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

• 批准号: 10016232
• 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
• 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/10016232
• 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; stemness; tumor

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.

项目摘要 博士丹娜-法伯癌症研究所的Peter Sicinski实验室研究了细胞周期蛋白在癌症中的功能。 正常发育和癌症。在过去的20年里，我们已经创造了许多小鼠敲除或敲入 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的小鼠的品系。使用这些 小鼠，我们描绘了正常小鼠发育和肿瘤中对细胞周期蛋白的需求 形成/进展。作为一个专家在生成和分析基因工程小鼠模型，博士。 研究专家Yan Geng一直在领导Sicinski博士实验室的工作， cyclin/CDK突变株。特别是在以下几个方面发挥了重要作用：1）设计 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 基因座; 2）监督胚胎干细胞（ES）基因操作的技术过程， 3）设计并进行小鼠肿瘤实验 模型，包括异种移植物/同种异体移植物模型。目前，研究专家正在制造一种新的小鼠品系， 条件性敲除Cdk 19基因使用该菌株，我们计划研究Cdk 19损失的影响， T细胞白血病中细胞周期蛋白C的丢失。结合Cdk 19敲除和细胞周期蛋白C敲除，我们希望创造一个 忠实模仿人类T细胞白血病的小鼠模型。研究专家还领导了 G1期细胞周期蛋白在肿瘤干细胞性中作用研究正如我们已经发现的，G1细胞周期蛋白直接调节细胞周期， 多能性因子Oct 4、Sox 2和Nanog的蛋白水平不仅在胚胎干细胞中， 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敲除 G1细胞周期蛋白将诱导胶质母细胞瘤细胞分化，从而消除/降低它们形成胶质母细胞瘤的可能性 体内肿瘤近年来，我们发现cyclin D/CDK 4/6在肿瘤免疫中发挥重要作用。使用肿瘤 在同种异体移植小鼠模型中，研究专家将探索是否抑制细胞周期蛋白D/CDK 4/6 将增强抗免疫检查点阻断在治疗黑素瘤中的功效。我们希望这一 这项研究将为黑色素瘤患者带来一种新的联合治疗策略。