Expression, function and endogenous modulators of transient receptor potential channels TRPV1, TRPV6 and TRPM8 in gastroenteropancreatic neuroendocrine tumors

瞬时受体电位通道TRPV1、TRPV6和TRPM8在胃肠胰神经内分泌肿瘤中的表达、功能和内源性调节剂

• 批准号: 221906675
• 负责人: Dr. Carsten Grötzinger
• 金额: --
• 依托单位: Klinik für Augenheilkunde (CVK)
• 依托单位国家: 德国
• 项目类别: Research Grants
• 财政年份: 2012
• 资助国家: 德国
• 起止时间: 2011-12-31 至 2015-12-31
• 项目状态: 已结题
• 来源: https://gepris.dfg.de/gepris/projekt/221906675?language=en
• 关键词: Expression; function; endogenous; modulators; transient

Neoplastic properties of neuroendocrine tumors of the gastroenteropancreatic system (GEP-NETs) are, similar to numerous other cancers, determined by calcium-dependent cellular mechanisms. Intracellular calcium is substantially regulated by transient receptor potential channels (TRPs). The functional relevance of the TRP channel subtypes TRPM8, TRPV1, and TRPV6 for the carcinogenesis has been described in various solid tumors. The distinct expression levels of these TRPs in certain solid malignancies (e. g. prostate carcinoma) correlate with the clinical prognosis, and therefore TRPs are considered as novel prognostic markers. In a recent study the applicants demonstrated for the first time that pancreatic NETs express TRPM8. Current investigations revealed overexpression of TRPV1 and decreased expression of TRPV6 in NETs of pancreas and ileum. Given the increased incidence and limited therapeutic options of GEP-NETs, the aim of the project consist of the characterization of the expression and properties of TRPM8, TRPV1 and TRPV6 in regulating tumor biological processes in this malignancy. Using GEP-NET cell models and primary cell cultures, we plan to investigate the molecular, biochemical and pharmacological characteristics of these TRPs and to study their crucial signaling pathways. In addition, we aim to characterize the functional cross-talk between TRPM8, TRPV1 and TRPV6 and the oncogenically-relevant ligands of membrane receptors for IGF-1, EGF and somatostatin in GEP-NETs. Lastly, using in-house established animal models of GEP-NETs, the oncogenic activities of these three different TRPs will be studied. Overall, the results of this study will contribute to a better understanding of the GEP-NETs biology and hold promise to improve and extend of the arsenal of diagnostic and therapeutic tools available to date in this unique neoplastic disease by utilizing TRPs.

胃肠胰腺系统神经内分泌肿瘤(GEP-NETs)的肿瘤特性与许多其他癌症相似，由钙依赖的细胞机制决定。细胞内钙在很大程度上受瞬时受体电位通道(TRPs)调节。Trp通道亚型TRPM8、TRPV1和TRPV6在多种实体肿瘤中的功能相关性已被描述。这些TRPs在某些实体恶性肿瘤(如前列腺癌)中的不同表达水平与临床预后相关，因此TRPs被认为是新的预后标记物。在最近的一项研究中，申请者首次证明了胰腺网络表达TRPM8。目前的研究表明，TRPV1在胰腺和回肠的Net中高表达，而TRPV6在Net中的表达降低。鉴于GEP-Net的发病率增加和治疗选择有限，该项目的目的是表征TRPM8、TRPV1和TRPV6在调节这种恶性肿瘤的肿瘤生物学过程中的表达和特性。利用GEP-Net细胞模型和原代细胞培养，我们计划研究这些TRP的分子、生化和药理学特性，并研究它们的关键信号通路。此外，我们的目的是描述GEP-Net中TRPM8、TRPV1和TRPV6之间的功能串扰以及IGF-1、EGF和生长抑素的膜受体的致癌相关配体。最后，使用内部建立的GEP-Net动物模型，研究这三种不同TRP的致癌活性。总体而言，这项研究的结果将有助于更好地了解GEP-Nets生物学，并有望通过利用TRP来改进和扩大迄今为止在这种独特的肿瘤疾病中可用的诊断和治疗工具的武器库。

项目成果

Functional significance of thermosensitive transient receptor potential melastatin channel 8 (TRPM8) expression in immortalized human corneal endothelial cells.

• DOI: 10.1016/j.exer.2013.10.003
• 发表时间: 2013-11
• 期刊: Experimental eye research
• 影响因子: 3.4
• 作者: S. Mergler;C. Mertens;M. Valtink;P. Reinach;Violeta Castelo Székely;N. Slavi;F. Garreis;Suzette Abdelmessih;Ersal Türker;G. Fels;U. Pleyer

Role of TRPV channels in regulating various pancreatic β-cell functions: Lessons from in vitro studies.

TRPV 通道在调节各种胰腺 β 细胞功能中的作用：体外研究的教训

• DOI: 10.5582/bst.2016.01226
• 发表时间: 2017
• 期刊: Bioscience trends
• 影响因子: 5.5
• 作者: Skrzypski M;Billert M;Mergler S;Khajavi N;Nowak K.W;Strowski M.Z.
• 通讯作者: Strowski M.Z.

Activation of TRPV4 channel in pancreatic INS‐1E beta cells enhances glucose‐stimulated insulin secretion via calcium‐dependent mechanisms

• DOI: 10.1016/j.febslet.2013.08.025
• 发表时间: 2013-10
• 期刊: FEBS Letters
• 影响因子: 3.5
• 作者: M. Skrzypski;M. Kakkassery;S. Mergler;C. Grötzinger;N. Khajavi;M. Sassek;D. Szczepankiewicz;B. Wiedenmann;K. Nowak;M. Strowski

L-Carnitine Reduces in Human Conjunctival Epithelial Cells Hypertonic-Induced Shrinkage through Interacting with TRPV1 Channels

• DOI: 10.1159/000363043
• 发表时间: 2014-01-01
• 期刊: CELLULAR PHYSIOLOGY AND BIOCHEMISTRY
• 作者: Khajavi, Noushafarin;Reinach, Peter S.;Mergler, Stefan
• 通讯作者: Mergler, Stefan

Calcium regulation by temperature-sensitive transient receptor potential channels in human uveal melanoma cells.

人葡萄膜黑色素瘤细胞中温度敏感瞬时受体电位通道的钙调节

• DOI: 10.1016/j.cellsig.2013.09.017
• 发表时间: 2014
• 期刊: Cellular signalling
• 影响因子: 4.8
• 作者: Mergler;Derckx;Reinach;Garreis;Schmelzer;Skosyrski;Ramesh;Abdelmessih;Khajavi;Riechardt
• 通讯作者: Riechardt