Genomic and Proteomic Biomarkers of Biological Responses to Exposure

暴露生物反应的基因组和蛋白质组生物标志物

• 批准号: 7627364
• 负责人: CORAL LAMARTINIERE
• 金额: $ 47.12万
• 依托单位: UNIVERSITY OF ALABAMA AT BIRMINGHAM
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-08-15 至 2011-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7627364
• 关键词: Animals; Arts; Biochemical; Bioinformatics; Biological; Biological Markers; Biological Models; Blood; Body Fluids; Breast; Centers for Disease Control and Prevention (U.S.); Chemical Exposure; Chemicals; Clinical; Core Facility; Custom; Data; Development; Dibutyl Phthalate; Entire hair of pubis; Environment; Epidemiologic Studies; Epidemiology; Evaluation; Experimental Designs; Exposure to; Future; Gene Chips; Gene Proteins; Genes; Genistein; Genomics; Goals; Hormones; Human; Immunoassay; Life; Liquid substance; Mammary gland; Mass Spectrum Analysis; Measurable; Measures; Methods; Microarray Analysis; Modeling; Monitor; Nature; Organ; Pattern; Peripheral; Plasma; Population; Predisposition; Procedures; Proteins; Proteomics; Puberty; Rattus; Reference Standards; Research; Risk; Rodent; Sampling; Serum; Site; Source; Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization; Swab; Technology; Time; Tissues; Two-Dimensional Polyacrylamide Gel Electrophoresis; Urine; Vagina; Validation; Work; base; bisphenol A; cohort; density; design; environmental chemical; environmental chemical exposure; girls; human data; insight; liquid chromatography mass spectrometry; malignant breast neoplasm; member; phthalates; prepuberty; repository; research study; response

DESCRIPTION (provided by applicant): It is our goal to develop genomic and proteomic technologies for identification of biomarkers of exposure in girls and rats exposed to bisphenol A (BPA), butyl benzyl phthalate (BBP), di-2-ethylhexyl phthalate (DEHP) and genistein that are measurable in the population. Our specific aims are: 1) to use microarray technology to measure genomic biomarkers of exposure from blood serum and buffy coat, and buccal swabs from (pre)pubertal girls and rats exposed to these chemicals; 2) to develop sensitive and reproducible methods (2D-PAGE and mass spectrometry) to measure protein biomarkers of exposure in blood plasma of (pre)pubertal girls and rats that are expressing high and low levels of these chemicals. An important aspect of this application is not only in the development of new, and use of present state of the art technology for identification of biomarkers of biological responses, but in the experimental design of using a rat model of exposure and a human cohort in similar biological conditions (puberty), also exposed to the same compounds. This unique experimental design will compare the genomic and proteomic changes in a target organ, in this case the rat mammary gland with the presence of peripheral changes in the animals. Whereas in humans we can not detect the changes in the target tissue, the experimented data will give us unbiased information on the target tissue and the peripheral tissue/body fluids that will be important to bioinformatically correlate with the human data. These studies can have a double relevance by first customizing biomarkers identified in a custom array for genes and proteins and second by providing the basis for future assessing these changes for evaluating risk in a larger population. This body of work will be possible because we are utilizing already procured samples from (pre)pubescent girls identified to have high chemical exposures and will have circulating hormone concentrations as indicators of puberty and exposure. From girls (and rats) going through puberty whose urine identifies them as being exposed to high or low concentrations of specific environmental chemicals, we will measure differentially regulated genes and proteins from the blood as biological indicators of chemical exposure. In the rats, we will also measure genes and proteins in the mammary glands as a function of exposure and puberty to gain insight into how environmental chemical exposure early in life predisposes for breast cancer later in life.

描述（由申请人提供）： 我们的目标是开发基因组和蛋白质组学技术，以鉴定暴露于双苯酚A（BPA），苯二甲酸丁二烯酯（BBP），DI-2-乙基己酯（DEHP）和基因生成蛋白的女孩和大鼠的暴露生物标志物以及在人群中可以测量的基因组。我们的具体目的是：1）使用微阵列技术来测量血清和Buffy Coat暴露的基因组生物标志物，以及（前）青春期女孩和暴露于这些化学物质的（前）青春期女孩和大鼠的颊拭子； 2）开发敏感和可重复的方法（2d-Page和质谱法），以测量（前）青春期女孩和大鼠的血浆中暴露的蛋白质生物标志物，这些血浆表达了这些化学物质的高水平和低水平。该应用的一个重要方面不仅在开发新的，并使用当前最先进的技术来识别生物学反应的生物标志物，而且在使用大鼠暴露模型和在相似的生物条件下（青春期）中使用大鼠模型的实验设计，也暴露于同一化合物中。这种独特的实验设计将比较靶器官的基因组和蛋白质组学变化，在这种情况下，大鼠乳腺与动物的外围变化。尽管在人类中，我们无法检测到目标组织的变化，但实验数据将为我们提供有关目标组织和外围组织/体液的无偏信息，这对于与人类数据的生物信息相关至关重要。这些研究可以通过首先自定义基因和蛋白质自定义阵列中鉴定的生物标志物的双重相关性，其次是通过为将来评估这些变化的基础，以评估较大人群的风险。这项工作将是可能的，因为我们正在利用（前）青春期女孩采购的样本，这些样本被确定为具有高化学暴露，并且将具有循环激素浓度作为青春期和暴露的指标。从女孩（和大鼠）经历青春期的女孩中，她的尿液将其识别为暴露于高浓度或低浓度的特定环境化学物质，我们将测量从血液中差异调节的基因和蛋白质，作为化学暴露的生物学指标。在大鼠中，我们还将测量乳腺中的基因和蛋白质，这是暴露和青春期的函数，以深入了解生命早期生命早期的环境化学暴露于生命后期的乳腺癌。