Cardiac Regenerative Therapy with Cyclin A2

Cyclin A2 心脏再生疗法

• 批准号: 7672687
• 负责人: Hina W Chaudhry
• 金额: $ 25万
• 依托单位: VENTRINOVA, INC.
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-09-01 至 2011-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7672687
• 关键词: Address; Adenovirus Vector; Adenoviruses; Adult; Affect; Animal Model; Animals; Area; Automobile Driving; Biological Assay; Birth; CMV promoter; Cardiac; Cardiac Myocytes; Cardiovascular Diseases; Cell Cycle; Cell Cycle Arrest; Cell Proliferation; Cells; Characteristics; Cicatrix; Clinical Trials; Commit; Complementary DNA; Congestive Heart Failure; Coronary; Cyclin A; Cyclin-Dependent Kinases; Cyclins; Data; Dependovirus; Development; Developmental Gene; Distal; Dose; Embryo; Exhibits; Face; Family suidae; Future; G2/M Transition; Gene Delivery; Gene Expression; Heart; Heart failure; Hospitalization; Human; Infarction; Infusion procedures; Injection of therapeutic agent; Injury; Long-Term Effects; Mammalian Cell; Mediating; Methods; Mitosis; Modeling; Molecular; Monitor; Morbidity - disease rate; Mus; Muscle Cells; Myocardial; Myocardial Infarction; Myocardium; Myosin Heavy Chains; Natural regeneration; Pathway interactions; Play; Population; Rattus; Recombinant adeno-associated virus (rAAV); Recovery; Reporter Genes; Role; Satellite Viruses; Side; Stem Cell Research; Stem cell transplant; Stem cells; Testing; Tissues; Transgenic Mice; Translations; Tropism; Troponin T; Ventricular Cardiac alpha-Myosin; Western World; base; cardiogenesis; cyclin A2; design; gene therapy; heart cell; human disease; indexing; innovation; mortality; mouse model; myogenesis; novel; novel therapeutic intervention; postnatal; preclinical study; progenitor; promoter; public health relevance; regenerative; regenerative therapy; repaired; response; vector

DESCRIPTION (provided by applicant): The morbidity and mortality due to cardiovascular disease is attributed to the lack of significant replicative potential of adult mammalian cardiomyocytes. Thus myocyte loss in response to ischemic injury typically results in scar formation and a decline of cardiac function that is usually irreversible. The cessation of myocyte proliferation is associated with an arrest of the cell cycle. Cyclin A2 is the sole cyclin regulating two major transitions of the cell cycle, both G1/S and G2/M. It is also the only cyclin to be completely silenced in mammalian hearts after birth. We have previously demonstrated in a transgenic mouse model that constitutive expression of cyclin A2 in the mouse myocardium elicits mitoses in postnatal hearts. Furthermore, we have shown that cyclin A2 is critical in mediating cardiac regeneration after myocardial infarction (MI) is induced in the transgenic mice. The regenerative ability of cyclin A2 appears to involve enhanced proliferation of endogenous cardiac progenitor cells, in addition to potential dedifferentiation of mature cardiomyocytes in the peri-infarct zone. We have also demonstrated that exogenously administered cDNA encoding cyclin A2 via adenoviral vector can ameliorate cardiac function post-MI in genetically naive adult rats with a significant increase in all proliferative indices examined. We now aim to explore whether cyclin A2 will affect cardiac repair after MI in a large animal model. These are critical pre-clinical studies that will form the basis of future human clinical trials. We will utilize both adenoviral cyclin A2 driven by the CMV promoter and a novel adeno-associated vector (AAV9) to deliver cyclin A2 cDNA to the infarcted porcine heart in a cardiac-specific manner. We will test both direct myocardial injection and antegrade coronary infusion methods. We will perform analyses of cardiac function in animals that receive cyclin A2 compared to those that receive null vectors. We will examine the effects of cyclin A2 on endogenous cardiac progenitor cells, and determine whether cyclin A2 can regulate proliferation of these cells in the porcine model. We will also examine the effect of cyclin A2 on the mature cardiomyocytes of the peri-infarct and distal zones. Our proposal offers a new and exciting approach to cardiac regeneration in the face of controversial results of stem cell transplantation as a method to achieve myogenesis. As cardiovascular disease remains the number one killer in the western world, cyclin A modulation may have a major impact on the spectrum of human disease. PUBLIC HEALTH RELEVANCE: Congestive heart failure is the leading cause of hospitalization in the U.S. and cardiovascular disease remains the number one killer in the western world. The morbidity and mortality of cardiovascular disease is due to the fact that the heart cannot regenerate after an injury such as myocardial infarction (MI). We have found that cyclin A2, a key developmental gene, is able to regenerate heart cells in small animal models of MI. We will now test the ability of cyclin A2 to regenerate the heart after MI in large animals as a basis for the future design of human clinical trials.

描述（由申请人提供）：心血管疾病引起的发病率和死亡率归因于成年哺乳动物心肌细胞缺乏显着的复制潜力。因此，缺血性损伤导致的肌细胞损失通常会导致疤痕形成和心脏功能下降，而这种下降通常是不可逆转的。肌细胞增殖的停止与细胞周期的停滞相关。细胞周期蛋白 A2 是唯一调节细胞周期两个主要转变（G1/S 和 G2/M）的细胞周期蛋白。它也是哺乳动物出生后心脏中唯一完全沉默的细胞周期蛋白。我们之前已经在转基因小鼠模型中证明，小鼠心肌中细胞周期蛋白 A2 的组成型表达会引发出生后心脏的有丝分裂。此外，我们还表明，在转基因小鼠中诱导心肌梗塞（MI）后，细胞周期蛋白 A2 对于介导心脏再生至关重要。细胞周期蛋白 A2 的再生能力似乎涉及内源性心脏祖细胞增殖的增强，以及梗塞周围区域成熟心肌细胞的潜在去分化。我们还证明，通过腺病毒载体外源施用编码细胞周期蛋白 A2 的 cDNA 可以改善未经基因处理的成年大鼠的 MI 后心脏功能，并且所有检查的增殖指数均显着增加。我们现在的目标是在大型动物模型中探讨细胞周期蛋白 A2 是否会影响 MI 后的心脏修复。这些是关键的临床前研究，将构成未来人体临床试验的基础。我们将利用由 CMV 启动子驱动的腺病毒细胞周期蛋白 A2 和新型腺相关载体 (AAV9) 以心脏特异性方式将细胞周期蛋白 A2 cDNA 递送至梗塞的猪心脏。我们将测试直接心肌注射和顺行冠状动脉输注方法。我们将对接受细胞周期蛋白 A2 的动物与接受空载体的动物进行心脏功能分析。我们将检查细胞周期蛋白 A2 对内源性心脏祖细胞的影响，并确定细胞周期蛋白 A2 是否可以在猪模型中调节这些细胞的增殖。我们还将检查细胞周期蛋白 A2 对梗塞周围和远端区域成熟心肌细胞的影响。面对干细胞移植作为实现肌生成的方法存在争议的结果，我们的建议为心脏再生提供了一种新的、令人兴奋的方法。由于心血管疾病仍然是西方世界的头号杀手，细胞周期蛋白 A 的调节可能对人类疾病谱产生重大影响。公共卫生相关性：充血性心力衰竭是美国住院的主要原因，而心血管疾病仍然是西方世界的头号杀手。心血管疾病的发病率和死亡率是由于心脏在心肌梗塞（MI）等损伤后无法再生所致。我们发现细胞周期蛋白 A2（一种关键的发育基因）能够在 MI 的小动物模型中再生心脏细胞。我们现在将在大型动物中测试细胞周期蛋白 A2 在心肌梗死后再生心脏的能力，作为未来人类临床试验设计的基础。