MECHANISMS AND SIGNIFICANCE OF HYPOXIA INDUCED G1 ARREST

描述（申请人的描述）：本提案旨在提供 首席调查员劳伦斯·加德纳带着必要的科学证据 成功过渡到独立临床医生的经验 科学家 加德纳博士从高中起就参与研究。 他 毕业于耶鲁大学医学院，经过额外的 年致力于研究。 医学院毕业后，博士。 加德纳在内科学上做了住院医师，然后接受了专业培训。 血液学和肿瘤学，都在约翰霍普金斯医院 过去两 多年来，加德纳博士将90%以上的精力投入到基础研究中， 医学和肿瘤学教授Chi Dang博士的实验室。 在此 他研究了正常细胞对缺氧的分子反应， 精通许多标准的分子和细胞生物学技术。 加德纳博士和当博士在这些研究中进行了一些新的观察。 问题研究 他们已经阐明了缺氧诱导的 G1期细胞周期阻滞，正常细胞的基本反应。 他们还 鉴定了几种肿瘤细胞系，这些细胞系不经历G1停滞， 缺氧 2000年7月，Gardner博士将成为教育部的一名教员。 约翰霍普金斯医学研究所的医学。 临床职责，包括 一个月两次的教学、门诊和一个月的会诊， 20%的时间。 他剩下的努力将致力于获得 逐步过渡到独立地位所需的培训。 的 拟议的培训包括教学法、参加国家和专业 会议，以及来自正式委员会的具体反馈。 本申请中详细介绍的研究计划建立在观察和 加德纳博士在邓博士实验室里获得的技能 的 研究人员已经确定，缺氧诱导的G1的关键调节因子 在正常细胞中的停滞是细胞周期蛋白的转录诱导， 依赖性激酶抑制剂p27。 该研究项目将首先研究 正常细胞在缺氧时诱导p27的分子信号。 然后他们将确定为什么一些肿瘤细胞在缺氧中不停止。 最后，使用在缺氧中不停滞的肿瘤细胞，以及 他们已经开发了消除缺氧诱导的G1期阻滞的方法，他们将 确定这种G1期阻滞在缺氧对基因组的影响中的作用， 不稳定性和辐射防护。

DESCRIPTION (Applicant's Description): This proposal is designed to provide the principal investigator, Lawrence Gardner, with the necessary scientific experience to allow for a successful transition to an independent clinician scientist. Dr. Gardner has been involved in research since high school. He graduated from the Yale University School of Medicine, after an additional year dedicated to research. Following the completion of medical school, Dr. Gardner pursued a residency in internal medicine, and then specialty training in hematology/oncology, all at The Johns Hopkins Hospital. Over the past two years Dr. Gardner has devoted over 90 percent effort to basic research in the laboratory of Dr. Chi Dang, a professor of Medicine and Oncology. During this time he has studied molecular responses to hypoxia in normal cells, and has become proficient in many standard molecular and cellular biology techniques. Drs. Gardner and Dang have made several novel observations during these studies. They have delineated the mechanism responsible for hypoxia-induced G1 cell cycle arrest, a fundamental response in normal cells. They have also identified several neoplastic cell lines that do not undergo a G1 arrest in hypoxia. In July 2000, Dr. Gardner will become an instructor in the Department of Medicine at the Johns Hopkins Medical Institution. Clinical duties, including teaching, clinic twice a month, and a month of consult attending, will occupy 20 percent of his time. His remaining effort will be dedicated to obtaining the training necessary for a gradual transition to independent status. The training proposed includes didactics, attendance at national and specialty meetings, and specific feedback from a formal committee. The research plan detailed in this application builds on the observations and skills obtained by Dr. Gardner in Dr. Dang's lab over the past two years. The investigators have determined that the key regulator of hypoxia-induced G1 arrest in normal cells is the transcriptional induction of the cyclin- dependent kinase inhibitor p27. The research project will first study the molecular signals by which normal cells induce p27 in response to hypoxia. They will then determine why some neoplastic cells do not arrest in hypoxia. Finally, using neoplastic cells that do not arrest in hypoxia, as well as methods they have developed to abrogate hypoxia-induced G1 arrest, they will determine the contribution of this G1 arrest in hypoxia's effect on genomic instability and radioprotection.