The Role of Runx1 in Cardiomyocyte Cell Cycle and Ploidy

Runx1 在心肌细胞周期和倍性中的作用

• 批准号: 10581489
• 负责人: Samantha K Swift
• 金额: $ 4.46万
• 依托单位: MEDICAL COLLEGE OF WISCONSIN
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-02-01 至 2023-12-27
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10581489
• 关键词: Adult; Attention; Behavior; Birth; Cardiac Myocytes; Cardiovascular Diseases; Cause of Death; Cell Cycle; Cessation of life; Cicatrix; Competence; DNA biosynthesis; Data; Development; Diploidy; Disease; Embryonic Development; Endothelial Cells; Exhibits; Frequencies; Future; Gene Activation; Gene Targeting; Generations; Genes; Genetic; Genetic Transcription; Goals; Heart; Heart Diseases; Heart Injuries; Heart failure; Human; Hybrids; Hypertrophy; Infarction; Injury; Knock-out; Knowledge; Literature; Lymphocyte; Molecular; Mononuclear; Mouse Strains; Mus; Muscle Fibers; Myocardial; Myocardial Infarction; Myocardium; Natural regeneration; Neonatal; Outcome; Patients; Ploidies; Population; Proliferating; Publishing; RNA analysis; RUNX1 gene; Research; Research Personnel; Rodent; Role; Scientist; Techniques; Testing; Therapeutic; Time; Tissues; Transcriptional Activation; Transcriptional Regulation; Work; cardiac regeneration; cell type; combat; daughter cell; falls; fetal; functional improvement; gain of function; gene induction; genetic analysis; genome wide association study; genome-wide; genomic locus; heart function; improved; loss of function; mouse model; neonatal mice; novel; novel therapeutic intervention; overexpression; postmitotic; postnatal development; regenerative; response; therapeutic development; therapeutic target; transcription factor; transcriptome; transcriptome sequencing; treatment strategy

PROJECT SUMMARY Cardiovascular disease remains the leading cause of death worldwide, necessitating continued research to develop novel therapeutic strategies. Historically, adult mammalian cardiomyocytes (CMs) were thought to be post-mitotic and therefore unable to regenerate the myocardium after injury. However, in recent years, scientists have shown that the adult mammalian CM is capable of a small amount of proliferation, though this competence is potentially restricted to a subset of cardiomyocytes. Patterson et. al demonstrated using the hybrid mouse diversity panel that having greater percentages of the rare mononuclear diploid cardiomyocyte (MNDCM) is associated with improved function, smaller scars, and enhanced CM proliferation after myocardial infarction. An accompanying genome-wide association analysis identified genetic loci associated with the frequency of the MNDCM population. One gene to come out of this screen was Runx1. Concurrently, RUNX1 captured the attention of cardiac regeneration researchers due to its increased presence in disease states, with some suggesting it may be a marker for dedifferentiation (fetal gene induction). CM-specific overexpression of Runx1 results in a doubling of the MNDCM population, thereby validating its influence on the population. Via multiple contexts including postnatal development and adult injury, knocking out Runx1 decreases DNA synthesis while overexpressing Runx1 increases DNA synthesis. Furthermore, an initial analysis of RNA sequencing data demonstrates that RUNX1 overexpression in a neonatal mouse upregulates known fetal CM genes and markers of CM cell cycle activity. These preliminary data are supported by the literature, which has shown in many other tissues that RUNX1, a transcription factor, directly regulates many genes associated with the cell cycle, indicating that RUNX1's role may be highly conserved across cell types. The central hypothesis of this study is that Runx1 regulates the CM response to heart failure via transcriptional induction of fetal genes and cell cycle activity. To test this idea the work proposed here will utilize both gain- and loss-of-function Runx1 mouse models temporally controlled by a CM-specific Cre. Aim 1 will investigate the effect of Runx1 on post-infarction outcomes and CM cell cycle. Aim 2 will assess transcriptional control of RUNX1 through two complementary genome-wide approaches: RNA sequencing and CUT&Tag. Results from this study will further advance the field's understanding of the genetic components involved during a cardiac injury and improve future treatment strategies.

项目摘要 心血管疾病仍然是全球死亡的主要原因，需要继续研究， 开发新的治疗策略。历史上，成年哺乳动物心肌细胞（CM）被认为是 有丝分裂后，因此不能再生损伤后的心肌。然而，近年来， 科学家们已经证明，成年哺乳动物CM能够进行少量增殖，尽管这 能力可能局限于心肌细胞的一个子集。帕特森等al使用 具有更高百分比的罕见单核二倍体心肌细胞的杂交小鼠多样性小组 （MNDCM）与心肌梗死后功能改善、瘢痕较小和CM增殖增强有关。 梗塞伴随的全基因组关联分析确定了与 MNDCM人群的频率。从这个筛选中出来的一个基因是Runx 1。RUNX1 由于其在疾病状态中的存在增加而引起了心脏再生研究人员的注意， 有些人认为它可能是去分化（胎儿基因诱导）的标志物。CM专用 Runx 1的过表达导致MNDCM群体加倍，从而验证了其对MNDCM的影响。 人口通过多种背景，包括出生后发育和成年损伤，敲除Runx 1 降低DNA合成，而过表达Runx 1增加DNA合成。此外，初始 RNA测序数据分析表明，新生小鼠中RUNX 1过表达上调了 已知的胎儿CM基因和CM细胞周期活性的标志物。这些初步数据得到了 文献中已经表明，在许多其他组织中，RUNX 1，一种转录因子，直接调节许多 与细胞周期相关的基因，表明RUNX 1的作用可能在细胞类型中高度保守。 本研究的中心假设是Runx 1通过转录调节CM对心力衰竭的反应， 诱导胎儿基因和细胞周期活性。为了测试这个想法，这里提出的工作将利用两个增益- 和暂时由CM特异性Cre控制的功能丧失Runx 1小鼠模型。目标1将调查 Runx 1对梗死后结局和CM细胞周期的影响。目的2将评估转录控制 RUNX 1通过两种互补的全基因组方法：RNA测序和CUT&Tag。结果 这项研究将进一步推进该领域对心脏病发生过程中所涉及的遗传成分的理解。 改善未来治疗策略。