Effects of Environmental Estrogen Exposure on Spontaneous Copy Number Variation

项目概要/摘要 我的长期目标是在一所研究型大学获得一个教职，这样我就可以继续 独立研究环境雌激素如何影响人类。短期目标 是确定环境雌激素是否能够改变脊椎动物的基因组。我的直系 目标是发展必要的技能和培训，主要是阵列比较基因组 杂交（CGH）和吗啉代注射，以开发一个独立的研究计划 使用这些方法和技巧。虽然计算全息图的使用不是一项新技术，但它作为一种 确定正常个体之间是否存在基因组变化的方法 最近才被使用。李博士是这项技术的先驱，在他的指导下， 布里格姆妇女医院，以及高度协作，教育环境，在 哈佛医学院，我将被允许学习和掌握它的使用。我完全相信这是 一个理想的环境，以促进我的职业生涯，并利用这个奖项，成为和独立 调查员环境雌激素是环境中的化学物质， 天然雌激素这些化学物质包括一系列广泛的化合物， 例如DDT、双酚A等增塑剂和人类生育等药物 控制药丸（17 <$-乙炔基炔雌醇; EE 2）。尽管它们与环境相关， 和怀疑对人类和动物的影响，没有研究已经完成，以确定 这些化学物质是否会引起基因组水平的变化。本研究的目的是 确定环境相关浓度的EE 2是否能够诱导基因组 水平变化使用模式生物斑马鱼。基因组变化将被确定为 诱导拷贝数变异的自发或从头变化。其他研究 以确定自发性CNV是如何产生的，并评价EE 2如何改变或 破坏了旨在防止这种变化的DNA修复机制。

Project Summary/Abstract My long-term goal is to obtain a faculty position at a research university so that I can continue to independently investigate how environmental estrogens affect humans. The short-term goal is to determine if environmental estrogens are able to alter vertebrate genomes. My immediate goal is to develop the skills and training necessary, primarily array comparative genomic hybridization (CGH) and morpholino injection, to develop an independent research program using these approaches and skills. While the use of CGH is not a new technique, its use as a method of determining whether genomic changes are present between normal individuals has only recently been used. Dr. Lee pioneered this technique and under his mentorship at Brigham and Women's Hospital, and the highly collaborative, educational environment at Harvard Medical School, I will be allowed to learn and master its use. I fully believe that this is an ideal environment to advance my career and use this Award to become and independent investigator. Environmental estrogens are chemicals in the environment that alter or interact with native estrogen. These chemicals include a broad array of compounds from pesticides such as DDT, plasticizers such as bisphenol A and pharmaceuticals such as human birth control pills (17¿-ethynylestradiol; EE2). Despite their relevance in the environment and known and suspected effects on humans and animals, no studies have been done to determine whether these chemicals induce genomic level changes. The purpose of this study is to determine whether environmentally relevant concentrations of EE2 are able to induce genomic level changes using the model organism zebrafish. Genomic changes will be determined as the induction of spontaneous, or de novo, changes in copy number variation. Additional studies will be performed to determine how spontaneous CNVs arise and evaluate how EE2 alters or impairs the DNA repair mechanisms that are designed to prevent such changes.