权益分类	功能权益	普通用户	{{item.name}}会员
{{category.name}}	{{benefitItem.name}}

Polymerase-mediated ultramutagenesis and carcinogenesis in mice

聚合酶介导的小鼠超突变和致癌作用

基本信息

批准号：
10548853
负责人：
DIEGO H CASTRILLON
金额：
$ 54.16万
依托单位：
UT SOUTHWESTERN MEDICAL CENTER
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：
2019-02-01 至 2025-01-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10548853
关键词：
Acceleration Alleles Amino Acid Substitution Animal Cancer Model Animal Model Bacterial Artificial Chromosomes Behavior Biology Breeding Bypass Cancer Model Carcinoma Cell division Cells Clinical Community Clinical Oncology Program Cre driver Cytotoxic T-Lymphocytes DNA Polymerase II DNA Sequence Alteration DNA biosynthesis Development Endometrial Endometrial Carcinoma Exhibits Female Frequencies Generations Genetic Genetic Engineering Genetic Heterogeneity Genetic study Genetically Engineered Mouse Genomics Goals Growth Hematopoietic Neoplasms Hereditary Nonpolyposis Colorectal Neoplasms Histologic Housekeeping Human Immune response Immunology Incidence Inflammatory Inherited Investigation KRASG12D Knock-in Malignant Neoplasms Malignant neoplasm of lung Mediating Methods Mismatch Repair Mismatch Repair Gene Inactivation Modeling Monitor Mus Mutation Mutation Spectra Normal Cell Nose Oncogenic Outcome Phenotype Polymerase Prediction of Response to Therapy Process Prognosis Research Project Grants Role Route Signal Pathway Somatic Mutation Survival Analysis T cell infiltration T-Lymphocyte Tissues Translational Research Tumor Biology Variant anti-PD-L1 therapy base behavioral response carcinogenesis cell growth cell mediated immune response checkpoint therapy exome experimental study gastrointestinal carcinoma genome editing genome sequencing humanized mouse immunological status improved interest mouse model neoantigens novel pre-clinical response sarcoma success tool translational cancer research translational model treatment response tumor tumor behavior tumor eradication tumor heterogeneity tumor immunology tumor progression whole genome

项目摘要

PROJECT SUMMARY/ABSTRACT Genetically-engineered mouse models (GEMMs) are essential tools for the study of cancer. However, there is growing concern that GEMMs fail to recapitulate the mutation burden of human carcinomas. GEMMs have startlingly low overall mutation rates, far below what is observed in their human counterparts. This makes such models useful for studies of oncogenic signaling pathways, but greatly restricts their utility for studies of genetic heterogeneity and clonal variation, tumor immunology, or the impact of mutational load/base substitution rates on tumor behavior and response to therapy. The latter has become particularly relevant with the advent of immune checkpoint therapies, given that the best predictor of treatment success is a high incidence of somatic mutations, irrespective of tumor type. The same limitations are likely to be encountered with GEMMs based on newer genome-editing methods, pointing to the need for alternative approaches to optimize with respect to mutational load, which we now know defines so many aspects of tumor biology, clinical behavior and treatment response. In this project, submitted in response to PAR-17-245 “Research Projects to Enhance Applicability of Mammalian Models for Translational Research”, we propose to generate and characterize the first mouse cancer models based on polymerase-driven ultramutation. These approaches will 1) catalyze modelling of any cancer driven by POLE ultramutagenesis and 2) permit efficient “humanization” of any GEMM with respect to mutational load. Our approach represents a new and widely-applicable route to the creation of mouse models that recapitulate the mutational loads inherent to human cancer. These new genetic tools and the diverse animal models they will enable will stimulate a wide range of translational and preclinical investigations for which GEMMs were previously not well-suited, thus fulfilling the goals of PAR-17-245.

项目总结/文摘

项目成果

期刊论文数量（5）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

The mismatch recognition protein MutSα promotes nascent strand degradation at stalled replication forks.

DOI：
10.1073/pnas.2201738119
发表时间：
2022-10-04
期刊：
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
影响因子：
11.1
作者：
Zhang, Junqiu;Zhao, Xin;Liu, Lu;Li, Hao-Dong;Gu, Liya;Castrillon, Diego H.;Li, Guo-Min
通讯作者：
Li, Guo-Min

Endometrial polyps are non-neoplastic but harbor epithelial mutations in endometrial cancer drivers at low allelic frequencies.

DOI：
10.1038/s41379-022-01124-5
发表时间：
2022-11
期刊：
MODERN PATHOLOGY
影响因子：
7.5
作者：
Sahoo, Subhransu S.;Aguilar, Mitzi;Xu, Yan;Lucas, Elena;Miller, Valerie;Chen, Hao;Zheng, Wenxin;Cuevas, Ileana C.;Li, Hao-Dong;Hitrys, David;Wachsmann, Megan B.;Bishop, Justin A.;Cantarell, Brandi;Gagan, Jeffrey;Koduru, Prasad;SoRelle, Jeffrey A.;Castrillon, Diego H.
通讯作者：
Castrillon, Diego H.

Histopathologic diagnosis of endometrial precancers: Updates and future directions.