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：
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
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/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

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，影响了超过600万的美国人，其零售价率为5年超过40％的心力衰竭已被啮齿动物“治愈” 人类。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，并且无法进步该项目。 BRD4，作为分子手电筒，以识别在病理条件下专门激活的新目标。该提案将测试迄今未研究的核蛋白Sertad4，以激活和维持其作用心脏成纤维细胞中的病理基因表达程序。比最近调查了引起极大热情的目标，包括BRD4 （在所有细胞中表达）。潜在的治疗方法的附带损害，尽管没有干预措施是真正的银子弹提案将确定sertad4的体内非自由构成成纤维细胞激活并保留CardiACC 在助理教授的心肌梗死之后，Stratton博士组装了共同投资者和合作者团队，以帮助坚强地检验这一假设。在实质性预启示数据中发现：1）SERTAD4是成纤维细胞激活的科学性（Prolityfration 肌纤维细胞的区分）响应TGF-β1刺激，2）SERTAD4蛋白表达升高在人缺血性心力衰竭样品中，3）用TGF-β1刺激诱导纤维细胞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。被支撑以定义SERTAD4如何引起纤维化活化的激活，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。严格测试tartad4的能力，同时建立CardiACC Fibros和心力衰竭关于这个新目标的分子机制的基本知识。