PHENOTYPE SCREENS FOR BONE MARROW FAILURE

骨髓衰竭的表型筛查

• 批准号: 6153493
• 负责人: HAGOP YOUSSOUFIAN
• 金额: $ 39.83万
• 依托单位: BAYLOR COLLEGE OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2000
• 资助国家: 美国
• 起止时间: 2000-09-30 至 2004-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6153493
• 关键词: aminoacid; blood cell count; bone marrow transplantation; chloramphenicol; genetic polymorphism; genetic screening; hematopoiesis; high throughput technology; laboratory mouse; mass spectrometry; mitomycin C; nucleic acid metabolism; oxidative stress; phenotype; technology /technique development; transplant rejection

DESCRIPTION (Adapted from the applicant's abstract) The major objective of this proposal is the development and characterization of efficient hematologic, genetic and physiologic assays of hematopoietic failure in the mouse. Although mutagenesis strategies have yielded a number of mouse models of human bone marrow failure syndromes, less attention has been paid to "acquired" disorders that may result from polygenic traits or gene-environment interactions. This is due in part to the lack of appropriate analytical models and strategies for the detection of these conditions, particularly in their presymptomatic phases. As an outgrowth of the genome project, rapid advances have been made in the development of comprehensive screens for differential gene expression. In parallel, advances in chemical biology have resulted in the development of sensitive methods for the identification of metabolites that may be altered in disease states. The fusion of these two approaches is likely to yield powerful screening tools and facilitate the detection and analysis of complex disorders. Accordingly, they propose to incorporate these assays in a panel that also includes complete blood counts, hematopoietic colony growth assays, and fluorescence-based techniques for the detection of presymptomatic bone marrow failure in mice, Specifically, they will utilize whole-genome microarrays to characterize genes that may have dysregulated expression patterns in bone marrow failure; tandem mass spectrometry to identify metabolites implicated in known syndromes of bone marrow failure; and fluorescence spectrometry for the detection of oxidative stress. These assays will be validated in inbred mouse strains and in mouse models of bone marrow failure at steady-state and after challenge with agents (mitomycin C and chloramphenicol) that can induce bone marrow failure. The data will be correlated with measurements of blood counts and hematopoietic colony growth, and the resulting pre- and post-challenge databases will provide the elements of a diagnostic algorithm for the high- throughput screening of bone marrow failure in mice. Finally, the algorithm will be applied for the detection of early bone marrow failure in a test trial of chemically-mutagenized mice. These studies should result in the development of well-defined assays for pathways that regulate the organismal response to exogenous and endogenous toxins and yield new insights into the pathogenesis of bone marrow failure. (End of Abstract.)

描述（根据申请人的摘要改编） 该提案的主要目的是发展和表征 造血的有效血液学，遗传和生理测定 鼠标故障。 尽管诱变策略产生了数量 人类骨髓衰竭综合症的小鼠模型，较少的注意 支付给可能由多基因特征或 基因环境相互作用。 这部分是由于缺乏适当的 分析模型和检测这些条件的策略， 特别是在其预症状阶段。 作为基因组的产物 项目，在综合发展方面已取得了快速的进步 鉴定基因表达的筛选。 同时，化学的进步 生物学导致开发了敏感方法 鉴定可能改变疾病状态的代谢产物。 这 这两种方法的融合可能会产生强大的筛选工具，并且 促进对复杂疾病的检测和分析。 因此，他们 建议将这些测定法纳入面板，还包括完整 血数，造血菌落生长测定和基于荧光的血液计数 检测小鼠预症状骨髓衰竭的技术， 具体而言，他们将利用全基因组微阵列来表征基因 在骨髓衰竭中的表达模式可能失调。串联 质谱法以识别与已知综合症有关的代谢产物 骨髓衰竭；和荧光光谱法检测 氧化应激。 这些测定将在近交小鼠菌株中得到验证，并且 在稳态和挑战之后的骨髓衰竭的小鼠模型中 与可以诱导骨髓的剂（丝裂霉素C和氯霉素） 失败。 数据将与血液计数的测量和 造血菌落的生长以及挑战后和挑战后 数据库将为高级提供诊断算法的元素 小鼠骨髓衰竭的吞吐量筛查。 最后，算法 将在测试试验中用于检测早期骨髓衰竭 化学杂志的小鼠。 这些研究应导致 开发针对调节生物体的途径定义明确的测定法 对外源和内源性毒素的反应，并对 骨髓衰竭的发病机理。 （摘要结束。）