The role of Sertad4 in pathologic cardiac remodeling.

Sertad4 在病理性心脏重塑中的作用。

基本信息

批准号：
10642929
负责人：
Matthew Stratton
金额：
$ 49.34万
依托单位：
OHIO STATE UNIVERSITY
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：
2022-07-01 至 2027-06-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10642929
关键词：
Acceleration Affect American Angiotensin II Biology Blood Vessels Cardiac Cardiac Myocytes Cause of Death Cells Cicatrix Clinic Clinical Data Deposition Essential Genes Extracellular Matrix Fibroblasts Fibrosis Flow Cytometry Functional disorder Gene Expression Genes Genetic Transcription Heart Heart failure Human Hypertrophy Immune In Vitro Individual Inflammation Injury Intervention Investigation Knock-out Knockout Mice Knowledge LacZ Genes MADH2 gene Macrophage Macrophage Activation Mediating Modeling Molecular Mus Myocardial Infarction Myocardial Ischemia Myocardial dysfunction Myocarditis Myofibroblast Neutrophil Infiltration Nuclear Protein Organ Pathologic Pathology Pathway interactions Patients Physiological Physiology Population Process Proliferating Property Proteasome Inhibition Proteins Public Health Reporter Research Personnel Risk Rodent Rodent Model Role SMAD2 protein Sampling Site Stress TGFB1 gene Testing Therapeutic Toxic effect Transcription Coactivator Transforming Growth Factor beta Ubiquitination Ventricular Western Blotting Work antifibrotic treatment cell type clinically relevant coronary fibrosis digital effective therapy heart function heart preservation immunoregulation in vivo innovation interstitial mortality multicatalytic endopeptidase complex nano-string neutrophil novel novel therapeutics p38 Mitogen Activated Protein Kinase preclinical development preservation prevent professor programs protein degradation protein expression prototype recruit response selective expression single nucleus RNA-sequencing targeted treatment tool transcription factor transcriptome sequencing

项目摘要

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.

心力衰竭是一个主要的公共卫生问题，影响着超过 600 万美国人，其 5 年死亡率很高超过 40% 的啮齿动物心力衰竭已被多次“治愈”，但仍然是啮齿类动物死亡的主要原因。这在一定程度上是因为许多策略在啮齿动物模型、目标分子和经过临床前开发中更严格的测试，对基线生理学至关重要的过程。这些策略被证明是不安全的，并且未能进入临床。该项目使用了一种重要的基因， BRD4，作为分子手电筒来识别在病理条件下特异性激活的新靶点。该提案将测试迄今为止尚未研究的核蛋白 Sertad4，以确定其在激活和维持心脏成纤维细胞中的病理基因表达程序在少得多的细胞类型中表达。比许多最近研究的引起相当大热情的目标（包括 BRD4）（在所有细胞中表达）我们希望具有更具选择性表达谱的靶向蛋白质将受到限制。潜在疗法的附带损害，尽管没有任何干预措施是真正的灵丹妙药。该提案将确定 Sertad4 的体内抑制是否可以阻止成纤维细胞激活并保护心脏作为助理教授，斯特拉顿博士收集了一份支持性报告。共同研究人员和合作者团队帮助有力地检验了这一假设。大量初步数据表明：1) Sertad4 对于成纤维细胞激活（增殖）至关重要和肌成纤维细胞分化）响应 TGF-β1 刺激，2）Sertad4 蛋白表达升高在人缺血性心力衰竭样本中，3) TGF-β1 刺激诱导成纤维细胞 Sertad4 表达以 BRD4 和 p38 依赖性方式（BRD4/p38 对于成纤维细胞激活也是必需的），4) Sertad4 是在间质和血管周围心脏纤维化部位强烈表达，5) 靶向 Sertad4 可减少 SMAD2/3 蛋白表达和 SMAD2/3 靶基因表达。创新和前沿的方法。建议定义 Sertad4 如何引起成纤维细胞激活，并确定是否操纵 Sertad4 体内表达改变心肌梗塞后的病理重塑过程。严格测试靶向 Sertad4 预防心脏纤维化和心力衰竭的能力，同时还建立有关该新靶点分子机制的基础知识。