COBRE PROJ 8: ROLES OF IKK ?LPHA IN SKIN DEVELOPMENT AND DYSPLASIA

COBRE 项目 8：IKK ?LPHA 在皮肤发育和发育不良中的作用

• 批准号: 8167781
• 负责人: Qiutang Li
• 金额: $ 24.16万
• 依托单位: UNIVERSITY OF LOUISVILLE
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-07-01 至 2011-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8167781
• 关键词: Address; Biochemical; Birth; Carcinogens; Cell Cycle; Cell Cycle Checkpoint; Complex; Computer Retrieval of Information on Scientific Projects Database; Data; Defect; Development; Dysplasia; Embryo; Frequencies; Funding; Genetic; Goals; Grant; Homeostasis; Immunoprecipitation; Institution; Knockout Mice; Knowledge; Loss of Heterozygosity; Mass Spectrum Analysis; Molecular; Mus; NF-kappa B; Phosphotransferases; Predisposition; Proteins; Regulation; Research; Research Personnel; Resources; Role; Signal Pathway; Signal Transduction; Skin; Skin Cancer; Skin Neoplasms; Source; Testing; Tumor Suppressor Genes; Tumor Suppressor Proteins; United States National Institutes of Health; clinically relevant; keratinocyte; tumor

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Qiutang Li, PI The long-term goal of this project is to elucidate the cellular and molecular mechanism by which IKKalpha exerts its effects on epidermal homeostasis. IKKalpha is a subunit of IKK complexes in the NF-kappa B signaling pathway. IKKalpha knockout mice die at birth from the skin defects associated with increased proliferation and impaired terminal differentiation in keratinocytes. The function of IKKalpha in keratinocytes is independent from its kinase activity and NF-kappa B signaling pathway. The mechanism by which the IKKalpha regulates keratinocyte proliferation and differentiation remains unclear. In the present studies, we will test the hypothesis that IKKalpha regulates keratinocyte cell cycle and functions as a tumor suppressor gene in skin. Specifically, the following questions will be addressed: (1) What are the roles of the IKKalpha in regulation of the keratinocyte cell cycle and cell cycle checkpoint? (2) What are the IKKalpha-interacting proteins in keratinocyte? (3) How do those interacting proteins participate in the IKKalpha signaling in the keratinocytes? (4) Does IKKalpha function as a tumor suppressor in skin? Cell cycle analysis and functional studies will be performed in the primary keratinocytes isolated from either wild-type or the IKKalpha deficient embryos at embryonic day 18.5 using a combination of genetics, cytological, and biochemical approaches. The data that have been generated from IKKalpha immunoprecipitation and mass spectrometry will be further validated and characterized to understand the IKKalpha function at a molecular level. We will examine skin tumor susceptibility and metastatic potential in IKKalpha+/- mice exposed to mutagenic carcinogen and check the loss of heterozygosity frequency at the IKKalpha locus in IKKalpha+/- mouse tumors. The knowledge will be important for elucidating clinically relevant problems such as skin cancers.

该副本是利用众多研究子项目之一 由NIH/NCRR资助的中心赠款提供的资源。子弹和 调查员（PI）可能已经从其他NIH来源获得了主要资金， 因此可以在其他清晰的条目中代表。列出的机构是 对于中心，这不一定是调查员的机构。 Qiutang li，pi 该项目的长期目标是阐明Ikkalpha对表皮稳态的影响的细胞和分子机制。 Ikkalpha是NF-KAPPA B信号通路中IKK复合物的一个亚基。 Ikkalpha敲除小鼠在出生时因皮肤缺陷而死亡，与增生和角质形成细胞的终末分化相关。 ikkalpha在角质形成细胞中的功能与其激酶活性和NF-kappa B信号通路无关。 Ikkalpha调节角质形成细胞增殖和分化的机制尚不清楚。 在目前的研究中，我们将检验以下假设：Ikkalpha调节角质形成细胞周期，并用作皮肤中肿瘤抑制基因。 具体而言，将解决以下问题：（1）Ikkalpha在角质形成细胞周期和细胞周期检查点调节中的作用是什么？ （2）角质形成细胞中的ikkalpha相互作用蛋白是什么？ （3）这些相互作用的蛋白如何参与角质形成细胞中的ikkalpha信号传导？ （4）Ikkalpha在皮肤中是否起抑制肿瘤的功能？ 细胞周期分析和功能研究将在胚胎第18.5天从野生型或ikkalpha缺陷的主要角质形成细胞中进行，使用遗传学，细胞学和生化方法的组合。 由Ikkalpha免疫沉淀和质谱法产生的数据将得到进一步验证并表征，以了解分子水平的Ikkalpha功能。 我们将检查暴露于诱变致癌物的Ikkalpha +/-小鼠中的皮肤肿瘤敏感性和转移性潜力，并检查Ikkalpha +/-小鼠肿瘤中Ikkalpha基因座的杂合性频率的损失。 知识对于阐明临床上相关的问题（例如皮肤癌）很重要。