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Targeting ZDHHC13-activated palmitoylation for melanoma treatment

靶向 ZDHHC13 激活的棕榈酰化治疗黑色素瘤

基本信息

批准号：
10645053
负责人：
Shuyang Chen
金额：
$ 24.9万
依托单位：
CLEVELAND CLINIC LERNER COM-CWRU
依托单位国家：
美国
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-07-01 至 2024-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10645053
关键词：
ATR gene Affect Animal Model Award Basic Science Biology Cell Proliferation Cessation of life Clinical Communication Data Development Enzymes Genetic Engineering Goals Hair Hair Color Incidence Intervention Knowledge Malignant Neoplasms Mass Spectrum Analysis Mediating Melanocortin 1 Receptor Melanoma Cell Mentors Metastatic Melanoma Methods Molecular Mus Nature Neoplasm Metastasis Outcome Paper Patients Phase Phenotype Phosphorylation Phosphorylation Site Physiological Pigmentation physiologic function Play Preventive Principal Investigator Proteins Publications Receptor Signaling Reporting Repression Research Research Personnel Risk Role Skin Skin Cancer Testing Therapeutic Therapeutic Effect Therapeutic Intervention Training Transferase Transgenic Mice Translating UVB induced Ultraviolet Rays Variant career human data improved in vivo inhibitor insight melanocyte melanoma melanomagenesis mouse model novel palmitoylation pharmacologic prevent preventive intervention skills targeted treatment treatment effect treatment strategy

项目摘要

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.

项目概要/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展的潜在机制需要深入研究。最近的研究结果表明，melanocortin-1 受体 (MC1R) 的棕榈酰化主要由蛋白质酰基介导转移酶 (PAT) ZDHHC13 对于激活 MC1R 信号传导和预防黑色素瘤生成至关重要。初步研究还表明，APT2是MC1R的主要去棕榈酰酶，对人体有害。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： ZDHHC13/APT2 调节的棕榈酰化可抑制黑色素瘤的发生和进展，并测试 ZDHHC13/APT2 调节的棕榈酰化对于黑色素瘤发生和黑色素瘤至关重要的假设体内转移。在K99指导阶段，我会阐明底层的监管机制通过使用新开发的ZDHHC13转基因小鼠，黑素细胞中的ZDHHC13。我还将描述效果通过靶向 APT2 抑制黑色素瘤发生中的去棕榈酰化。在独立R00阶段，我计划确定 ZDHHC13/APT2 调节的棕榈酰化在体内黑色素瘤转移中的作用并鉴定抑制去棕榈酰化是否可以通过抑制转移来提高生存率。此外，我还需要奖励期间额外培训黑色素瘤小鼠模型、靶向治疗以及专业培训这将有助于我的长期职业目标的技能。总而言之，成功完成了我提出的研究将为 ZDHHC13/APT2 调节的作用和分子机制带来新的见解黑色素瘤发生和进展中的棕榈酰化，可以转化为新的干预措施和治疗策略。获得该奖项将使我能够扩展我的研究计划并为我提供一个平台我接受额外的培训，从而准备自己成为一名独立的首席研究员黑色素瘤研究领域。