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）： 心脏通过安装自适应或代偿性肥厚性反应来应对压力和需求增加，以使心脏输出正常化。随着压力的延长，这种自适应相位变成了适应不良或代谢性的肥大，标志着代谢枯竭的心肌细胞死亡，并通过产生粘液纤维化的胶原蛋白成纤维细胞而替换。在向代偿性肥大发展，代谢衰竭和疤痕型纤维化进展的过程中，最重要的是使其成为治疗干预的关键目标。这些过程本质上是遗传性的，具有明确的基因和控制其表达的调节机制。但是，肥厚应激信号与这些调节机制相互作用，以控制代谢或纤维化基因表达，以及这如何使心脏适应（或不适应压力）尚未得到充分定义。没有这些知识，试图通过维持适应性或防止适应不良反应来设计疗法来治疗心脏肥大。我们研究的长期目标是了解心脏将肥厚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称为CLP-1（心脏谱系蛋白-1）的分子，我们证明这对于将肥厚应激信号整合到基因组应力反应中至关重要。 CLP-1是一种抑制转录调节剂，可控制P-TEFB的活性（P-Transcrient伸长因子B），这是一种转录调节剂，它激活RNA聚合酶II以转录基因。作为基因转录的关键调节剂，CLP-1在各种生理和病理过程中起重要作用，涉及将细胞外信号整合到协调的基因组反应中。该应用的目的是确定如何响应肥厚刺激CLP-1如何控制代谢程序中基因的转录，从而调节能量底物的使用以及调节肥厚性心肌心肌重塑的纤维化程序。 我们的假设是，降低的CLP-1转录抑制剂水平可能是增加了包括代谢性基因在内的代偿胁迫反应基因的转录能力和反应能力，以维持心肌细胞的生存能力，以减轻纤维化形式，重复性或疤痕纤维化的更具破坏性形式的水平。我们检查该假设的实验模型是降低Clp-1基因剂量CLP-1 +/-杂合小鼠的小鼠，在物理上或与已建立的肥大小鼠模型交叉相交。为了检验我们的假设，我们提出了三个具体目标。在AIM＃1中，我们将确定指导能量底物使用的基因是否被上调以维持肥厚性心肌细胞的代谢输出和生存能力。在AIM＃2中，我们将检查在从补偿性到代偿性肥大的进展过程中CLP-1 +/-肥厚心脏中发展的纤维化类型，以确定肥大性心肌细胞的CLP-1水平和持续代谢性的持续代谢可使纤维化形式更为严重。在AIM＃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其表达的信号转导途径来直接上调特定的应力响应基因。 这种方法具有创新性，因为它将重点从对心脏病的原因的研究转移到了那些专注于如何防止患病心脏发展到失败的人们。由于大多数心脏病患者属于后一类，因此他们将从我们的研究提供的见解中受益。总的来说，我们的研究应证明CLP-1通过控制压力反应基因来控制心脏细胞对肥厚刺激的反应的关键位置。这些研究很重要，因为它们将为适应性肥厚反应的基础的分子事件提供更大的了解，以及如何控制它们以减轻肥大性心脏对收缩功能障碍和失败的进展。

项目成果

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• 发表时间: 2022-05
• 期刊: The Lancet. Microbe
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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
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SARS-CoV-2 immunity and functional recovery of COVID-19 patients 1-year after infection.

• DOI: 10.1038/s41392-021-00777-z
• 发表时间: 2021-10-13
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• 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