Plasma Mitochondrial Peptide Assays as Biomarkers of Environmental Toxin Exposure

描述(申请人提供)：血浆线粒体多肽分析作为环境毒素暴露的生物标志物线粒体功能障碍与许多慢性疾病有关，线粒体是许多环境毒素的靶标，但尚无有效的循环标志物可用于评估环境暴露引起的线粒体功能或功能障碍。线粒体含有近千种核源蛋白质，但线粒体染色体只编码13种蛋白质。该团队最近发现了一类新的线粒体衍生多肽(MDP)。这些包括人蛋白和六个我们称为SHLPs的人蛋白样肽，它们在体外和体内都能有效地调节细胞的存活和代谢过程。有人认为，循环中的人蛋白和其他MDP的酶联免疫吸附试验是线粒体功能的可靠标记物，并将作为与环境侮辱相关的线粒体功能障碍的早期指标。该项目的目标包括在人类和小鼠中继续开发和鉴定人蛋白和SHLP的酶联免疫吸附试验。初步数据显示，在与线粒体功能障碍相关的人类疾病状态和急性阿霉素暴露的小鼠中，它们的水平异常。线粒体毒素鱼藤酮和阿霉素在体外对细胞系和原代培养细胞的影响也将从它们对线粒体肽的表达和产生的影响方面进行检测，并将其与线粒体功能的测量相关联。最后，在短期和长期研究中，确定暴露于线粒体毒素鱼藤酮和阿霉素的小鼠的血浆线粒体肽水平与线粒体功能障碍的关系。将评估毒素暴露后循环中MDP水平的变化，并将其与牺牲动物的这些多肽的器官特异性水平以及体内和体外线粒体功能分析相关联。总之，这些研究将确立循环线粒体多肽分析作为环境毒素暴露引起的线粒体功能障碍的标记的实用性，并将为未来的研究创建一套关键的工具，以监测暴露在此类毒素下的人类。这将能够预防和干预与线粒体功能障碍相关的疾病的亚临床阶段。

DESCRIPTION (provided by applicant): Plasma Mitochondrial Peptide Assays as Biomarkers of Environmental Toxin Exposure Mitochondrial dysfunction is associated with a number of chronic diseases and mitochondria are a target for numerous environmental toxins, but no validated circulating markers are available for assessing mitochondrial function or dysfunction resulting from environmental exposures. Mitochondria contain nearly a thousand proteins of nuclear origin, but the mitochondrial chromosome only encodes 13 proteins. This team recently identified a family of novel mitochondrial derived peptides (MDPs). These include humanin and six humanin-like peptides we named SHLPs, which potently regulate cell survival and metabolic processes in vitro and in vivo. It is proposed that ELISA assays for circulating humanin and other MDPs represent robust markers of mitochondrial function and will serve as early indicators of mitochondrial dysfunction associated with environmental insults. The goals in this project include continued development and characterization of ELISA assays for humanin and SHLPs in humans and mice. Preliminary data demonstrates abnormalities in their levels in human diseases states associated with mitochondrial dysfunction and in mice subjected to acute doxorubicin exposure. The in vitro effects of the mitochondrial toxins Rotenone and Doxorubicin on cell lines and primary cultures will also be examined in terms of their effect on the expression and production of mitochondrial peptides, and correlate this to measures of mitochondrial function. Finally a determination of the relationship between plasma levels of mitochondrial peptides and mitochondrial dysfunction, in mice exposed to the mitochondrial toxins Rotenone and Doxorubicin in short term and long-term studies. Changes will be assessed in circulating levels of MDPs following toxin exposure and correlated to organ-specific levels of these peptides from sacrificed animals as well as to in vivo and ex vivo analysis of mitochondrial function. Together, these studies will establish the utility of circulating mitochondrial peptide assays as markers of mitochondrial dysfunction resulting from environmental toxin exposure and will create a critical set of tools for future studies to monitor humans exposed to such toxins. This will enable prevention and intervention in subclinical stages of diseases related to mitochondrial dysfunction.