Role of Csn5 in Epidermal Homeostasis

描述（由申请人提供）：8q扩增是人类鳞状细胞癌（SCC）中最常见的染色体异常之一，但驱动这些癌症的8q癌基因尚不清楚。染色体8q13上CSN5与8q24上MYC的协调扩增最近被证明是人类肿瘤转移和患者死亡风险增加的标志。此外，已经发现CSN5和MYC是上皮转化和进展所必需的。CSN5抑制正常紫外光诱导的表皮细胞凋亡反应，同时增加MYC的转录效力，提示CSNS促进癌变的多种潜在机制。为了明确CSN5与MYC协同破坏表皮稳态并驱动SCC的机制，本研究的目的是研究CSN5在DMA损伤反应、表皮分化和表皮干细胞维持中的作用。CSN5蛋白酶活性不仅是癌症的潜在治疗靶点，也是其他皮肤增生和光介导疾病的潜在治疗靶点。该奖项将使首席研究员，一位受过皮肤科训练的内科科学家，在上皮生物学研究方面接受强化培训，并发展他自己的独立研究项目。他完成了癌症生物学的研究生工作，并完成了皮肤病学的临床培训。他选择在实验室工作，以获得皮肤生物学和体内哺乳动物模型系统方面的专业知识，为他建立自己的实验室做准备，重点研究调节严厉和致癌的途径，以及开发针对皮肤疾病的新型靶向治疗方法。斯坦福大学正在为他提供全面的制度支持、广泛的资源以及与该领域专家合作的机会。他将进一步接受伦理行为、实验设计、资助和实验室管理方面的培训，以使他成为转化医学研究的全职学术职位，并获得终身教职，将90%的时间用于研究，10%用于临床活动。

DESCRIPTION (provided by applicant): Amplification of 8q is one of the most common chromosomal abnormalities in human squamous cell carcinoma (SCC), but the oncogenes on 8q that drive these cancers have been unclear. Coordinate amplification of CSN5 on chromosome 8q13 with MYC on 8q24 has been recently shown to be a hallmark of human tumors with increased risk of metastasis and patient mortality. Moreover, CSN5 and MYC have been found to be required for epithelial transformation and progression. CSN5 inhibits the normal ultraviolet light- induced apoptotic response in the epidermis and also increases the transcriptional potency of MYC, suggesting multiple potential mechanisms for CSNS's promotion of carcinogenesis. In order to define the mechanism by which CSN5 cooperates with MYC to disrupt epidermal homeostasis and drive SCC, the aims of this proposal are to examine the role of CSN5 in DMA damage response, epidermal differentiation and epidermal stem cell maintenance. CSN5 protease activity represents a potential therapeutic target of not only cancers, but also other proliferative and light-mediated disorders of the skin. This award will enable the principal investigator, a dermatology-trained physician-scientist, to receive intensive training in epithelial biology research and develop his own independent research program. He performed his graduate work in cancer biology and has completed his clinical training in dermatology. He has chosen to work in a laboratory to gain expertise with skin biology and in vivo mammalian model systems to prepare him to establish his own laboratory focusing on pathways that regulate sternness and carcinogenesis as well as the development of novel targeted therapeutics for skin disease. Stanford University is providing him with full institutional support, extensive resources, and opportunity for collaborations with experts in the field. He will be further trained in ethical conduct, experimental design, grantsmanship, and laboratory management to transition him to a full time academic position in translational medical research on a tenure track spending 90% of his time on research and 10% on clinical activities.