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类血液的DNA损伤分析，并开发它们 变成了商业工具包。这些检测方法监测与重要人类疾病相关的损害类型。 而PIG-A检测报告的是基因突变，微核网织红细胞(MN-RET)检测是 对染色体断裂和/或丢失做出反应。这些生物标志物适用于人类和 并将满足两个重要需求：将在实验室动物模型中的发现扩展到 直接在人体上进行研究，并了解受控良好的机械实验室研究的表现 最早是在人类身上观察到的。在流式细胞术之前，这些分析利用免疫磁分离来 极大地丰富了相关的细胞群体，从而提高了分析的精确度和灵敏度。通过 提供简单易用的试剂盒，具有充分记录的重复性和实验室间的可转移性； 为了验证生物标记物的具体用途，研究人员将拥有前所未有的可用工具 综合研究导致个体间差异的因素的效率 人类DNA损伤。应用包括对药物治疗、宿主和/或生活方式因素的研究 导致DNA损伤和修复的个体间差异，对反病毒的敏感性被夸大 肿瘤治疗和基于人群的环境暴露流行病学研究，包括 职业接触。该项目得益于国际上强大的多学科团队 公认的科学家，有成功地将研究进展转化为可靠的记录 商业检测试剂盒。

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