Cell cycle block by HMG co-A reductase inhibitors

HMG co-A 还原酶抑制剂阻断细胞周期

• 批准号: 6801016
• 负责人: Chinweike Ukomadu
• 金额: $ 13.39万
• 依托单位: BRIGHAM AND WOMEN'S HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2003
• 资助国家: 美国
• 起止时间: 2003-09-15 至 2008-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6801016
• 关键词: HMG coA reductases; SDS polyacrylamide gel electrophoresis; cell cycle; cell growth regulation; cell line; cell proliferation; cyclin dependent kinase; enzyme activity; enzyme substrate; flow cytometry; lovastatin; oncoprotein p21; oxidoreductase inhibitor; phosphorylation; plasmids; transfection /expression vector; western blottings

DESCRIPTION (provided by applicant): This application is intended to provide outstanding mentorship and a supportive laboratory environment to foster the development of Chinweike Ukomadu, M.D., Ph.D., towards a career as an independent scientist. The candidate has completed graduate studies and published several papers in the field of ion channel physiology. Following clinical training in internal medicine and gastroenterology he returned to the laboratory to study mechanisms of cell cycle regulation. The proposed research will be carried out in the laboratory of Anindya Dutta, M.D., Ph.D., an internationally recognized investigator in the area of cell cycle regulation. Dr. Dutta's record in mentoring numerous junior scientists as they transitioned to careers as principal investigators provides an ideal setting for implementation of the goals of this proposal. Dr. Dutta's laboratory has extensive expertise in cell biological, biochemical, and genetic methodologies related to cell cycle studies. Seminars, conferences, and collegial interactions within the Departments of Pathology and Internal Medicine at Brigham and Women's Hospital will offer additional opportunity for scientific and career development. This proposal outlines detailed studies aimed at further understanding the regulation of cyclin dependent kinase 2 (Cdk2), a key enzyme required for progression through the cell cycle. The studies will be carried out using established cancer cell lines. In preliminary studies, mevastatin, a cholesterol lowering agent, inhibited Cdk2 by preventing activating phosphorylation. The specific aims are: 1) to determine the molecular mechanism by which mevastatin inhibits the activation of Cdk2; 2) to show that cyclin H:cdk7, which has been felt to be essential for activation of Cdk2, is not required in some cancer cell lines; and 3) to elucidate the events underlying the inability of p21 to inhibit Cdk2 in some cancer cells.

描述（由申请人提供）：本申请旨在提供出色的指导和支持性实验室环境，以促进 Chinweike Ukomadu 医学博士、博士的发展，走向独立科学家的职业生涯。 该候选人已完成研究生学习并在离子通道生理学领域发表了多篇论文。 经过内科和胃肠病学的临床培训后，他回到实验室研究细胞周期调节机制。 拟议的研究将在 Anindya Dutta 医学博士、哲学博士的实验室进行，他是细胞周期调控领域国际公认的研究者。 杜塔博士在指导众多初级科学家过渡到主要研究人员的职业生涯方面拥有丰富的经验，为实现该提案的目标提供了理想的环境。 Dutta 博士的实验室在与细胞周期研究相关的细胞生物学、生化和遗传方法学方面拥有丰富的专业知识。 布莱根妇女医院病理学和内科部门内的研讨会、会议和同事互动将为科学和职业发展提供额外的机会。 该提案概述了旨在进一步了解细胞周期蛋白依赖性激酶 2 (Cdk2) 调节的详细研究，细胞周期蛋白依赖性激酶 2 是细胞周期进展所需的关键酶。 这些研究将使用已建立的癌细胞系进行。 在初步研究中，美伐他汀（一种降胆固醇药物）通过阻止激活磷酸化来抑制 Cdk2。 具体目标是：1）确定美伐他汀抑制Cdk2激活的分子机制； 2) 证明细胞周期蛋白 H:cdk7（人们认为它对于激活 Cdk2 至关重要）在某些癌细胞系中不是必需的； 3) 阐明 p21 在某些癌细胞中无法抑制 Cdk2 的潜在事件。