Deciphering structural bases of TRP channel inhibition as foundations for the design of new drugs

任何身体或精神活动都涉及离子通道。离子通道也与许多人类疾病有关，包括由突变引起的疾病（通道病）。许多药物，包括局部麻醉剂，抗焦虑剂和镇静剂，目标离子通道。然而，由于我们对其分子调控机制的了解有限，许多离子通道缺乏高效和选择性的药物。我对瞬时受体电位（TRP）香草酸亚家族（TRPV）通道特别感兴趣。这些多模态感觉传感器对化学物质、温度、机械应力和膜电压做出响应，并且涉及视觉、味觉、嗅觉、听觉、触觉、热感知和伤害感受。在我提出的研究项目中，我专注于这个家族的两个（病理）生理学上重要的成员，TRPV3和TRPV6。钙选择性通道TRPV6在上皮组织中的钙摄取中起核心作用。TRPV 6是一种分类的致癌通道，在各种类型的人类癌细胞中过表达，包括乳腺癌、前列腺癌、结肠癌、卵巢癌、甲状腺癌、子宫内膜癌和白血病癌细胞。TRPV6在癌症中的中心作用似乎是通过刺激Ca2+进入细胞来损害Ca2+稳态。相应地，迫切需要TRPV6介导的钙摄取的抑制剂来治疗富含TRPV6的肿瘤。我还研究了温度敏感通道TRPV3，它被热和几种天然化合物激活，如樟脑，百里酚，香芹酚，丁香酚和大麻酚。TRPV3主要在皮肤角质形成细胞中表达，并且除了维持皮肤屏障、伤口愈合和毛发生长之外，还涉及皮肤感觉，包括热感觉、伤害感受和瘙痒。TRPV3通道的功能障碍，通常是基因突变的结果，与许多人类皮肤病相关，包括称为Olmsted综合征的遗传性皮肤病，特应性皮炎和红斑痤疮。此外，TRPV3的过表达与结直肠癌和肺癌的发展和进展有关。我的目标是解决TRPV3和TRPV6与不同的激动剂，拮抗剂，变构调节剂和离子通道阻滞剂的复合物的结构。将通过定点诱变和功能记录检测识别的结合位点。从结构和功能相结合的方法衍生的分子模型将作为模板，用于设计更具选择性和有效性的药物，靶向炎症性皮肤病，瘙痒，疼痛和癌症。

Any physical or mental activity involves ion channels. Ion channels are also associated with numerous human diseases, including those caused by mutations (channelopathies). Many drugs, including local anaesthetics, antianxiety agents and sedatives, target ion channels. However, highly efficient and selective drugs are missing for many ion channels due to our limited knowledge about their molecular mechanisms of regulation. I am particular interested in transient receptor potential (TRP) vanilloid subfamily (TRPV) channels. These polymodal sensory transducers respond to chemicals, temperature, mechanical stress and membrane voltage and are involved in vision, taste, olfaction, hearing, touch, thermal perception and nociception. In my proposed research project, I focus on two (patho-)physiologically important members of this family, TRPV3 and TRPV6. The calcium-selective channel TRPV6 plays a central role in calcium uptake in epithelial tissues. A classified oncochannel, TRPV6 is overexpressed in various types of human cancer cells, including breast, prostate, colon, ovarian, thyroid, endometrial, and leukaemia cancer cells. It appears that the central role of TRPV6 in cancer is to impair Ca2+ homeostasis by stimulating Ca2+ entry into the cell. Correspondingly, inhibitors of TRPV6-mediated calcium uptake are urgently needed for the treatment of TRPV6-rich tumours. I also study the thermo-sensitive channel TRPV3 which is activated by heat and several natural compounds like camphor, thymol, carvacrol, eugenol, and cannabinol. TRPV3 is predominantly expressed in skin keratinocytes and implicated in cutaneous sensation, including thermo-sensation, nociception and itch, in addition to maintenance of the skin barrier, wound healing, and hair growth. The dysfunction of TRPV3 channels, often a result of genetic mutations, is associated with numerous human skin diseases including a genodermatosis known as Olmsted syndrome, atopic dermatitis, and rosacea. Furthermore, overexpression of TRPV3 is implicated in the development and progression of colorectal and lung cancer. I aim to solve structures of TRPV3 and TRPV6 in complex with different agonists, antagonists, allosteric modulators, and ion channel blockers. Identified binding sites will be tested by site-directed mutagenesis and functional recordings. Molecular models derived from the combined structural and functional approaches will serve as templates for the design of more selective and efficacious drugs targeting inflammatory skin conditions, itch, pain, and cancer.