Validation of Cross-Species Biomarkers of DNA Damage

DNA 损伤跨物种生物标志物的验证

• 批准号: 9769037
• 负责人: Jeffrey C Bemis
• 金额: $ 61.75万
• 依托单位: LITRON LABORATORIES, LTD.
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-01-15 至 2021-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9769037
• 关键词: Affect; Age; Aging; Aliquot; Antineoplastic Agents; Benchmarking; Biological Assay; Biological Markers; Blood; Blood Volume; Blood specimen; Bloom Syndrome; Body mass index; C-reactive protein; Cancer Patient; Cells; Chromosomal Breaks; Code; Congenital Abnormality; DNA Damage; DNA Repair; DNA Repair Disorder; Data; Development; Disease; Dose; Environmental Exposure; Erythropoiesis; Evaluation; Exhibits; Family suidae; Fanconi' s Anemia; Flow Cytometry; Folic Acid; Frequencies; Gene Mutation; Genes; Genomic Instability; Genotype; Hematopoietic; Heritability; Human; Human Pathology; Immunomagnetic Separation; Individual; Individual Differences; Inflammation; Inflammatory Bowel Diseases; Integration Host Factors; International; Investigation; Kinetics; Laboratories; Laboratory Animal Models; Laboratory Animals; Laboratory Study; Malignant Neoplasms; Measurement; Messenger RNA; Monitor; Mus; Mutagens; Mutation; Nature; Newborn Infant; Nijmegen Breakage Syndrome; Obesity; Occupational Exposure; Operative Surgical Procedures; Patients; Performance; Pharmaceutical Preparations; Pharmacotherapy; Phase; Phenotype; Physiological; Platinum; Play; Population; Population Study; Race; Rattus; Reporting; Reproducibility; Research; Research Personnel; Reticulocytes; Rodent; Rodent Model; Role; Sampling; Scientist; Sickle Cell Anemia; Small Business Innovation Research Grant; Source; Specimen; TP53 gene; Testing; Validation; Work; arm; base; chemotherapy; epidemiology study; genotoxicity; human DNA damage; human disease; human study; hydroxyurea; lifestyle factors; mouse model; multidisciplinary; next generation; patient population; phase 2 study; population based; prototype; response; sex; specific biomarkers; temozolomide; tool

Project Summary This project will validate two high throughput human blood-based DNA damage assays and develop them into commercial kits. The assays monitor types of damage associated with important human diseases. Whereas the PIG-A assay reports on gene mutation, the micronucleated reticulocyte (MN-RET) assay is responsive to chromosomal breaks and/or losses. The biomarkers are applicable to both humans and laboratory animals and will fulfill two important needs: extension of findings in laboratory animal models to direct studies in humans, and performance of well-controlled mechanistic laboratory studies to understand observations first made in humans. The assays utilize immunomagnetic separation prior to flow cytometry to dramatically enrich the relevant cell populations and thereby enhance assay precision and sensitivity. By providing simple-to-use kits with thoroughly documented reproducibility and inter-laboratory transferability, and validating the biomarkers for specific uses, researchers will have available tools with unprecedented efficiencies for comprehensively studying those factors that contribute to inter-individual differences in human DNA damage. Applications include the study of drug treatments, host and/or life-style factors that contribute to inter-individual differences in DNA damage and repair, exaggerated sensitivities to anti- neoplastic therapies, and population-based epidemiology studies of environmental exposures, including occupational exposures. The project benefits from a strong multidisciplinary team of internationally recognized scientists with a proven track record of successfully converting research advances into reliable commercial assay kits.

项目摘要 该项目将验证两种高通量的基于人血的DNA损伤检测方法并开发它们 转化为商业试剂盒。这些检测监测与重要人类疾病相关的损害类型。 PIG-A试验报告基因突变，而微核网织红细胞（MN-RET）试验报告基因突变。 响应于染色体断裂和/或丢失。所述生物标志物适用于人类和 实验动物，并将满足两个重要的需求：在实验室动物模型中的发现， 在人类中进行直接研究，并进行良好控制的机制实验室研究，以了解 最早在人类身上进行的观察。该测定在流式细胞术之前利用免疫磁性分离， 显著地富集相关的细胞群，从而提高测定的精确度和灵敏度。通过 提供具有完整记录的再现性和实验室间可转移性的简单易用的试剂盒， 并验证生物标志物的特定用途，研究人员将拥有前所未有的可用工具， 全面研究这些因素，有助于个体间差异的效率， 人类DNA损伤应用包括研究药物治疗、宿主和/或生活方式因素， 有助于DNA损伤和修复的个体间差异，夸大了对抗- 肿瘤治疗和基于人群的环境暴露流行病学研究，包括 职业暴露。该项目得益于一个强大的多学科团队， 公认的科学家，成功地将研究进展转化为可靠的 商业测定试剂盒。

项目成果

Assessment of systemic genetic damage in pediatric inflammatory bowel disease.

• DOI: 10.1002/em.22403
• 发表时间: 2020-11
• 期刊: Environmental and molecular mutagenesis
• 影响因子: 2.8
• 作者: Baig A;Avlasevich SL;Torous DK;Bemis JC;Saubermann LJ;Lovell DP;MacGregor JT;Dertinger SD
• 通讯作者: Dertinger SD

Human blood PIG-A mutation and micronucleated reticulocyte flow cytometric assays: Method optimization and evaluation of intra- and inter-subject variation.

• DOI: 10.1002/em.22393
• 发表时间: 2020-10
• 期刊: Environmental and molecular mutagenesis
• 影响因子: 2.8
• 作者: Torous DK;Avlasevich SL;Khattab MG;Baig A;Saubermann LJ;Chen Y;Bemis JC;Lovell DP;Walker VE;MacGregor JT;Dertinger SD
• 通讯作者: Dertinger SD

Recommendations for conducting the rodent erythrocyte Pig-a assay: A report from the HESI GTTC Pig-a Workgroup.

• DOI: 10.1002/em.22427
• 发表时间: 2021-03
• 期刊: Environmental and molecular mutagenesis
• 影响因子: 2.8
• 作者: Dertinger SD;Bhalli JA;Roberts DJ;Stankowski LF Jr;Gollapudi BB;Lovell DP;Recio L;Kimoto T;Miura D;Heflich RH
• 通讯作者: Heflich RH

Lack of hydroxyurea-associated mutagenesis in pediatric sickle cell disease patients.

儿童镰状细胞病患者缺乏羟基脲相关诱变。

• DOI: 10.1002/em.22536
• 发表时间: 2023
• 期刊: Environmental and molecular mutagenesis
• 影响因子: 2.8
• 作者: Torous,DorotheaK;Avlasevich,Svetlana;Bemis,JeffreyC;Howard,Thad;Ware,RussellE;Fung,Chunkit;Chen,Yuhchyau;Sahsrabudhe,Deepak;MacGregor,JamesT;Dertinger,StephenD
• 通讯作者: Dertinger,StephenD