Functions of Cyclin/CDK complexes in development and cancer

细胞周期蛋白/CDK 复合物在发育和癌症中的功能

基本信息

批准号：
10220905
负责人：
YAN GENG
金额：
$ 17.96万
依托单位：
DANA-FARBER CANCER INST
依托单位国家：
美国
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-09-11 至 2024-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10220905
关键词：
Allografting Area CDK4 gene Cancer Cell Growth Cell Cycle Proteins Cell Cycle Regulation Cell Proliferation Cell physiology Cells Complex Cyclin D1 Cyclins Dana-Farber Cancer Institute Development Genetic Genetically Engineered Mouse Glioblastoma Human Injections Knock-in Knock-in Mouse Knock-out Knockout Mice Laboratories Malignant Neoplasms Modeling Mouse Strains Mus Mutation Normal Cell Patients Play Processed Genes Proteins Research Role Specialist Supervision T-Cell Leukemia Testing Therapeutic Tumor Immunity Xenograft Model Xenograft procedure blastocyst cancer cell cancer therapy conditional knockout cyclin C cyclin G1 design embryonic stem cell experimental study genetic manipulation genomic locus immune checkpoint blockade in vivo insight knock-down melanoma mouse development mouse model mutant neoplastic cell pluripotency factor stemness tumor

项目摘要

Project Summary Dr. Peter Sicinski's laboratory at the Dana-Farber Cancer Institute studies the functions of cell cycle proteins in normal development and in cancer. For the past 20 years, we have created many mouse knockout or knock-in strains including mice either lacking cyclins or CDKs, or expressing modified cyclins or CDKs. Using those mice, we delineated the requirement for cell cycle proteins during normal mouse development and in tumor formation/progression. As an expert in generating and analyzing genetically engineered mouse models, Dr. Yan Geng, the Research Specialist, has been leading the efforts in Dr. Sicinski's lab to create different cyclin/CDK mutant strains. Particularly, she has played a crucial role in the following areas: 1) design the genetic targeting strategies for knockout cyclin genes or knock-in mutations/tags into a cyclin or CDK gene locus; 2) supervise the technical processes for gene manipulation in embryonic stem (ES) cells and creating chimeric mice by blastocyst injection of ES cells; 3) design and perform the experiments using mouse tumor models including xenograft/allograft models. Currently, the Research Specialist is making a new mouse strain of conditional knockout Cdk19. Using this strain, we plan to investigate the effect of Cdk19 loss together with loss of cyclin C in T-cell leukemia. Combining Cdk19 knockout with cyclin C knockout, we hope to create a mouse model that faithfully mimicking human T-cell leukemia. The Research Specialist is also leading the study of G1 cyclins' function in cancer cell stemness. As we have found that G1 cyclins directly regulate the protein levels of pluripotency factors Oct4, Sox2 and Nanog not only in embryonic stem cells but also in glioblastoma tumor initiating cells, we will investigate whether decreasing the levels/activities of G1 cyclins would impact on the stemness of tumor cells. We will use a xenograft model to test whether knocking down the G1 cyclins will induce differentiation of glioblastoma cells thus to eliminate/reduce their potential to form tumors in vivo. Recently, we have found that cyclin D/CDK4/6 play roles in cancer immunity. Using tumor allograft mouse models, the Research Specialist is going to explore whether inhibition of cyclin D/CDK4/6 would enhance the efficacy of anti-immune checkpoint blockade in treatment of melanoma. We hope that this study will lead to a new combinational therapeutic strategy for melanoma patients.

项目概要达纳法伯癌症研究所 Peter Sicinski 博士的实验室研究细胞周期蛋白的功能正常发育和癌症。在过去的20年里，我们创造了许多小鼠基因敲除或基因敲入品系，包括缺乏细胞周期蛋白或 CDK 或表达修饰的细胞周期蛋白或 CDK 的小鼠。使用那些小鼠，我们描述了正常小鼠发育和肿瘤过程中对细胞周期蛋白的需求形成/进展。作为生成和分析基因工程小鼠模型的专家，Dr. 研究专家严耿一直在 Sicinski 博士的实验室中领导着创造不同的细胞周期蛋白/CDK突变株。特别是，她在以下领域发挥了至关重要的作用：1）设计用于敲除细胞周期蛋白基因或将突变/标签敲入细胞周期蛋白或 CDK 基因的遗传靶向策略轨迹; 2) 监督胚胎干细胞基因操作的技术流程并创造通过囊胚注射ES细胞来获得嵌合小鼠； 3）使用小鼠肿瘤设计并进行实验模型包括异种移植/同种异体移植模型。目前，研究专家正在培育新的小鼠品系条件性敲除Cdk19。使用该菌株，我们计划研究 Cdk19 丢失的影响 T 细胞白血病中细胞周期蛋白 C 的缺失。将Cdk19敲除与cyclin C敲除相结合，我们希望创建一个忠实模仿人类 T 细胞白血病的小鼠模型。研究专家还领导 G1 细胞周期蛋白在癌细胞干性中的功能研究。我们发现G1细胞周期蛋白直接调节多能因子 Oct4、Sox2 和 Nanog 的蛋白质水平不仅在胚胎干细胞中，而且在胶质母细胞瘤肿瘤起始细胞，我们将研究是否降低 G1 细胞周期蛋白的水平/活性会影响肿瘤细胞的干性。我们将使用异种移植模型来测试是否击倒 G1 细胞周期蛋白将诱导胶质母细胞瘤细胞分化，从而消除/减少其形成的潜力体内肿瘤。最近，我们发现cyclin D/CDK4/6在癌症免疫中发挥作用。使用肿瘤同种异体移植小鼠模型中，研究专家将探讨是否抑制cyclin D/CDK4/6 将增强抗免疫检查点阻断治疗黑色素瘤的疗效。我们希望这研究将为黑色素瘤患者带来新的联合治疗策略。