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The role of E-cadherin mediated cell-cell contact in melanocyte homeostasis

E-钙粘蛋白介导的细胞间接触在黑素细胞稳态中的作用

基本信息

批准号：
BB/G001111/1
负责人：
Claudia Wellbrock
金额：
$ 50.28万
依托单位：
University of Manchester
依托单位国家：
英国
项目类别：
Research Grant
财政年份：
2008
资助国家：
英国
起止时间：
2008 至无数据
项目状态：
已结题

来源：
https://gtr.ukri.org/projects?ref=BB%2FG001111%2F1
关键词：
role cadherin mediated cell contact

项目摘要

Background Melanocytes are highly specialised cells within the skin, where they act as a protective shield against harmful UV rays in a process called the tanning response. Melanocytes are part of the Epidermal Melanin Unit, in which each melanocyte exists in a symbiotic relationship with ca. 36 keratinocytes at the basement membrane of the epidermis. Sun exposure triggers the production of the pigment melanin within the melanocytes, and this melanin is transferred to the surrounding mitotically active keratinocytes in order to protect them from UV induced DNA damage. On the other hand keratinocytes secrete factors that control the survival, differentiation and growth of melanocytes in response to UV radiation. In fact keratinocytes are mainly responsible for the regulation of melanocyte homeostasis and they ensure that melanocytes stay localised within the Epidermal Melanin Unit and that differentiation is favoured over proliferation. In order to function within this symbiotic relationship an accurate communication between melanocytes and keratinocytes is absolutely essential and direct cell-cell contact is a prerequisite for this communication. At the molecular level the major mediators of cell-cell contacts are cadherins and they regulate cellular functions through multi-protein complexes. Any disturbance of the melanocyte-keratinocyte interaction, and this means the controlled contact between these two cell types, can create a pathological situation. The best-known example for such a situation is the loss of the cell-cell contact protein E-cadherin in melanocytes. This loss results in deregulated melanocyte proliferation and contributes to the transformation into malignant melanoma, the most deadly form of skin cancer. Challenge Elucidating the mechanisms regulating the concerted actions between melanocytes and keratinocytes under physiological conditions will allow to identify dysregulations in pathological situations. Therefore it is important to fully comprehend how cell-cell contact with keratinocytes contributes to the regulation of melanocyte homeostatsis. The main focus in the investigation of melanocyte regulation over the past years has been on the direct effects of keratinocyte-derived growth and differentiation factors on melanocyte monocultures. This does not reflect the physiological situation in which melanocytes adhere to keratinocytes via E-cadherin during growth-factor exposure. Therefore more complex cell systems are required to accurately investigate keratinocyte-mediated regulation of melanocyte function. In addition, although E-cadherin is known to be critical for the malignant transformation of melanocytes, the function and regulation of E-cadherin and its associated proteins in melanocytes is greatly unknown. Approach This project will identify cell-cell contact dependent effects on melanocyte homeostasis within a system that closely recapitulates the human tissue. I will set up a melanocyte-keratinocyte co-culture system, in which melanocytes will be exposed to keratinocyte-derived factors in the context of cell-cell contact to keratinocytes. A technique will be applied that allows monitoring the formation of E-cadherin complexes in the cell-cell contacts. By manipulating the cells (e.g. using specific inhibitors of cellular signalling networks), the molecular signals involved in the regulation of E-cadherin complexes will be identified. Furthermore, the function of E-cadherin in melanocyte homeostasis will be dissected by analysing cellular signalling activities in melanocytes after E-cadherin depletion. This approach will allow uncovering the molecular basis of important control mechanisms in a physiological context. These mechanisms are often lost in the case of disease. Understanding the molecular basis will help to efficiently interfere with a pathological situation and to design drugs that can restore the lost control, ultimately helping to cure the patient.

背景黑素细胞是皮肤内高度特化的细胞，在称为晒黑反应的过程中，它们充当抵御有害紫外线的保护屏障。黑素细胞是表皮黑素单位的一部分，其中每个黑素细胞与CA存在共生关系。36个角质形成细胞位于表皮的基底膜处。阳光照射引发黑色素细胞内黑色素的产生，并且这种黑色素被转移到周围的有丝分裂活性角质形成细胞，以保护它们免受UV诱导的DNA损伤。另一方面，角质形成细胞分泌控制黑素细胞响应于UV辐射的存活、分化和生长的因子。事实上，角质形成细胞主要负责调节黑素细胞的稳态，并且它们确保黑素细胞保持定位在表皮黑素单位内，并且分化优于增殖。为了在这种共生关系中发挥作用，黑素细胞和角质形成细胞之间的准确通信是绝对必要的，并且直接的细胞-细胞接触是这种通信的先决条件。在分子水平上，细胞与细胞接触的主要介质是钙粘蛋白，它们通过多蛋白复合物调节细胞功能。黑素细胞-角质形成细胞相互作用的任何干扰，这意味着这两种细胞类型之间的受控接触，都可能造成病理情况。这种情况最著名的例子是黑素细胞中细胞-细胞接触蛋白E-钙粘蛋白的丢失。这种损失导致黑素细胞增殖失调，并有助于转化为恶性黑色素瘤，最致命的皮肤癌形式。阐明在生理条件下调节黑素细胞和角质形成细胞之间的协同作用的机制将允许识别病理情况下的失调。因此，充分了解细胞与角质形成细胞的接触如何有助于黑素细胞稳态的调节非常重要。在过去的几年里，黑素细胞调节的研究主要集中在角质形成细胞衍生的生长和分化因子对黑素细胞单一培养物的直接影响上。这并不反映生长因子暴露期间黑素细胞通过E-钙粘蛋白粘附于角质形成细胞的生理情况。因此，需要更复杂的细胞系统来准确地研究角质形成细胞介导的黑素细胞功能调节。此外，虽然已知E-钙粘蛋白对于黑素细胞的恶性转化是关键的，但是E-钙粘蛋白及其相关蛋白在黑素细胞中的功能和调节是非常未知的。方法本项目将确定细胞接触依赖的黑素细胞内稳态的系统，密切概括人体组织的影响。我将建立一个黑素细胞-角质形成细胞共培养系统，其中黑素细胞将在细胞-细胞接触角质形成细胞的背景下暴露于角质形成细胞衍生因子。将应用允许监测细胞-细胞接触中E-钙粘蛋白复合物形成的技术。通过操纵细胞（例如，使用细胞信号传导网络的特异性抑制剂），将鉴定参与调节E-钙粘蛋白复合物的分子信号。此外，E-钙粘蛋白在黑素细胞稳态中的功能将通过分析E-钙粘蛋白耗尽后黑素细胞中的细胞信号传导活动来剖析。这种方法将允许揭示在生理背景下的重要控制机制的分子基础。这些机制往往在疾病中消失。了解分子基础将有助于有效地干预病理情况，并设计可以恢复失去控制的药物，最终帮助治愈患者。