaired; response; small molecule; stem; virus core

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.

描述（由申请人提供）：修复受损心脏的策略主要集中在输注、直接注射或移植各种类型的干细胞/祖细胞。我们最近报道了GSK-3b特异性在心肌细胞中的条件性缺失导致心肌细胞增殖。此外，我们发现，在胸主动脉缩窄（左心室收缩压显著增加）或心肌梗死（MI）引起的应激环境中，增殖程度被放大。事实上，我们已经发现GSK-3b的缺失（或抑制）导致小鼠胚胎干细胞衍生的胚状体中、培养的新生大鼠心室肌细胞中、发育中的心脏中的心肌细胞中、正常心脏中的心肌细胞中以及如上所述特别是应激心脏中的心肌细胞中的心肌细胞增殖。如果这种增殖足够稳健，则可以诱导有意义的再生而不需要移植（即原位再生）。我们将通过三个具体目标来解决这个假设。 我们将首先通过定量正常心脏和应激心脏中的增殖速率和心肌细胞质量来确定GSK-3b缺失导致的心肌细胞增殖的稳健性。然后，我们将通过确定是否对左心室功能有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的缺失是否可以在中度晚期心力衰竭小鼠中产生有益效果-重现晚期心力衰竭患者的临床情况，除了心脏移植或目的LVAD治疗外，这些患者的治疗选择很少。 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。我们建议研究在增殖反应产生新的心肌细胞后，通过腺相关病毒基因转移恢复GSK-3b的表达。因此，任何响应GSK-3b缺失而形成的未成熟肌细胞将分化为成熟的、功能齐全的肌细胞，从而最大限度地提高LV功能的机会。 我们相信，这一应用完全符合R21机制的目标，即支持突破性研究，并有可能显著推进心力衰竭患者的治疗选择-这种疾病多年来没有新的重要药物进入市场。