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上的癌基因尚不清楚。染色体8q13上的CSN 5与8q24上的MYC的协同扩增最近已被证明是具有增加的转移风险和患者死亡率的人类肿瘤的标志。此外，已发现CSN5和MYC是上皮转化和进展所需的。CSN 5抑制表皮中正常的紫外光诱导的凋亡反应，并且还增加MYC的转录效力，这表明CSNS促进致癌的多种潜在机制。为了确定CSN 5与MYC合作破坏表皮稳态并驱动SCC的机制，本提案的目的是检查CSN 5在DMA损伤反应、表皮分化和表皮干细胞维持中的作用。CSN 5蛋白酶活性不仅代表癌症的潜在治疗靶标，而且代表皮肤的其他增殖性和光介导的病症的潜在治疗靶标。该奖项将使首席研究员，皮肤科培训的医生，科学家，接受上皮生物学研究的强化培训，并制定自己的独立研究计划。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的专业知识，为他建立自己的实验室做好准备，重点研究调节干性和致癌作用的途径，以及开发新的皮肤病靶向治疗方法。斯坦福大学正在为他提供全面的机构支持，广泛的资源，并与该领域的专家合作的机会。他将接受伦理行为，实验设计，实验室管理和实验室管理方面的进一步培训，以使他在终身教职轨道上的转化医学研究中获得全职学术职位，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.