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CTRP9 from the heart: Impact on cellular signal transduction, myocardial remodeling, systemic insulin resistance and prospects for gene-therapy approaches.

来自心脏的 CTRP9：对细胞信号转导、心肌重塑、全身胰岛素抵抗的影响以及基因治疗方法的前景。

基本信息

批准号：
234125093
负责人：
Professor Dr. Jörg Heineke
金额：
--
依托单位：
Klinik für Innere Medizin III: Schwerpunkte Kardiologie, Angiologie und internistische Intensivmedizin
依托单位国家：
德国
项目类别：
Research Grants
财政年份：
2013
资助国家：
德国
起止时间：
2012-12-31 至 2018-12-31
项目状态：
已结题

来源：
https://gepris.dfg.de/gepris/projekt/234125093?language=en
关键词：
CTRP9 heart Impact cellular signal

项目摘要

Chronic heart failure is a common and deadly disease. Epidemiologic data reveal an increasing prevalence of diabetes among heart failure patients. On the one hand diabetes with insulin resistance can lead to heart failure, but on the other hand heart failure itself predisposes to the development of insulin resistance and diabetes. It has been proposed in this regard that endocrine factors released from the heart influence systemic metabolism (e.g. in skeletal muscle) and insulin resistance. During screening for cardiac secreted factors we identified the glycoprotein CTRP9, which exerts homology to adiponectin, and which is preferentially expressed in the heart and released into the circulation. Interestingly, systemic overexpression of CTRP9 was shown to reduce serum glucose levels. We found cardiac CTPR9 to be specifically upregulated during compensated cardiac hypertrophy, but not heart failure. Our preliminary data show a prominent anti-hypertrophic role of CTRP9 in cardiomyocytes. Cardiac hypertrophy emerges during diabetes and also arterial hypertension and predisposes to the development of heart failure. We propose that CTRP9 from the heart improves systemic insulin resistance and prevents the development of cardiac dysfunction locally in the myocardium. Here, we aim to identify receptors, intracellular signalling, transcription factors and target genes activated by CTRP9 in cardiomyocytes, skeletal muscle, liver and fat cells. Furthermore, we will use CTRP9 knock-out mice and gene-therapy driven myocardial CTRP9 overexpression to investigate its impact on systemic metabolism and insulin resistance as well as myocardial remodelling during the development of heart failure due to cardiac pressure overload or metabolic stimulation.

慢性心力衰竭是一种常见且致命的疾病。流行病学数据显示，糖尿病在心力衰竭患者中的患病率不断上升。一方面，糖尿病合并胰岛素抵抗可导致心力衰竭，但另一方面，心力衰竭本身又易发展为胰岛素抵抗和糖尿病。在这方面，已经提出了从心脏释放的内分泌因子影响全身新陈代谢(例如在骨骼肌中)和胰岛素抵抗。在筛选心脏分泌因子的过程中，我们鉴定了与脂联素同源的糖蛋白CTRP9，它优先在心脏表达并释放到循环中。有趣的是，全身性过表达CTRP9可以降低血糖水平。我们发现心脏CTPR9在代偿性心肌肥厚期间特异性上调，但在心力衰竭期间没有上调。我们的初步数据显示，CTRP9在心肌细胞中具有显著的抗肥大作用。糖尿病和动脉高血压时会出现心肌肥厚，并易发展为心力衰竭。我们认为来自心脏的CTRP9改善了全身胰岛素抵抗，并防止了心肌局部心功能不全的发展。在这里，我们的目标是确定CTRP9激活的心肌细胞、骨骼肌、肝脏和脂肪细胞中的受体、细胞内信号转导、转录因子和靶基因。此外，我们将利用CTRP9基因敲除小鼠和基因治疗驱动的心肌CTRP9过表达来研究其在心脏压力超负荷或代谢刺激所致心力衰竭发展过程中对全身代谢和胰岛素抵抗以及心肌重塑的影响。