Genetic Regulation of Metabolic and Fibrotic Programs in Hypertrophic Heart

肥厚心脏代谢和纤维化程序的基因调控

• 批准号: 8971948
• 负责人: M.A.Q Siddiqui
• 金额: --
• 依托单位: VA NEW YORK HARBOR HLTHCARE/SYS/BROOKLYN
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-04-01 至 2017-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8971948
• 关键词: Aging; Automobile Driving; Cardiac; Cardiac Myocytes; Cardiac Output; Categories; Cells; Cessation of life; Cicatrix; Collagen; Complex; DNA Polymerase II; Development; Disease; Event; Experimental Models; Extracellular Matrix; Failure; Fibrosis; Functional disorder; Gene Dosage; Gene Expression; General Population; Genes; Genetic; Genetic Processes; Genetic Programming; Genetic Transcription; Genomics; Goals; Heart; Heart Diseases; Heart Hypertrophy; Heart failure; Hypertension; Hypertrophy; Incidence; Individual; Institute of Medicine (U.S.); Knowledge; Laboratories; Lead; Left; Metabolic; Metabolic Control; Molecular; Mus; Myocardial Ischemia; Myocardium; Myofibroblast; Nature; Outcome; Output; Pathologic Processes; Pathway interactions; Phase; Physiological; Play; Positioning Attribute; Process; Proteins; RNA; RNA Polymerase II; Regimen; Regulation; Regulator Genes; Reporting; Research; Research Proposals; Role; STAT3 gene; Signal Pathway; Signal Transduction; Signal Transduction Pathway; Staging; Stimulus; Stress; Testing; Therapeutic; Therapeutic Intervention; Transcriptional Activation; Transcriptional Elongation Factors; Transducers; Translating; Ventricular; Veterans; Vietnam; War; agent orange; base; biological adaptation to stress; effective therapy; energy balance; extracellular; falls; gene interaction; inhibitor/antagonist; innovation; insight; mouse model; preclinical study; prevent; programs; public health relevance; response; targeted treatment

DESCRIPTION (provided by applicant): The heart responds to stress and increased demand by mounting an adaptive or compensatory hypertrophic response to normalize cardiac output. With prolonged stress, this adaptive phase devolves to a maladaptive or decompensatory hypertrophy marked by the death of metabolically depleted cardiomyocytes and replacement by collagen-producing myofibroblasts that produce a scarring fibrosis. Of the processes underlying the progression to decompensatory hypertrophy, metabolic failure and scarring fibrosis are the most consequential making them key targets for therapeutic intervention. These processes are genetic in nature with well-defined genes and regulatory mechanisms controlling their expression. But exactly how hypertrophic stress signals interact with these regulatory mechanisms to control metabolic or fibrotic gene expression and how this allows the heart to adapt (or not) to stress has yet to be adequately defined. Without this knowledge, attempts to devise therapies to treat cardiac hypertrophy by either maintaining the adaptive or preventing the maladaptive response are likely to be unproductive. The long-term goal of our research is to understand the molecular mechanisms with which the heart translates hypertrophic stress signals into a genomic stress response. Our laboratory has been studying a molecule called CLP-1 (Cardiac Lineage Protein-1) that we have shown to be critical for integrating hypertrophic stress signals into a genomic stress response. CLP-1 is an inhibitory transcriptional modulator that controls the activity of P-TEFb (P-Transcriptional Elongation Factor b), a transcriptional regulator that activates RNA polymerase II to transcribe genes. As a critical regulator of gene transcription, CLP-1 plays an important role in a variety of physiologicl and pathological processes that involve integration of extracellular signals into a coordinated genomic response. The objective of this application is to determine how in response to hypertrophic stimuli CLP-1 controls the transcription of genes in the metabolic program regulating energy substrate usage and in the fibrotic program regulating remodeling of the hypertrophic ventricular myocardium. Our hypothesis is that reduced levels of the CLP-1 transcriptional inhibitor could be increasing the transcriptional competency and responsiveness of compensatory stress response genes, including metabolic genes, in order to maintain cardiomyocyte viability at levels that mitigate formation of the more damaging form of fibrosis, reparative or scarring fibrosis. Our experimental model for examining this hypothesis are mice with reduced CLP-1 gene dosage, CLP-1+/- heterozygous mice, rendered hypertrophic physically or by crossing with established mouse models of hypertrophy. To test our hypothesis, we propose three specific aims. In aim #1, we will determine if the genes directing energy substrate usage are up-regulated to maintain the metabolic output and viability of hypertrophic cardiomyocytes. In aim #2, we will examine the type of fibrosis that develops in CLP-1+/- hypertrophic hearts during the progression from compensatory to decompensatory hypertrophy to determine if reduced CLP-1 levels and sustained metabolic viability of hypertrophic cardiomyocytes mitigates formation of the more severe form of reparative or scarring fibrosis. And in aim #3, we will determine if the CLP-1-P-TEFb regulatory mechanism can directly up-regulate specific stress response genes by potentiating the signal transduction pathway controlling their expression. This approach is innovative in that it shifts the focus away from studies on the causes of heart disease to those focusing on how to prevent the diseased heart from progressing to failure. Since most people with heart disease fall into this latter category, they stand to benefit from the insights our research can provide. In all, our studies should demonstrate that CLP-1 occupies a critical position for controlling the response of cardiac cells to hypertrophic stimuli via its control of stress response genes. These studies are significant since they will provide greater insight into the molecular events underlying the adaptive hypertrophic response and how they can be controlled to mitigate the progression of hypertrophic hearts to contractile dysfunction and failure.

描述(由申请人提供)： 心脏对压力和需求增加的反应是通过启动适应性或代偿性肥厚反应来正常化心输出量。随着长时间的应激，这一适应阶段演变为适应不良或失代偿性肥大，其特征是代谢耗竭的心肌细胞死亡，取而代之的是产生胶原的肌成纤维细胞，从而产生瘢痕纤维化。在发展为失代偿性肥厚的过程中，代谢衰竭和瘢痕纤维化是最重要的，使它们成为治疗干预的关键靶点。这些过程本质上是遗传的，有明确定义的基因和控制其表达的调控机制。但肥大应激信号如何与这些调控机制相互作用来控制代谢或纤维化基因的表达，以及这如何允许心脏适应(或不适应)应激，尚未得到充分的定义。如果没有这方面的知识，试图通过保持适应或防止适应不良反应来设计治疗心肌肥厚的方法可能是徒劳的。我们研究的长期目标是了解心脏将肥大应激信号转化为基因组应激反应的分子机制。我们的实验室一直在研究一种名为CLP-1(心脏谱系蛋白-1)的分子，我们已经证明，该分子对于将肥大应激信号整合到基因组应激反应中至关重要。CLP-1是一种抑制转录调节因子，控制P-TEFb(P-转录延伸因子b)的活性，P-TEFb是一种转录调节因子，激活RNA聚合酶II转录基因。作为基因转录的关键调控因子，CLP-1在多种生理和病理过程中发挥着重要作用，这些生理和病理过程涉及细胞外信号整合到协调的基因组反应中。这项应用的目的是确定CLP-1如何在肥大刺激的反应中控制代谢程序中调节能量底物使用的基因的转录，以及如何在纤维化程序中调节肥厚心肌的重塑。 我们的假设是，CLP-1转录抑制物水平的降低可能会增加包括代谢基因在内的代偿性应激反应基因的转录能力和反应性，从而将心肌细胞的活力维持在一定水平，以减轻更具破坏性的纤维化、修复性或瘢痕纤维化的形成。我们检验这一假说的实验模型是CLP-1基因剂量降低的小鼠，CLP-1+/-杂合子小鼠，身体肥大或通过与已建立的肥大小鼠模型杂交而呈现肥大。为了检验我们的假设，我们提出了三个具体目标。在目标1中，我们将确定指导能量底物使用的基因是否上调以维持肥大心肌细胞的代谢输出和活性。在目标#2中，我们将研究CLP-1+/-肥厚的心脏在从代偿性肥厚向失代偿性肥厚发展的过程中发展的纤维化类型，以确定肥厚心肌细胞CLP-1水平降低和持续的代谢活性是否可以缓解更严重的修复性或瘢痕纤维化的形成。在目标3中，我们将确定CLP-1-P-TEFb调节机制是否可以通过增强控制特定应激反应基因表达的信号转导途径来直接上调它们。这种方法是创新的，因为它将重点从研究心脏病的原因转移到那些关注如何防止疾病的心脏进展为衰竭的研究上。由于大多数心脏病患者属于后一类，他们将从我们的研究提供的见解中受益。总之，我们的研究应该证明，CLP-1通过控制应激反应基因，在控制心肌细胞对肥大刺激的反应方面占据了关键地位。这些研究意义重大，因为它们将更深入地了解适应性肥厚反应背后的分子事件，以及如何控制这些事件以缓解肥厚性心脏向收缩功能障碍和衰竭的进展。

项目成果

Clinical evidence of an interferon-glucocorticoid therapeutic synergy in COVID-19.

• DOI: 10.1038/s41392-021-00496-5
• 发表时间: 2021-03-03
• 期刊: Signal transduction and targeted therapy
• 影响因子: 39.3
• 作者: Lu Y;Liu F;Tong G;Qiu F;Song P;Wang X;Zou X;Wan D;Cui M;Xu Y;Zheng Z;Hong P
• 通讯作者: Hong P

SARS-CoV-2 immunity and functional recovery of COVID-19 patients 1-year after infection.

感染后1年后，SARS-COV-2免疫和功能性恢复。

• DOI: 10.1038/s41392-021-00777-z
• 发表时间: 2021-10-13
• 期刊: Signal transduction and targeted therapy
• 影响因子: 39.3
• 作者: Zhan Y;Zhu Y;Wang S;Jia S;Gao Y;Lu Y;Zhou C;Liang R;Sun D;Wang X;Hou Z;Hu Q;Du P;Yu H;Liu C;Cui M;Tong G;Zheng Z;Xu Y;Zhu L;Cheng J;Wu F;Zheng Y;Liu P;Hong P
• 通讯作者: Hong P

Association of neutralizing breadth against SARS-CoV-2 with inoculation orders of heterologous prime-boost vaccines.

SARS-CoV-2 中和广度与异源初免-加强疫苗接种顺序的关联

• DOI: 10.1016/j.medj.2022.05.003
• 发表时间: 2022-08-12
• 期刊: MED
• 影响因子: 17
• 作者: Zhu, Yufan;Lu, Yingyin;Zhou, Cail;Tong, Ganglin;Gao, Manman;Zhan, Yan;Wang, Yan;Liang, Ran;Li, Yawei;Gao, Tianjiao;Wang, Li;Zhang, Muyun;Cheng, Jin;Gong, Jun;Wang, Jimin;Zhang, Wei;Qi, Junhua;Cui, Miao;Zhu, Longchao;Xiao, Fenglian;Zhu, Linyu;Xu, Yunsheng;Zheng, Zhihua;Zhou, Zhiyu;Cheng, Zhengjiang;Hong, Peng
• 通讯作者: Hong, Peng