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.

项目概要/摘要： 心力衰竭（HF）是世界范围内发病率和死亡率的主要原因，预计人数不断增加 不断上升，要求对新的治疗方法的需求。HF发展的一个共同特征是 心肌细胞的肥大性生长和相关的心肌细胞大小、尺寸和功能的重塑， 心病理性肥大最初是一种适应性反应，导致个体宽度增加， 心肌细胞，并导致同心生长，其特征在于增厚的心脏壁，减少壁应变， 保持功能。如果不加以控制，这种肥大性生长就会变得适应不良，并重新定向生长 沿着肌细胞长度，引起相对壁变薄、心脏扩张和功能下降，导致HF。我们 目前对这种转变的机制了解不多，但观察有限 其中保持适应性生长的地方显示出对HF发展的抗性。因此，这项建议旨在 确定适应性和适应不良肥大性生长的基本机制，并研究 有针对性的干预措施，以维持和/或恢复HF预防的适应状态。该提案将解决 关键的区别是，并非所有的病理性肥大都是不利的， 这种状态在治疗上对慢性应激反应是有利的。初步数据显示， 转录因子STAT3在介导这种转变中的磷酸化调节。特别是， STAT3上丝氨酸残基727的磷酸化被揭示为具有显著影响的关键靶点 同心/偏心生长。因此，我们的中心假设是STAT3 Ser727磷酸化是一个重要的信号通路。 直接负责诱导基因程序，这些基因程序驱动适应性肥大与适应不良肥大 并且代表HF治疗中的治疗靶点。方法将是：1）确定分子 STAT3 Ser727磷酸化调节与肥大定向的联系机制。2)定义新的基因靶点 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， 在体内病理性肥大期间支持适应性心脏重塑，以评估HF的有效性 预防总的来说，我们预计这些数据将扩大我们对HF重塑的理解，描绘HF重塑的过程。 适应性、向心性肥大的本质，并揭示了HF的新治疗机会。此外，委员会认为， STAT3磷酸调节和转录活性的表征将提供重要的 病理生理学洞察许多其他疾病状态，如癌症，纤维化，炎症和免疫 其中STAT3活性已被牵连的信号传导。