Targeting ZDHHC13-activated palmitoylation for melanoma treatment

项目摘要/摘要 黑色素瘤是最致命的皮肤癌，也是最难治疗的癌症之一。因此， 黑色素瘤发生和黑色素瘤发生的潜在机制需要深入研究。近期 研究结果表明，黑素皮质素-1受体(MC1R)的棕榈酰化主要由蛋白质-酰基介导 转移酶(PAT)ZDHHC13在激活MC1R信号和防止黑色素瘤发生中起重要作用。 初步研究还表明，APT2是MC1R的主要脱氨酶，对 转移性黑色素瘤患者。在这项拟议的研究中，我的目标是通过以下方式阐明深入的分子机制 哪些ZDHHC13/APT2调节的棕榈酰化抑制黑色素瘤的发生和进展，并测试 假设ZDHHC13/APT2调节的棕榈酰化是黑色素瘤发生和黑色素瘤的关键 体内转移。在指导K99阶段，我将阐明 ZDHHC13转基因小鼠在黑素细胞中的表达我还将描述这些影响的特征 通过靶向APT2研究黑色素瘤发生中的脱氨基转移抑制。在独立的R00阶段，我计划 确定ZDHHC13/APT2调节的棕榈酰化在黑色素瘤体内转移中的作用 抑制脱氨酶是否通过抑制转移而提高存活率。此外，我还需要 在获奖期间，对黑色素瘤小鼠模型、靶向治疗以及专业培训进行了额外的培训 这些技能将有助于我实现长期的职业目标。总而言之，圆满完成了我提出的 研究将为ZDHHC13/APT2调控的作用和分子机制带来新的见解 棕榈酰化在黑色素瘤的发生和发展中的作用，这可以转化为新的干预和 治疗策略。获得这一奖项将使我能够扩大我的研究计划，并成为一个平台 我将接受额外的培训，从而使自己成为一名独立的首席调查员。 黑色素瘤研究领域。

PROJECT SUMMARY/ABSTRACT Melanoma is the deadliest form of skin cancer and is one of the most difficult cancer to treat. Therefore, the underlying mechanism of melanomagenesis and melanoma development demands intensive study. Recent findings identified that palmitoylation of melanocortin-1 receptor (MC1R), primarily mediated by the protein-acyl transferase (PAT) ZDHHC13, is essential for activating MC1R signaling and prevent melanomagenesis. Preliminary studies also revealed that APT2 is the major depalmitoylating enzyme of MC1R and is harmful for metastatic melanoma patients. In this proposed study, I aim to elucidate the in-depth molecular mechanism by which ZDHHC13/APT2-regulated palmitoylation repress melanoma development and progression, and test the hypothesis that ZDHHC13/APT2-regulated palmitoylation is essential for melanomagenesis and melanoma metastasis in vivo. During the mentored K99 phase, I will elucidate the underlying regulatory mechanism of ZDHHC13 in melanocytes by using new developed ZDHHC13 transgenic mice. I will also characterize the effects of depalmitoylation inhibition in melanomagenesis by targeting APT2. During the independent R00 phase, I plan to determine the role of ZDHHC13/APT2-regulated palmitoylation in melanoma metastasis in vivo and identify whether inhibition of depalmitoylation improves survival by suppressing metastasis. Furthermore, I will need additional trainings during the award period in melanoma mouse model, targeted therapy, as well as professional skills which will contribute to my long term career goal. In summary, successful completion of my proposed studies will bring novel insights into the roles and molecular mechanisms of ZDHHC13/APT2-regulated palmitoylation in melanoma development and progression, which can be translated into new intervention and treatment strategies. Receipt of this award will allow me to expand my research plan and serve as a platform for me to receive additional trainings, thus prepare myself becoming an independent principal investigator in the field of melanoma research.