Cell cycle activation for cardiac repair

细胞周期激活促进心脏修复

基本信息

批准号：
8676558
负责人：
LOREN J FIELD
金额：
$ 37.73万
依托单位：
INDIANA UNIV-PURDUE UNIV AT INDIANAPOLIS
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：
2011-07-15 至 2016-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8676558
关键词：
Adult Amino Acid Substitution Amino Acids Animals BMP10 gene Biochemical Cardiac Cardiac Myocytes Cell Culture System Cell Cycle Cell Cycle Regulation Chronic Cicatrix Complex Coronary artery Cyclin D1 Cyclins Data Development Event Exhibits Fibrosis G1/S Checkpoint Pathway Genetically Modified Animals Goals Growth Heart Heart Atrium Heart Hypertrophy Hematopoietic Stem Cell Mobilization Hypertrophy Infarction Injury Intervention Isoproterenol Large T Antigen Lead Ligation Mediating Modeling Molecular Target Mus Myocardial Myocardial Infarction Myocardium Natural regeneration Nature Nuclear Export Phosphorylation Population Post-Translational Protein Processing Proteins Regulatory Pathway Simian virus 40 Stem cells TSC2 gene Tamoxifen Testing Therapeutic Transcriptional Regulation Transgenic Mice Transgenic Model Transplantation cardiac regeneration cardiac repair cyclin D2 cyclin D3 functional restoration injured member mimetics mouse model prevent promoter reconstitution regenerative repaired research study response restoration transgene expression ubiquitin-protein ligase

项目摘要

DESCRIPTION (provided by applicant): Although the adult mammalian myocardium exhibits a limited ability to undergo regenerative growth, the intrinsic renewal rate is insufficient to reverse pathophysiologic cardiomyocyte loss. The ability to reconstitute lost cardiac mass in injured hearts could thus be of considerable therapeutic value. One approach to accomplish this entails inducing cell cycle activity in the surviving cardiomyocytes. Preliminary data indicate that targeted expression of cyclin D2, a key member of the regulatory complex which drives transit through the G1/S cell cycle check-point, is sufficient to induce cardiomyocyte cell cycle activity in adult hearts. Moreover, cyclin D2-induced cell cycle activity can reverse structural damage and restore function following myocardial injury. The experiments proposed in this application will further elucidate the mechanism of cyclin D-mediated cardiomyocyte cell cycle regulation. Specific Aim 1 will test the hypothesis that post-translational modification of the D-type cyclins regulates their ability to mediate regenerative growth following myocardial injury. These experiments will utilize newly generated transgenic mice expressing D-type cyclins carrying the relevant phospho-mimetic and non-phosphorylatable amino acid residue substitutions. Other studies in Aim 1 will test the hypothesis that specific phosphorylation events mediate the interaction of D-type cyclins and the p193/Cul7 E3 ubiquitin ligase, and that blocking this interaction enhances cell cycle activity in injured hearts. Experiments proposed in Specific Aim 2 will further test the hypothesis that cyclin D2-mediated cardiomyocyte cell cycle activation can be used to promote myocardial repair in the adult heart. Initial experiments will utilize a conditional transgenic mouse model to determine if cyclin D2 can induce de novo cardiomyocyte proliferation in adult hearts. Other studies are proposed to determine the degree to which pharmacologic interventions which limit adverse post-injury remodeling are able to benefit long-term, cardiomyocyte cell cycle-induced regeneration. Collectively, these studies will help establish the mechanism by which D-type cyclins regulate cardiomyocyte cell cycle entry, and the degree to which targeted expression of cyclin D2 is able to promote myocardial regeneration. The overall goal is to gain an understanding of how cell cycle regulatory pathways can be manipulation to promote the repair of injured hearts. Identification of such molecular targets may ultimately lead to the development of pharmacologic agents to promote regenerative growth in diseased hearts.

描述（由申请人提供）：尽管成年哺乳动物心肌表现出有限的经历再生生长的能力，但固有的更新率不足以逆转病理生理的心肌细胞损失。因此，重建受伤心脏中心脏肿块的损失的能力可能具有相当大的治疗价值。实现这一目标的一种方法是在存活的心肌细胞中引起细胞周期活性。初步数据表明，靶向Cyclin D2的靶向表达，Cyclin D2是调节复合物的关键成员，该调节络合物通过G1/S细胞周期检查点驱动转运，足以诱导成人心脏中的心肌细胞周期活性。此外，细胞周期蛋白D2诱导的细胞周期活性可以逆转结构性损害并在心肌损伤后恢复功能。本应用中提出的实验将进一步阐明细胞周期蛋白D介导的心肌细胞周期调节的机理。具体目标1将检验以下假设：D型细胞周期蛋白的翻译后修饰调节其介导心肌损伤后介导再生生长的能力。这些实验将利用表达携带相关磷酸化和非磷酸化氨基酸残基取代的新的转基因小鼠。 AIM 1中的其他研究将检验以下假设：特定的磷酸化事件介导了D型细胞周期蛋白和P193/CUL7 E3泛素连接酶的相互作用，并且阻断这种相互作用会增强受伤心脏的细胞周期活性。特定目标2中提出的实验将进一步检验：细胞周期蛋白D2介导的心肌细胞周期活化可用于促进成人心脏的心肌修复。最初的实验将利用条件转基因小鼠模型来确定细胞周期蛋白D2是否可以诱导成人心脏中的从头心肌细胞增殖。提出了其他研究以确定限制伤害后重塑的药理干预措施的程度，能够使长期的心肌细胞周期诱导的再生受益。总的来说，这些研究将有助于建立D型细胞周期蛋白调节心肌细胞周期的机制，以及细胞周期蛋白D2的靶向表达能够促进心肌再生的程度。总体目标是了解如何操纵细胞周期调节途径以促进受伤的心脏的修复。这种分子靶标的识别最终可能导致药理学剂的发展，以促进患病心脏的再生生长。