P16 IN HEAD AND NECK SQUAMOUS CELL CARCINOGENESIS

描述(申请人的描述)： 雅布罗博士的长期目标是成为一名学者 可以进行独立基础研究的耳鼻喉科医生。穿过 住院医生和研究员，他获得了初步的研究经验和 癌症患者外科治疗方面的临床专业知识。这就是Dr。 雅布罗的最终目标是完成从临床到临床的自然进展 带着学到的知识回到临床做基础研究面临的问题 通过基础研究造福患者。这项研究提出了 计划的职业发展将使雅布罗博士能够获得 的分子生物学、细胞周期和翻译研究 爱迪生·刘博士的指导，他是该领域的知名研究员 以翻译研究著称的上皮癌和岳博士 熊，细胞周期调控和细胞周期蛋白依赖性激酶的专家 抑制功能。 该项目的重点是细胞周期蛋白依赖性激酶的作用。 (CDK)抑制因子p16在头颈部鳞状细胞发育中的作用 癌症(H&N SCCA)。在前期工作中发现，p16是 在大约33%的H&N SCCA中发生了改变，并且胚系p16突变 与H&N SCCA的倾向有关。辨识点的分析 突变显示部分突变体保留了部分生化和 生物功能。有趣的是，一个与CDK结合的突变体 不抑制CDK6激酶能力使细胞滞留于G1期，提示 CDK6的抑制不是p16在细胞中直接停止所必需的 学习。此外，所有生化功能受损的p16突变体都有 显示出与一种未知蛋白质p31的亲和力增加，p31与其发生交叉反应 带有CDK6抗体。拟议的研究将确定 种系突变在H&N SCCA发生发展中的作用 分析胚系和体细胞p16突变体，以关联结构 有功能的图案。P16‘S生化和生物功能状态 将与H&N SCCA患者的肿瘤分期、分级和生存期相关。 此外，文献中发现的来自食道的p16突变体 肿瘤、肺肿瘤和黑色素瘤将进行类似的功能分析 为了确定肿瘤类型与肿瘤残留之间是否存在相关性 部分函数。P31‘S的纯化、克隆及鉴定 与p16的相互作用将有助于进一步了解p16的功能。

DESCRIPTION (Applicant's Description): The long-term goals of Dr. Yarbrough are to become an academic Otolaryngologist who can conduct independent basic research. Through residency and fellowship, he has gained preliminary research experience and clinical expertise in the surgical management of cancer patients. It is Dr. Yarbrough's ultimate goal to complete the natural progression from clinical problems to bench research by returning to the clinic with knowledge gained through basic research to benefit patients. The research proposed and career development planned will enable Dr. Yarbrough to gain expertise in molecular biology, the cell cycle, and translational research under the guidance of Dr. Edison Liu, an established investigator in the field of epithelial cancers who is well known for translational research and Dr. Yue Xiong, an expert in cell cycle regulation and cyclin dependent kinase inhibitor function. The proposed project focuses on the role of the cyclin-dependent kinase (CDK) inhibitor, p16, in the development of head and neck squamous cell carcinomas (H&N SCCAs). In preliminary work, it was found that p16 is altered in roughly 33 percent of H&N SCCAs and that germline p16 mutations are associated with propensity to H&N SCCAs. Analysis of identified point mutations revealed a portion of the mutants retained partial biochemical and biological function. Of interest, one mutant which bound to CDKs but did not inhibit CDK6 kinase ability arrested cells in G1, suggesting that inhibition of CDK6 is not necessary for p16 directed arrest in the cells studied. Further, all p16 mutants with impaired biochemical function have shown an increased affinity for an unknown protein, p31, which cross reacts with an antibody to CDK6. The proposed study will establish the role of germline mutations in the development of H&N SCCA and extend the functional analysis of both germline and somatic p16 mutants, to correlate structural motifs with function. p16's biochemical and biological functional status will be correlated with H&N SCCA patient's tumor stage, grade, and survival. Additionally, p16 mutants identified in the literature from esophageal tumors, lung tumors, and melanomas will be similarly functionally analyzed to determine if there is correlation between tumor type and retention of partial function. Purification, cloning, and characterization of p31's interaction with p16 will further aid in the understanding of p16 function.