The Physiological Function and Regulation of INK4 Genes

INK4基因的生理功能及调控

• 批准号: 7913867
• 负责人: YUE XIONG
• 金额: $ 34.83万
• 依托单位: UNIV OF NORTH CAROLINA CHAPEL HILL
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-08-01 至 2011-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7913867
• 关键词: Affect; Back; Biochemical; CDK6-associated protein p18; CDKN2A gene; Cells; Complex; Development; Family; Financial compensation; Funding; Gene Dosage; Gene Expression; Gene Family; Genes; Genetic; Genetically Engineered Mouse; Goals; Human; Individual; Investigation; Lung; Lung Neoplasms; Malignant Neoplasms; Malignant neoplasm of lung; Mammary Neoplasms; Mammary gland; Molecular Profiling; Mus; Mutant Strains Mice; Physiological; Principal Investigator; Protein Family; Regulation; Repression; Research; Stem cells; System; Tumor Stem Cells; Tumor Suppression; Work; inhibitor/antagonist; malignant breast neoplasm; mouse model; senescence; success; tumor

DESCRIPTION (provided by applicant): This is the second competing renewal of CA68837, an investigation aimed at the long-term goal of understanding the INK4 family of CDK inhibitors. Looking back at the journey over the past 10 years, we are pleased to see the contributions we made and, more remarkably, the advancement achieved collectively by others working in this field. The focus of our own research, following the initial discovery of p16Ink4a in 1993, has moved forward from the discovery and biochemical characterization of three additional INK4 genes during the first funding period (1994 - 1999), to the creation and histological analyses of various Ink4 mutant mouse strains during the second funding period (2000 - present). Built upon the large volume of phenotypical and pathological information we accumulated over the past several years, the research outlined in this application will move toward achieving the following two long-term goals: (1) developing and characterizing mouse models for human lung and breast cancers, and (2) to determine the mechanism and regulation of INK4 genes in stem cell control. Combining our strength and success in genetic and tumor analysis in mice, biochemical characterization of CDK activities, and cellular studies of G1 progression, we propose three aims to achieve these two goals. (1) To determine the function and mechanism of p18lnk4c and Men1 in lung tumor suppression and stem cell control. (2) To determine how p18lnk4c and Brca1 functionally collaborate to suppress mammary tumors and regulate mammary stem cell expansion. (3) To determine the mechanisms regulating p16 gene expression. Three features of this investigation are: (1) Extensive use of genetically engineered mice and their derived isogenic cells as the primary experimental system, providing a highly sophisticated physiological setting to examine the function of INK4 family genes. (2) A combination of investigation of two INK4 genes with demonstrated tumor suppression function in one study would not only provide a comprehensive view of their individual function, but also uncover possible functional compensation and allow a comparison of their regulatory mechanisms. (3) The critical importance of this gene family in tumor suppression, stem cell control, and development of mouse models for different type of human cancers.

描述（由申请人提供）：这是CA68837的第二次竞争续约，该调查旨在长期了解CDK抑制剂的Ink4家族。回顾过去10年的旅程，我们很高兴看到我们所做的贡献，更明显地，在该领域工作的其他人共同取得了进步。在1993年最初发现P16INK4A之后，我们自己的研究的重点已从第一个融资期（1994-1999）的三个其他Ink4基因的发现和生化表征转变为对第二个融资期（2000-现在）各种Ink4突变小鼠菌株的创建和组织学分析。基于我们在过去几年中积累的大量表型和病理信息，该应用中概述的研究将朝着实现以下两个长期目标朝着实现以下两个长期目标：（1）开发和表征人类肺和乳腺癌的小鼠模型，以及（2）确定干细胞控制中Ink4基因的机理和调节。我们在小鼠中的遗传和肿瘤分析，CDK活性的生化表征以及G1进展的细胞研究中结合了我们的力量和成功，我们提出了三个目标以实现这两个目标。 （1）确定p18LNK4C和MEN1在肺肿瘤抑制和干细胞控制中的功能和机制。 （2）确定P18LNK4C和BRCA1如何在功能上合作以抑制乳腺肿瘤并调节乳细胞的扩张。 （3）确定调节p16基因表达的机制。这项研究的三个特征是：（1）广泛使用基因工程的小鼠及其衍生的同源细胞作为主要的实验系统，提供了高度复杂的生理环境，以检查Ink4家族基因的功能。 （2）在一项研究中对两个INK4基因进行研究的研究不仅可以全面地观察其个体功能，而且还可以发现可能的功能补偿，并允许比较其调节机制。 （3）该基因家族在肿瘤抑制，干细胞控制和针对不同类型的人类癌症的小鼠模型的开发中的至关重要性。