CORE D

芯

基本信息

批准号：
10225397
负责人：
Ming Li
金额：
$ 13.01万
依托单位：
UNIVERSITY OF MINNESOTA
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：
2019-08-09 至 2022-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10225397
关键词：
Adjuvant Affect Antibodies Bacteriophages Biochemical Biological Assay Biology Biophysics Bladder Cells Cervical Charge Chemicals Clinical Collaborations Communities Comparative Study Complex Cytosine DNA Data Deaminase Development Diagnosis Drug resistance Ensure Enzyme-Linked Immunosorbent Assay Enzymes Escherichia coli Estrogen receptor positive Evolution Family member Flow Cytometry Goals Head and neck structure Human Immunoassay Immunoglobulin G Immunohistochemistry Immunoprecipitation Libraries Lung Malignant Neoplasms Mammary Neoplasms Measures Mediating Methods Microscopy Monoclonal Antibodies Mus Mutagenesis Mutate Mutation Neoplasm Metastasis Nucleic Acids Oryctolagus cuniculus Outcome Patients Primary Neoplasm Procedures Process Production Prognosis Protocols documentation Publications Quality Control Reagent Recombinants Reporting Reproducibility Research Research Personnel Resolution Services Single-Stranded DNA Solubility Standardization Structure Testing Therapeutic Time Treatment Failure United States National Institutes of Health Uracil Virus Diseases anticancer research base cancer cell cancer diagnosis cancer type improved malignant breast neoplasm member mouse model multidisciplinary overexpression prevent programs scaffold small molecule structural biology therapy outcome therapy resistant tumor

项目摘要

CORE D – ENZYMES & ANTIBODIES ABSTRACT APOBEC enzymes are single-stranded DNA cytosine-to-uracil deaminases that normally protect cells from viral infections. One family member, APOBEC3B (A3B), is overexpressed in over half of all breast tumors and its mutation signature is found in 20% of primary and 50% of metastatic breast tumors. A3B overexpression and mutation signature have also been associated with therapy failure and poor overall survival. Our Program has shown that inhibition of A3B-mediated tumor evolution contributes to improved therapy outcomes in a mouse model of estrogen receptor-positive breast cancer. These data support our Program's unifying hypothesis that A3B inhibition, as an adjuvant to primary treatment options, will help to prevent detrimental mutation-driven outcomes such as drug resistance and metastasis. Our Program members are collaborating to test this hypothesis through 3 tightly integrated Projects focusing on the biology, chemical biology, and structural biology of A3B. These Projects are supported by 4 service Cores, including Core D – Enzymes & Antibodies, which has 2 specific aims: Aim 1 is to produce recombinant APOBEC enzymes and to perform standard DNA deaminase assays with these enzymes, which will allow standardization of APOBEC studies across labs and time. Aim 2 is to develop specific monoclonal antibodies for A3B and related human APOBEC3 enzymes. The availability of specific antibodies will move the Program's research forward and is important for the Program's translational goal of developing an antibody-based assay for diagnosing A3B- positive tumors in order to inform patient prognosis and, ultimately, therapeutic plans. The reagents resulting from both Aims are vital for expediting the goals of each Project, ensuring maximal rigor and reproducibility across Projects and collaborating labs and fueling Program collaborations and APOBEC research in the greater cancer research community. Overall, despite its relatively modest size, Core D is a powerful enabling feature of our Program.

核心 D – 酶和抗体抽象的 APOBEC 酶是单链 DNA 胞嘧啶至尿嘧啶脱氨酶，通常可以保护细胞免受 APOBEC3B (A3B) 是一个家族成员，在超过一半的乳腺肿瘤中过度表达。其突变特征存在于 20% 的原发性乳腺肿瘤和 50% 的转移性乳腺肿瘤中。和突变特征也与治疗失败和总体生存率低有关。研究表明，抑制 A3B 介导的肿瘤进化有助于改善治疗结果雌激素受体阳性乳腺癌小鼠模型这些数据支持我们计划的统一。假设 A3B 抑制作为主要治疗方案的辅助手段将有助于预防疾病我们的计划成员正在合作解决突变驱动的结果，例如耐药性和转移。通过 3 个紧密结合的项目来检验这一假设，这些项目侧重于生物学、化学生物学和 A3B 的结构生物学由 4 个服务核心支持，包括核心 D – 酶和抗体，有 2 个具体目标：目标 1 是生产重组 APOBEC 酶并执行使用这些酶进行标准 DNA 脱氨酶测定，这将使 APOBEC 研究标准化目标 2 是跨实验室和跨时间开发 A3B 和相关人类的特异性单克隆抗体。 APOBEC3 酶的可用性将推动该计划的研究向前发展。对于该计划开发基于抗体的 A3B 诊断检测方法的转化目标非常重要- 阳性肿瘤，以便告知患者预后并最终制定治疗计划。这两个目标对于加快实现每个项目的目标、确保最大的严谨性和可重复性至关重要跨项目和合作实验室，并推动项目合作和 APOBEC 研究总体而言，尽管 Core D 规模相对较小，但它是一个强大的支持者。我们计划的特色。