The role of Sertad4 in pathologic cardiac remodeling.

心力衰竭是一个主要的公共卫生问题，影响着600多万美国人，5年死亡率高 超过40%。在啮齿动物身上，心力衰竭已经被治愈了很多次，但仍然是导致人类死亡的主要原因。 人类。这在一定程度上是因为，许多在啮齿动物模型、靶分子和 对基线生理学至关重要的过程。在临床前开发中进行更严格的测试后， 这些策略被证明是不安全的，未能进入临床。这个项目使用了一种重要的基因， BRD4，作为分子闪光灯，识别在病理条件下特异激活的新靶点。 该提案将测试一种迄今未被研究的核蛋白Sertad4，以确定其在激活和维持生命过程中的作用 心脏成纤维细胞中的病理基因表达程序。Sertad4在更少的细胞类型中表达 比包括BRD4在内的许多最近调查的目标都引起了相当大的热情 (在所有单元格中表达)。我们希望，具有更多选择性表达谱的靶向蛋白将限制 潜在疗法的附带损害，尽管没有干预措施是真正的银弹。归根结底， 一项提案将确定体内抑制Sertad4是否能阻止成纤维细胞激活并保存心脏 心肌梗死后的功能。作为一名助理教授，斯特拉顿博士组织了一项支持 一组合作研究人员和合作者帮助有力地检验这一假说。对这一假设的支持是 在大量的初步数据中发现：1)Sertad4对于成纤维细胞的激活(增殖)是必不可少的 和肌成纤维细胞分化)作为对转化生长因子-β1刺激的响应，2)Sertad4蛋白表达增加 在人的缺血性心力衰竭样本中，3)转化生长因子-β1刺激诱导成纤维细胞Sertad4的表达 以依赖于BRD4和p38的方式(BRD4/p38对于成纤维细胞的激活也是必需的)，4)Sertad4 在间质和血管周围的心肌纤维化部位强健表达，5)靶向Sertad4减少 Smad2/3蛋白表达和Smad2/3靶基因表达。创新和前沿的方法 来定义Sertad4是如何引起成纤维细胞激活的，并确定是否操纵Sertad4 在体内的表达改变了心肌梗死后的病理重构过程。这个项目将 严格测试靶向Sertad4以预防心脏纤维化和心力衰竭的能力，同时还建立 关于这一新靶点的分子机制的基础知识。

Heart failure is a major public health problem, affecting over 6 million Americans with a 5 year mortality rate over 40%. Heart failure has been “cured” many times in rodents, yet remains a leading cause of death in humans. This is in part, because many of the strategies so effective in rodent models, target molecules and processes that are essential for baseline physiology. Upon more rigorous testing in pre-clinical development, these strategies are proven unsafe and fail to progress into the clinic. This project uses an essential gene, BRD4, as a molecular flashlight to identify new targets that are specifically activated in pathologic conditions. The proposal will test a thus far unstudied nuclear protein, Sertad4, for its role in activating and sustaining pathologic gene expression programs in the cardiac fibroblast. Sertad4 is expressed in far fewer cell-types than many recently investigated targets that have generated considerable enthusiasm, including BRD4 (expressed in all cells). It is our hope that targeting proteins with more selective expression profiles will limit collateral damage of potential therapeutics, though no interventions are true silver bullets. Ultimately, the proposal will establish if in vivo inhibition of Sertad4 prevents fibroblast activation and preserves cardiac function following myocardial infarction. As an assistant professor, Dr. Stratton has assembled a supporting team of co-investigators and collaborators to help robustly test this hypothesis. Support for the hypothesis is found in substantial preliminary data showing that: 1) Sertad4 is essential for fibroblast activation (proliferation and myofibroblast differentiation) in response to TGF-β1 stimulation, 2) Sertad4 protein expression is elevated in human ischemic heart failure samples, 3) fibroblast Sertad4 expression is induced with TGF- β 1 stimulation in a BRD4 and p38 dependent manner (BRD4/p38 are also necessary for fibroblast activation), 4) Sertad4 is robustly expressed at sites of interstitial and perivascular cardiac fibrosis, and 5) targeting Sertad4 reduces SMAD2/3 protein expression and SMAD2/3 target gene expression. Innovative and cutting edge approaches are proposed to define how Sertad4 causes fibroblast activation, and determine if manipulating Sertad4 expression in vivo alters the course of pathologic remodeling following myocardial infarction. This project will rigorously test the ability to target Sertad4 to prevent cardiac fibrosis and heart failure, while also establishing fundamental knowledge regarding the molecular mechanisms of this novel target.