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Deciphering the Relationship Between Cardiomyocyte Metabolic Configuration and Cell Cycle Re-entry

破译心肌细胞代谢结构与细胞周期重入之间的关系

基本信息

批准号：
10373927
负责人：
Riham Abouleisa
金额：
$ 8.11万
依托单位：
UNIVERSITY OF LOUISVILLE
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-01-01 至 2023-12-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10373927
关键词：
Adult Affect Anabolism CDC2 gene CDK4 gene Carbon Cardiac Myocytes Cell Cycle Cell Cycle Regulation Pathway Cell Proliferation Cell division Cells Collaborations Cyclin D1 Cytokinesis Data Development Down-Regulation Echocardiography Energy Metabolism Fetus Foundations Genes Heart Heart Diseases Heart failure Hexosamines Hip region structure Histology Human Knowledge Label Link Metabolic Metabolism Mitochondria Mitotic Modeling Mus Muscle Cells Myocardial Myocardial Infarction Myocardium Natural regeneration Pathway interactions Patients Pentosephosphate Pathway Pharmacology Phosphoenolpyruvate Carboxylase Proliferating Protocols documentation Rattus Respiration Salamander Serine Technology Up-Regulation Viral Virus Zebrafish base cardiac repair cyclin B1 enzyme pathway fatty acid oxidation glucose metabolism heart function in vivo induced pluripotent stem cell derived cardiomyocytes metabolomics mouse model novel strategies novel therapeutics overexpression programs stable isotope transcriptome sequencing

项目摘要

Myocardial infarction causes irreversible loss of cardiomyocytes (CMs) and often leads to heart failure. To replace the lost cells, we identified a combination of cell-cycle regulators that induces stable cytokinesis in adult post-mitotic cells. Overexpression of cyclin-dependent kinase 1 (CDK1), CDK4, cyclin B1, and cyclin D1 (referred to as 4F) promotes cell division in post-mitotic mouse, rat, and human cardiomyocytes. The high efficiency of this protocol in inducing myocyte renewal provides new opportunities for understanding the mechanisms involved in cardiomyocyte proliferation. One of the most interesting findings related to this discovery was the confirmation of a link between metabolic reprogramming and cardiomyocyte proliferation. Although in proliferating cells there is a strong correlation between metabolic changes and cellular proliferation, it remains unclear how metabolism influences the proliferative potential of cardiomyocytes. During the past 2 years, in collaboration with Dr. Hill’s group, I have generated preliminary data which indicate that cardiomyocyte proliferation is associated with marked reprogramming in energy metabolism. In proliferating cardiomyocytes isolated from lineage tracing (MADM) mice, RNA-seq data indicate profound downregulation of fatty acid oxidation genes and upregulation of biosynthetic pathway enzyme expression; in human iPSC-derived cardiomyocytes (hiPSC-CMs), 4F expression decreases mitochondrial respiration and catabolic activities. Using stable isotope-resolved metabolomics (SIRM), we demonstrate that 4F-infected hiPS-CMs show significant elevation in 13C labeled intermediates or end products of the hexosamine biosynthetic pathway (HBP), serine biosynthesis pathway (SBP), and pentose phosphate pathway (PPP). In line with these findings, our results also demonstrate that augmenting the carbon availability for these biosynthetic pathways by overexpressing phosphoenolpyruvate carboxykinase (PCK1 or PCK2) augments the ability of cardiomyocytes to proliferate. These data suggest that higher biosynthetic pathway flux may be required for cardiomyocyte proliferation. Informed by these results, we propose the general hypothesis that activation of ancillary biosynthetic pathways of glucose metabolism are required for cardiomyocyte proliferation. We suggest that higher biosynthetic pathway flux is required for building block synthesis and may be important for regulating pro-proliferative gene programs. During this project we will delineate the importance of each biosynthetic pathway in influencing cardiomyocyte proliferation. First, using pharmacological and virus-based approaches, we will determine the specific contribution of the HBP, SBP and PPP pathways to myocyte proliferation. In addition, we will investigate the influence of increasing the carbon flux in biosynthetic pathway through overexpression of PCK1, or PCK2 on cardiac function and repair in vivo. The aims of this project are: Specific Aim 1: Delineate the contribution of each biosynthetic pathway on cardiomyocyte proliferation. Specific Aim 2: Investigate the functional efficacy of increasing carbon flux in biosynthetic pathways on cardiac repair in vivo.

心肌梗死导致心肌细胞（CMs）的不可逆损失，并经常导致心力衰竭。来