Dissecting Regulatory Mechanisms of Cardiac Regeneration Enhancers

剖析心脏再生增强剂的调节机制

基本信息

  • 批准号:
    10656156
  • 负责人:
  • 金额:
    $ 3.4万
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 财政年份:
    2022
  • 资助国家:
    美国
  • 起止时间:
    2022-06-01 至 2025-05-31
  • 项目状态:
    未结题

项目摘要

PROJECT SUMMARY/ABSTRACT Adult mammals possess a limited ability to regenerate cardiac tissue after an injury, such as a myocardial infarction. Following a myocardial infarction, up to a billion or more heart muscle cells die and are replaced by scar tissue that contributes to heart failure and sudden death. In contrast, adult zebrafish remarkably regenerate injured hearts with no residual scarring. Although zebrafish and mammals share homologs of genes vital for heart regeneration, their transcriptional responses to cardiac injury are distinct. However, the mechanisms governing gene expression during heart regeneration remain poorly understood. My research aims to elucidate how injury-responsive gene expression is regulated to facilitate heart regeneration. My lab identified the cardiac leptin b-linked regeneration enhancer (cLEN), which activates gene expression upon cardiac injury. Using in vivo transgenic assays, I found that multiple activation elements are required for injury-dependent cardiac enhancer activity. Surprisingly, I also found that cLEN contains a repressive element that is required for preventing enhancer activation in uninjured hearts, providing the first example of an inhibitory element within a cardiac regeneration enhancer. Based on these data, I hypothesize that cardiac regeneration enhancers are dually governed by activation and repression to direct injury-restricted expression for heart regeneration. In Aim 1, I will utilize pharmacological and genetic approaches to test the model that injury-induced MEK–ERK– AP-1 pathway signaling activates cardiac regeneration enhancers. I will also utilize ATAC-seq, ChIP-seq, and RNA-seq using FACS-sorted endocardial cells from uninjured and regenerating hearts to test whether AP-1 regulates chromatin accessibility, deposition of active histone marks, and injury-induced paracrine factor expression. In Aim 2, I will use transgenic assays to determine whether cLEN-like enhancer candidates I identified in the zebrafish, mouse, and human genomes drive regeneration-induced expression. The functionality of candidate repressive elements will be determined via mutational analyses. I will also utilize in vivo loss-of- function assays to determine whether prdm1a, a transcriptional repressor that is predicted to bind to the repressive element in cLEN, mediates heart regeneration and repression of regeneration enhancers in uninjured hearts. These studies will utilize genetic tools and the endogenous regenerative ability of the zebrafish heart to improve our understanding of transcriptional mechanisms underlying heart regeneration, build gene regulatory networks, and identify potential targets for improving heart repair.
项目摘要/摘要 成年哺乳动物在损伤后再生心脏组织的能力有限,例如心肌损伤。 梗塞心肌梗死后,多达10亿或更多的心肌细胞死亡,并被 导致心力衰竭和猝死的疤痕组织。相比之下,成年斑马鱼的再生能力 没有残留疤痕的受伤心脏虽然斑马鱼和哺乳动物有着相同的基因, 心脏再生,它们对心脏损伤的转录反应是不同的。然而,机制 在心脏再生过程中控制基因表达仍然知之甚少。 我的研究旨在阐明如何调节损伤反应基因的表达,以促进心脏再生。 我的实验室发现了心脏瘦素b连锁再生增强剂(cLEN),它激活基因表达 在心脏损伤时。使用体内转基因测定,我发现, 损伤依赖性心脏增强子活性。令人惊讶的是,我还发现cLEN含有一种抑制因子, 这是防止未受伤的心脏中增强子激活所必需的,提供了抑制剂的第一个例子。 心脏再生增强剂中的元素。基于这些数据,我假设心脏再生 增强子受激活和抑制双重控制,以指导心脏的损伤限制表达, 再生 在目的1中,我将利用药理学和遗传学的方法来测试损伤诱导的MEK-ERK-ERK的模型, AP-1信号通路激活心脏再生增强剂。我还将利用ATAC-seq、ChIP-seq和 使用来自未损伤和再生心脏的FACS分选的内皮细胞的RNA-seq来测试AP-1是否 调节染色质可及性、活性组蛋白标记的沉积和损伤诱导的旁分泌因子 表情在目标2中,我将使用转基因测定来确定cLEN样增强子候选物I 在斑马鱼、小鼠和人类基因组中鉴定的基因驱动再生诱导的表达。的功能 将通过突变分析来确定候选阻遏元件。我也会利用体内的- 功能测定,以确定是否prdm 1a,一个转录阻遏物,预测结合到 cLEN中的抑制元件,介导心脏再生和未受伤的再生增强剂的抑制 心中 这些研究将利用遗传工具和斑马鱼心脏的内源性再生能力来提高 我们对心脏再生的转录机制的理解,建立基因调控网络, 并确定改善心脏修复的潜在目标。

项目成果

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Ian BEGEMAN其他文献

Ian BEGEMAN的其他文献

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{{ truncateString('Ian BEGEMAN', 18)}}的其他基金

Dissecting Regulatory Mechanisms of Cardiac Regeneration Enhancers
剖析心脏再生增强剂的调节机制
  • 批准号:
    10387644
  • 财政年份:
    2022
  • 资助金额:
    $ 3.4万
  • 项目类别:

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