The role of Sertad4 in pathologic cardiac remodeling.

Sertad4 在病理性心脏重塑中的作用。

• 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
• 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

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，影响了超过600万的美国人，死亡率为5年 超过40％。心力衰竭已在啮齿动物中多次“治愈”，但仍然是死亡的主要原因 人类。这部分是因为在啮齿动物模型，靶向分子和 对于基线生理必不可少的过程。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，无法进入诊所。该项目使用一个基本基因， BRD4，作为一种分子手电筒，以识别在病理条件下专门激活的新靶标。 该提案将测试迄今未研究的核蛋白Sertad4，以激活和维持的作用 心脏成纤维细胞中的病理基因表达程序。 SERTAD4以较少的细胞类型表示 比最近调查的许多已经产生了考虑因素的目标，包括BRD4 （在所有细胞中表达）。我们希望靶向具有更多选择性表达曲线的蛋白质将限制 潜在疗法的附带损害，尽管没有干预措施是真正的银色灯泡。最终， 提案将确定体内抑制Sertad4是否可以防止成纤维细胞激活并保留心脏 心肌梗塞后的功能。作为助理教授，斯特拉顿博士召集了支持 共同投资者和合作者团队，以帮助坚强地检验这一假设。对假设的支持是 在大量的初步数据中发现：1）Sertad4对于成纤维细胞激活至关重要（增殖 响应TGF-β1刺激的肌纤维细胞分化），2）SERTAD4蛋白表达升高 在人缺血性心力衰竭样品中，3）用TGF-β1模拟诱导成纤维细胞SERTAD4表达 以BRD4和p38的依赖方式（BRD4/p38也是成纤维细胞激活所必需的），4）Sertad4 IS 在间质和血管周心纤维化部位强烈表达，5）靶向sertad4减少 SMAD2/3蛋白表达和Smad2/3靶基因表达。创新和最前沿的方法 建议定义SERTAD4如何引起成纤维细胞激活，并确定是否操纵Sertad4 体内表达会改变心肌梗塞后的病理重塑过程。这个项目将 严格测试靶向SERTAD4以防止心脏纤维化和心力衰竭的能力，同时还建立 关于这个新目标的分子机制的基本知识。