PKD参与介导的自噬在心肌肥厚中的分子机制研究

Hypertension is the most important risk factor for cardiovascular disease. Hypertrophy myocardial remodeling is an independent risk factor for lethal cardiovascular events, and is the key pathological manifestations during the transition of heart function from compensation to decompensation. Protein kinase D family develop the important roles in the cardiovascular system.Protein Kinase D (PKD) is a recent addition to the calcium/calmodulin-dependent serine/threonine protein kinase. PKD family consists of 3 isoforms, these are the original PKD1 which now is also referred to as PKD, PKD2 and PKD3. Increasing evidence now points toward important roles for PKD-mediated signaling pathways in the cardiovascular system, particularly in the regulation of myocardial contraction, hypertrophy and remodeling. Lots of studies have reported that cardiac specific expression of a constitutively active PKD mutant in transgenic mice leads to cardiac hypertrophy, and a chronic increase in PKD activity is sufficient to induce adverse myocardial remodeling. Studies also show that mice lacking cardiac PKD display an impaired response to stress signals that normally lead to cardiac hypertrophy.In our reach before，we found that protein kinase 1 high expressed in hypertrophy myocardium of spontaneously hypertensive rats,while low expression in heart failure period. Some research indicate that aotuphagy participate the procedure of hypertrophy.Protein kinase D may involve in the process of autophagy in recent research.There is not reported that wether protein kinase D is involed in autophay taking part in hypertrohy to heart failure.We will investigate beyond study before.First in animal study，observing the relationship between PKD and autophagy during hypertrophy to heart failur.In cell study，we will identify the role of PKD in autophagy through inhibiting its expression and genes of autophagy.We use pressur-load mice and hypertropic myocardial cell,trying to demonstrate that PKD regulate Beclin 1 through MAPKs in hypertrophy fibrosis and heart failure.The research will prove autophagy which PKD involved in during the progression from hypertrophy to heart failure.

心肌肥厚和心力衰竭是心脏病患者死亡的主要原因之一。蛋白激酶D(PKD)家族在心血管系统中发挥了重要的调节作用。我们前期研究业已证实心肌肥厚发生早期PKD表达明显升高，同时首次发现PKD是通过调节MAPK家族中的ERK5来实现这一过程的。我们课题组最新的预实验提示，PKD参与自噬过程，并且在心肌肥厚不同阶段与自噬水平有时效特征和量效特征的相关性。本项目拟在前期研究及预实验的基础上，进一步深入明确PKD调控自噬在心肌肥厚各阶段的具体分子机制。以压力负荷小鼠以及肥大细胞为模型，分别在体内及体外实验中，通过腺病毒转染技术，过表达重组PKD及沉默相关基因，研究PKD通过MAPKs调控自噬蛋白Beclin 1而参与心肌肥厚、心肌纤维化乃至心力衰竭的过程。本项目旨在揭示PKD介导自噬参与调控心肌肥厚到心力衰竭的内在机制，为心肌肥厚的治疗提供新的依据。

高血压是心血管病重要的危险因素。心肌肥厚是致死性心血管事件的独立危险因素，是心脏功能由代偿到失代偿转变过程中的重要病理表现。肥厚和心力衰竭是心脏病患者死亡的主要原因之一。蛋白激酶 D(PKD)家族在心血管系统中发挥了重要的调节作用。我们前期研究业已证实心肌肥厚发生早期 PKD表达明显升高，同时首次发现 PKD是通过调节 MAPK家族中的ERK5 来实现这一过程的。我们课题组最新的预实验提示，PKD参与自噬过程，并且在心肌肥厚不同阶段与自噬水平有时效特征和量效特征的相关性。本项目拟在前期研究及预实验的基础上，进一步深入明确 PKD调控自噬在心肌肥厚各阶段的具体分子机制。以压力负荷小鼠以及肥大细胞为模型，分别在体内及体外实验中，通过腺病毒转染技术， 过表达重组 PKD及沉默相关基因， 研究PKD通过 MAPKs调控自噬蛋白 Beclin 1 而参与心肌肥厚、心肌纤维化乃至心力衰竭的过程。本项目旨在揭示PKD介导自噬参与调控心肌肥厚到心力衰竭的内在机制，为心肌肥厚的治疗提供新的依据。