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

• 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
• 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

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，预计数字不断 上升，要求需要新颖的治疗方法。 HF开发的一个共同特征是 心肌细胞的肥厚性生长以及相关的大小，尺寸和功能的重塑 心。病理肥大最初是作为自适应反应而发生的，导致个体宽度增加 心肌细胞并引起同心生长，其特征是心脏增厚，壁应变和 保持功能。不受限制地，这种肥厚的生长变得不良适应性，并重新对生长进行重新选择 沿着心肌长度，导致相对壁变薄，心脏扩张和功能下降，导致HF。我们 目前对控制这种过渡的机制的理解很差，但是观察到有限的观察 保留自适应生长的地方显示出对HF发展的抵抗力。因此，该提议试图 确定适应性和适应不良的肥厚性生长的基本机制 有针对性的干预措施维持和/或恢复预防HF的自适应状态。该建议将解决 并非所有病理肥大都是不利的，并且保留适应性，同心的临界区别 状态在响应慢性应激方面具有治疗上有利的。初步数据暗示了 转录因子STAT3的磷酸调节在介导该过渡时。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 超过同心/偏心生长。因此，我们的中心假设是Stat3 Ser727磷酸化是 直接负责诱导自适应与不良适应性肥大的基因程序 并代表HF治疗中的治疗靶标。该方法将是：1）确定分子 将STAT3 SER727磷酸调节与肥厚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。具体来说，这种方法将解决 通过CHIP-SEQ和RNA-SEQ TO改变SER727磷酸化的STAT3转录活性改变了 确定制定同心/偏心状态的基因程序。 3）最后，我们将测试新颖的治疗策略 支持在体内病理肥大期间的自适应心脏重塑以评估HF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，描述 适应性，同心肥大的性质，并在HF中揭示了新的治疗机会。此外， STAT3磷酸化调节和转录活性的表征将提供显着 对许多其他疾病状态（例如癌症，纤维化，炎症和免疫）的病理生理洞察力 STAT3活性涉及的信号传导。