TLR4相关蛋白PRAT4A对心脏重构的影响及其机制的研究

Heart remodeling is the common symptoms in chronic heart failure caused by all kinds of cardiovascular disease. Restraining and reversing heart remodeling can stem heart failure progress and improve cardiac function. Toll-like receptors(TLRs) is the most important innate immune receptors, represent a first line of defense against infectious pathogens, and play a pivotal role in initiating and shaping innate and adaptive immune responses. TLRs are not only expressed in immune cells, but also in cardiovascular cells. In addition to their role in response to microbial infections, evidence suggests that TLRs can also recognize endogenous ligands and may play a role in mediating cardiomyocyte cell death and survival after non-infectious injury. Protein Associated with Toll-Like Receptor 4 (PRAT4A) is associated with the immature form of TLR4. Our pre-experiments show that the expression of PRAT4A in cardiac muscular tissue is higher in dilated cardiomyopathy than normal. And the heart size and myocardial cell area is smaller in PRAT4A-/- mouse than WT mouse. However, the role of PRAT4A in heart remains unclear. In this project, we will use PRAT4A knockout mice and cardiac specific-expressed transgenic mice as model to investigate the role of PRAT4A in heart remodeling by analyzing the phenotype of these mice, detecting its signaling pathways and revealing the mechanism of PRAT4A in heart remodeling. Therefore, the aim of this study is to test whether PRAT4A is a novel molecular target for preventing cardiac disease.

心脏重构是各种心血管疾病引起的慢性心力衰竭的共同病理表现，抑制和逆转心脏重构是扼制心力衰竭进展，改善心脏功能的希望所在。TLR信号通路介导的天然免疫信号通路与心血管疾病的发生发展密切相关。预实验显示TLR-4相关蛋白（PRAT4A）在扩张性心肌病病人(DCM)的心肌组织中的表达显著升高，PRAT4A基因敲除小鼠心脏体积的增加与心肌细胞面积的扩大较野生型小鼠均有明显降低,而PRAT4A在心脏疾病中的功能未知。本项目以PRAT4A基因敲除小鼠及心脏特异性转基因小鼠为材料，建立小鼠心肌肥厚和心肌梗死模型，研究PRAT4A对心脏重构的影响及其分子机理。同时运用分子生物学和细胞生物学技术，在细胞水平探讨PRAT4A对心肌细胞肥大、凋亡和炎症、心肌成纤维细胞的增值和胶原合成的影响及其可能的分子机制。力图明确PRAT4A对心脏重构的影响，阐明该基因对心脏重构的根本机制。

本项目已按原计划顺利实施。心脏重构是各种心血管疾病所致心力衰竭发生发展的核心机制。本项目意在阐明PRAT4A对心脏重构的影响及其具体机制。项目通过Western Blot等方法发现在扩张型心肌病患者心肌组织以及压力负荷诱导的小鼠肥厚性心肌组织中PRAT4A蛋白的表达量显著升高。通过PRAT4A全身性基因敲除小鼠、心脏特异性PRAT4A转基因小鼠等多种基因工程小鼠，研究了PRAT4A在心脏重构中的作用，结果表明，PRAT4A能促进心脏重构的病理过程。进一步机制研究发现PRAT4A通过参与TGF-beta信号通路影响心肌肥厚，PRAT4A与NLK相互作用，介导NLK与Smad2/3的相互作用并磷酸化Smad2/3的Linker区从而抑制了Smad2/3活性区的磷酸化，最终抑制TGF-信号通路，影响细胞的迁移，最终促进心脏重构的病理进程。

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