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: 10686395
• 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/10686395
• 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; 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; tumor initiation

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 Dana-Farber癌症研究所的Peter Sicinski博士的实验室研究细胞周期蛋白在 正常发育和癌症。在过去的20年中，我们创建了许多老鼠淘汰或敲门 包括缺乏细胞周期蛋白或CDK的小鼠，或表达改良的细胞周期蛋白或CDK的菌株。使用这些 小鼠，我们描述了在正常小鼠发育期间和肿瘤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，博士 研究专家Yan Geng一直在Sicinski博士的实验室领导着努力，以创建不同的 细胞周期蛋白/CDK突变菌株。特别是，她在以下领域发挥了至关重要的作用：1）设计 敲除细胞周期蛋白基因或敲除突变/标签的遗传靶向策略进入细胞周期蛋白或CDK基因 轨迹; 2）监督胚胎茎（ES）细胞中基因操纵的技术过程并创建 通过注射ES细胞的嵌合小鼠； 3）使用小鼠肿瘤设计和执行实验 包括异种移植/同种异体移植模型在内的模型。目前，研究专家正在增加新的鼠标应变 有条件的基因敲除CDK19。使用这种菌株，我们计划研究CDK19损失的影响 T细胞白血病中细胞周期蛋白C的丧失。将CDK19淘汰与细胞周期蛋白C淘汰赛相结合，我们希望创建一个 忠实模仿人类T细胞白血病的老鼠模型。研究专家也在领导 G1细胞周期蛋白在癌细胞干性中的功能的研究。正如我们发现G1细胞周期蛋白直接调节 多能因素的蛋白质水平OCT4，SOX2和NANOG不仅在胚胎干细胞中，而且在 胶质母细胞瘤肿瘤引发细胞，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测试是否敲门 G1细胞周期蛋白将诱导胶质母细胞瘤细胞的分化，从而消除/降低其形成的潜力 体内肿瘤。最近，我们发现细胞周期蛋白D/CDK4/6在癌症免疫中起着作用。使用肿瘤 同种异体小鼠模型，研究专家将探索抑制细胞周期蛋白D/CDK4/6是否抑制 将增强抗免疫检查点阻滞在治疗黑色素瘤方面的疗效。我们希望这个 研究将导致黑色素瘤患者的新组合治疗策略。