The role of Sertad4 in pathologic cardiac remodeling.

Sertad4 在病理性心脏重塑中的作用。

• 批准号: 10522521
• 负责人: Matthew Stratton
• 金额: $ 49.81万
• 依托单位: OHIO STATE UNIVERSITY
• 依托单位国家: 美国
• 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/10522521
• 关键词: Affect; American; Angiotensin II; Biology; 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; Lead; MADH2 gene; 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; Property; Proteasome Inhibition; Proteins; Public Health; Reporter; Research Personnel; Risk; Rodent; Rodent Model; Role; SMAD2 protein; Sampling; Site; Small Nuclear RNA; Stress; Testing; Therapeutic; Time; 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; macrophage; 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; targeted treatment; tool; transcription factor; transcriptome sequencing

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，影响超过600万美国人，5年死亡率 超过40%心力衰竭在啮齿类动物中已被“治愈”多次，但仍是啮齿类动物死亡的主要原因。 人类这部分是因为许多在啮齿动物模型中如此有效的策略，靶分子和 对基本生理学至关重要的过程。在临床前开发的更严格测试中， 这些策略被证明是不安全的，并且不能进入临床。这个项目使用了一种必需基因， BRD 4作为分子手电筒，用于识别在病理条件下特异性激活的新靶点。 这项提议将测试一种迄今为止尚未研究的核蛋白Sertad 4，以确定它在激活和维持细胞核内的蛋白质中的作用。 心脏成纤维细胞中的病理基因表达程序。Sertad 4在更少的细胞类型中表达 比许多最近调查的目标，产生了相当大的热情，包括BRD 4 （在所有细胞中表达）。我们希望，靶向具有更多选择性表达谱的蛋白质将限制 潜在疗法的附带损害，尽管没有干预措施是真正的银子弹。最终 该提案将确定Sertad 4的体内抑制是否阻止成纤维细胞活化并保护心脏 心肌梗死后的功能。作为一名助理教授，斯特拉顿博士组建了一个支持 共同研究者和合作者的团队，以帮助强有力地测试这一假设。支持这一假设的是 在大量的初步数据中发现，显示：1）Sertad 4对于成纤维细胞活化（增殖）是必需的 和肌成纤维细胞分化），2）Sertad 4蛋白表达升高 在人缺血性心力衰竭样品中，3）成纤维细胞Sertad 4表达由TGF- β 1刺激诱导 以BRD 4和p38依赖的方式（BRD 4/p38也是成纤维细胞活化所必需的），4）Sertad 4是 在间质性和血管周围心脏纤维化的位点稳健表达，和5）靶向Sertad 4降低 SMAD 2/3蛋白表达和SMAD 2/3靶基因表达。创新和前沿方法 提出定义Sertad 4如何引起成纤维细胞活化，并确定是否操纵Sertad 4 体内表达改变了心肌梗死后病理性重塑的过程。该项目将 严格测试靶向Sertad 4预防心脏纤维化和心力衰竭的能力，同时建立 关于这种新靶点的分子机制的基础知识。