Proteomic determination of arsenical action

砷作用的蛋白质组学测定

基本信息

批准号：
6998064
负责人：
PARTHA BASU
金额：
$ 5.57万
依托单位：
UNIVERSITY OF PITTSBURGH AT PITTSBURGH
依托单位国家：
美国
项目类别：
财政年份：
2005
资助国家：
美国
起止时间：
2005-08-01 至 2006-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/6998064
关键词：
angiogenesis arsenic biological signal transduction cardiovascular disorder cell differentiation cytotoxicity embryonic stem cell matrix assisted laser desorption ionization muscle cells posttranslational modifications proteomics tissue /cell culture vascular smooth muscle

项目摘要

DESCRIPTION (provided by applicant): The cardiovascular diseases caused by As(lll)-compounds, such as hypertension, peripheral vascular disease, and ischemic heart disease, share common components of vascular remodeling and inappropriate proliferative responses in the vessel walls. Sub-chronic (ca. 5 weeks) exposures of mice to low levels of arsenic in drinking water enhanced neovascularization of Matrigel implants and differentially affected cardiac angiogenic gene expression. While these effects are known for inorganic arsenic, precious little is known regarding the effects of widely used agricultural organic arsenic compounds. This proposal focuses on defining mechanisms for the toxic effects of 3-nitro-4-hydroxy phenyl arsonic acid (roxarsone) in the vasculature. There are two specific aims of the proposed research: 1) to investigate the role of roxarsone and related aromatic arsenic compounds in promoting angiogenesis. This will be tested in a novel mouse embryonic stem cell assay that measures vessel development in Matrigel. 2) To use a novel proteomic approach to investigate the transient effects of arsenic and arsenicals on cell signaling proteins. We will use new chemical labeling methods, 2-dimensional protein separation, and matrix assisted laser desorption ionization time of flight mass spectrometry (MALDI-TOF-MS) to identify proteins that are either differentially expressed, post-translationally modified, or directly bound to arsenicals when vascular smooth muscle cells are exposed to low, environmentally relevant levels of arsenic or roxarsone. These studies will greatly expand the understanding of the biochemical activation of vascular cell signaling that is relevant to arsenic-related vascular diseases.

描述（申请人提供）：由As(III)-化合物引起的心血管疾病，例如高血压、外周血管疾病和缺血性心脏病，具有血管重塑和血管壁不适当增殖反应的共同成分。小鼠亚慢性（约 5 周）暴露于饮用水中低水平砷会增强基质胶植入物的新血管形成，并对心脏血管生成基因表达产生不同影响。虽然无机砷的这些影响是已知的，但对于广泛使用的农业有机砷化合物的影响却知之甚少。该提案的重点是确定 3-硝基-4-羟基苯基胂酸（洛克沙胂）在脉管系统中的毒性作用机制。该研究有两个具体目的：1）研究洛克沙胂和相关芳香砷化合物在促进血管生成中的作用。这将在一种新型小鼠胚胎干细胞测定中进行测试，该测定可测量基质胶中的血管发育。 2) 使用一种新的蛋白质组学方法来研究砷和砷化合物对细胞信号蛋白的瞬时影响。我们将使用新的化学标记方法、二维蛋白质分离和基质辅助激光解吸电离飞行时间质谱 (MALDI-TOF-MS) 来识别差异表达、翻译后修饰或直接结合的蛋白质当血管平滑肌细胞暴露于与环境相关的低水平的砷或洛克沙胂时，就会产生砷。这些研究将极大地扩展对与砷相关血管疾病相关的血管细胞信号转导生化激活的理解。