Targeting ZDHHC13-activated palmitoylation for melanoma treatment

项目总结/摘要 黑色素瘤是皮肤癌中最致命的一种，也是最难治疗的癌症之一。 黑色素瘤发生和黑色素瘤发展的潜在机制需要深入研究。最近 研究结果表明，黑皮质素-1受体（MC 1 R）的棕榈酰化，主要是由蛋白质酰基介导的， 转移酶（PAT）ZDHHC 13是激活MC 1 R信号传导和防止黑色素瘤形成所必需的。 初步研究还表明，APT 2是MC 1 R的主要脱棕榈酰酶， 转移性黑素瘤患者。在这项拟议的研究中，我的目标是阐明深入的分子机制， ZDHHC 13/APT 2调节的棕榈酰化抑制黑色素瘤的发展和进展，并测试 ZDHHC 13/APT 2调节棕榈酰化对黑色素瘤发生和黑色素瘤至关重要的假说 体内转移。在辅导K99阶段，我将阐明 ZDHHC 13在黑素细胞中的表达。我也会描述 通过靶向APT 2抑制黑色素瘤发生中的去棕榈酰化。在独立R 00阶段，我计划 确定ZDHHC 13/APT 2调节的棕榈酰化在体内黑色素瘤转移中的作用， 抑制去棕榈酰化是否通过抑制转移而提高存活率。另外，我需要 在授予期间，在黑色素瘤小鼠模型、靶向治疗以及专业 这些技能将有助于我的长期职业目标。总之，圆满完成了我提出的 这些研究将为ZDHHC 13/APT 2调节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展和进展，这可以转化为新的干预， 治疗策略。获得这个奖项将使我能够扩大我的研究计划，并作为一个平台， 我接受额外的培训，从而为自己成为一名独立的主要研究者做好准备。 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.