Cell cycle block by HMG co-A reductase inhibitors

描述(申请人提供)：此申请旨在提供杰出的导师和支持性的实验室环境，以促进Chinweike Ukomadu，M.D.，Ph.D.的发展，成为一名独立的科学家。这位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。在接受了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 duta，M.D.，Ph.D.的实验室进行，他是国际公认的细胞周期调节领域的研究人员。杜塔博士在许多初级科学家过渡到首席研究人员的职业生涯中指导他们的记录为实现这一建议的目标提供了理想的环境。杜塔博士的实验室在与细胞周期研究相关的细胞生物学、生化和遗传学方法方面拥有广泛的专业知识。布里格姆女子医院病理学和内科的研讨会、会议和大学互动将为科学和职业发展提供更多的机会。 这项建议概述了详细的研究，旨在进一步了解细胞周期蛋白依赖性激酶2(CDK2)的调节，CDK2是细胞周期中进行过程所需的关键酶。这些研究将使用已建立的癌细胞株进行。在初步研究中，降胆固醇药物美伐他汀通过阻止激活磷酸化来抑制CDK2。其具体目的是：1)确定美伐他汀抑制CDK2激活的分子机制；2)证明某些癌细胞不需要细胞周期蛋白H：CDK7来激活CDK2；以及3)阐明p21在某些癌细胞中无法抑制CDK2的事件。

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.