Regulation of STAT3 phosphorylation and its role in orienting myocyte hypertrophy

项目摘要/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，迫切需要新的治疗方法。HF发展的一个共同特征是 心肌细胞肥大生长及其相关的大小、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。 并引起向心性生长，其特征是心壁增厚，室壁应变减少，以及 维持功能。如果不加以控制，这种肥大的生长会变得不适应，并重新定位为生长 沿着心肌细胞长度，导致相对的室壁变薄，心脏扩张，功能下降，导致心衰。我们 目前对管理这一过渡的机制了解很少，但观察结果有限 保持适应性生长的地方显示出对HF发育的抵抗。因此，这项建议旨在 确定适应性和非适应性肥厚性生长的基本机制，并调查 有针对性的干预措施，以维持和/或恢复预防心力衰竭的适应状态。这项提案将解决 并不是所有的病理性肥厚都是不利的，而是保留了适应性的、同心性的 在应对慢性压力时，状态在治疗上是有利的。初步数据表明， 转录因子STAT3在介导这一转变过程中的磷酸化调节。特别是， 丝氨酸残基727在STAT3上的磷酸化被揭示为一个具有显著影响的关键目标 超过同心/偏心的增长。因此，我们的中心假设是STAT3 Ser727的磷酸化是 直接负责诱导基因程序驱动适应性肥大与非适应性肥厚 代表了心衰治疗的一个治疗靶点。方法将是：1)确定分子 STAT3Ser727磷酸化调控与肥大定位的联系机制。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。具体地说，这种方法将解决 通过ChIP-seq和RNA-seq改变STAT3转录活性依赖于Ser727的磷酸化 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 支持在体病理性肥厚期间适应性心脏重构以评估心力衰竭的疗效 预防。总体而言，我们预计这些数据将扩大我们对HF重塑的理解，勾勒出 适应性、向心性肥厚的本质，并揭示了心力衰竭的新治疗机会。此外， STAT3的磷酸化调节和转录活性的表征将提供重要的 对许多其他疾病状态的病理生理学洞察，如癌症、纤维化、炎症和免疫 在STAT3活动被牵连的地方发出信号。

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.