Regulation of STAT3 phosphorylation and its role in orienting myocyte hypertrophy

STAT3磷酸化的调控及其在定向肌细胞肥大中的作用

基本信息

批准号：
10615896
负责人：
Drew Nassal
金额：
$ 11.18万
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：
2022-05-01 至 2024-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10615896
关键词：
Aortic Valve Stenosis Area Automobile Driving Cardiac Cardiac Myocytes Cardiac Output Cardiomegaly Cardiovascular system Cause of Death Cells ChIP-seq Chronic Chronic stress Clinical Complex Cytoskeletal Proteins DNA Binding Data Development Dimensions Disease Disease Progression Fibrosis Framingham Heart Study Future Gene Targeting Genes Genetic Genetic Transcription Grant Growth Heart Heart Diseases Heart Hypertrophy Heart failure Human Hypertrophy Immune signaling Incidence Individual Inflammation Intervention Investigation Knowledge Left Left Ventricular Hypertrophy Length Link MAPK3 gene Malignant Neoplasms Mediating Mentorship Microtubule Proteins Microtubules Molecular Morbidity - disease rate Mus Muscle Cells Myocardial Myocardial Infarction Nature Organ Organism Outcome Pathologic Pathway interactions Performance Phosphorylation Prevention Regulation Reporting Research Resistance Risk Factors Role Scientist Serine Signal Transduction Source Spectrin Stat3 protein Stimulus Stress Switch Genes Testing Therapeutic Thinness Time Tissues Treatment Failure Universities Ventricular Width Work Writing acute stress betaIV spectrin career career development design effectiveness evaluation gene induction gene therapy heart function heart preservation improved in vivo insight mortality mouse model novel novel therapeutic intervention novel therapeutics oral communication pharmacologic preservation pressure prevent programs recruit response skills stressor targeted agent therapeutic evaluation therapeutic target transcription factor transcriptome sequencing translational study

项目摘要

Project Summary/Abstract: Heart failure (HF) is a leading cause of morbidity and mortality worldwide, with projected numbers continually rising, mandating a need for novel therapeutic approaches. A common feature in the development of HF is hypertrophic growth of cardiac myocytes and associated remodeling of the size, dimensions, and function of the heart. Pathologic hypertrophy initially occurs as an adaptive response, leading to increased width of individual myocytes and causing concentric growth characterized by thickened heart walls, reduced wall strain, and maintained function. Left unchecked, this hypertrophic growth becomes maladaptive and reorients to growth along myocyte length, causing relative wall thinning, heart dilation, and declining function leading to HF. We currently have a poor understanding of the mechanisms which govern this transition, yet, limited observations where adaptive growth is preserved shows resistance to HF development. Therefore, this proposal seeks to identify the fundamental mechanisms underlying adaptive and maladaptive hypertrophic growth and investigate targeted interventions to maintain and/or restore the adaptive state for HF prevention. This proposal will address the critical distinction that not all pathologic hypertrophy is adverse and that preserving the adaptive, concentric state is therapeutically advantageous in response to chronic stress. Preliminary data has implicated a role for the phospho-regulation of the transcription factor STAT3 in mediating this transition. In particular, phosphorylation of the serine residue 727 on STAT3 was revealed as a critical target with dramatic influence over concentric/eccentric growth. Therefore, our central hypothesis is that STAT3 Ser727 phosphorylation is directly responsible for the induction of gene programs which drive adaptive versus maladaptive hypertrophy and represents a therapeutic target in HF treatment. The approach will be to: 1) Determine the molecular mechanism linking STAT3 Ser727 phospho-regulation to hypertrophic orientation. 2) Define novel gene targets and pathways which tune cardiac myocyte growth and hypertrophy. Specifically, this approach will address altered STAT3 transcriptional activity dependent on Ser727 phosphorylation through ChIP-seq and RNA-seq to identify gene programs which enact concentric/eccentric states. 3) Lastly, we will test novel therapeutic strategies to support adaptive cardiac remodeling during pathologic hypertrophy in vivo to assess effectiveness in HF prevention. Overall, we anticipate that these data will expand our understanding of HF remodeling, delineate the nature of adaptive, concentric hypertrophy, and reveal novel therapeutic opportunity in HF. Furthermore, characterization of STAT3 phospho-regulation and transcriptional activity will provide significant pathophysiologic insight to numerous other disease states such as cancer, fibrosis, inflammation, and immune signaling where STAT3 activity has been implicated.

项目摘要/摘要：心力衰竭 (HF) 是全球发病率和死亡率的主要原因，预计数字将不断增加上升，需要新的治疗方法。 HF发展的一个共同特点是心肌细胞的肥大生长以及相关的大小、尺寸和功能的重塑心。病理性肥大最初作为适应性反应发生，导致个体宽度增加心肌细胞并引起同心生长，其特征是心壁增厚、壁应变减少，以及维持功能。如果不加以控制，这种肥大的生长会变得适应不良并重新定向生长沿着肌细胞长度，导致壁相对变薄、心脏扩张和功能下降，导致心力衰竭。我们目前对控制这一转变的机制了解甚少，但观察有限适应性生长得以保留的地方显示出对 HF 发展的抵抗力。因此，本提案旨在确定适应性和适应不良肥厚性生长的基本机制并进行研究有针对性的干预措施，以维持和/或恢复心力衰竭预防的适应性状态。该提案将解决关键的区别是，并非所有病理性肥大都是不利的，并且保留适应性、同心性肥大状态对于应对慢性应激有治疗上的优势。初步数据表明，转录因子 STAT3 的磷酸化调节介导了这一转变。尤其， STAT3 上丝氨酸残基 727 的磷酸化被揭示为具有巨大影响的关键目标过度同心/偏心增长。因此，我们的中心假设是 STAT3 Ser727 磷酸化是直接负责诱导基因程序，驱动适应性肥大与适应不良性肥大并代表了 HF 治疗的治疗靶点。该方法将是： 1) 确定分子将 STAT3 Ser727 磷酸化调节与肥大方向联系起来的机制。 2) 定义新的基因靶标以及调节心肌细胞生长和肥大的途径。具体而言，该方法将解决通过 ChIP-seq 和 RNA-seq 改变依赖于 Ser727 磷酸化的 STAT3 转录活性识别产生同心/偏心状态的基因程序。 3）最后，我们将测试新的治疗策略支持体内病理性肥厚期间的适应性心脏重塑，以评估心力衰竭的有效性预防。总体而言，我们预计这些数据将扩展我们对 HF 重塑的理解，描绘适应性向心肥大的本质，并揭示了心力衰竭的新治疗机会。此外， STAT3 磷酸化调节和转录活性的表征将提供重要的信息对许多其他疾病状态（例如癌症、纤维化、炎症和免疫）的病理生理学见解 STAT3 活性涉及的信号传导。