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: 6902585
• 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/6902585
• 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）：此申请旨在提供出色的指导和支持性的实验室环境，以促进医学博士学位的Chinweike Ukomadu的发展，以成为独立科学家的职业。 候选人已经完成了研究生研究，并在离子通道生理学领域发表了几篇论文。 在内科和胃肠病学接受临床培训后，他回到实验室研究细胞周期调节的机制。 拟议的研究将在医学博士Anindya Dutta博士的实验室中进行，该研究人员是细胞周期调节领域的国际认可的研究者。 Dutta博士在指导众多初级科学家的记录中过渡到职业，因为主要研究人员为实施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有关的细胞生物学，生化和遗传学方法方面具有广泛的专业知识。 Brigham和妇女医院病理学和内科部门内的研讨会，会议和大学互动将为科学和职业发展提供更多机会。 该建议概述了旨在进一步了解细胞周期蛋白依赖激酶2（CDK2）的详细研究，这是一种在整个细胞周期中进展所需的关键酶。 研究将使用已建立的癌细胞系进行。 在初步研究中，降低胆固醇剂梅伐他汀通过防止激活磷酸化抑制了CDK2。 具体目的是：1）确定甲瓦生着抑制CDK2激活的分子机制； 2）在某些癌细胞系中，不需要Cyclin H：CDK7，这对于激活CDK2至关重要。 3）阐明p21无法抑制某些癌细胞中CDK2的事件。