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Plasma Mitochondrial Peptide Assays as Biomarkers of Environmental Toxin Exposure

血浆线粒体肽测定作为环境毒素暴露的生物标志物

基本信息

批准号：
8697052
负责人：
Pinchas Cohen
金额：
$ 36.53万
依托单位：
UNIVERSITY OF SOUTHERN CALIFORNIA
依托单位国家：
美国
项目类别：
财政年份：
2011
资助国家：
美国
起止时间：
2011-09-19 至 2016-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8697052
关键词：
Acute Amino Acids Animals Biological Biological Assay Biological Markers Blood Circulation Brain Cardiac Myocytes Cell Line Cell Survival Cells Chromosomes Chronic Chronic Disease Clinical Research Data Development Disease Dose Doxorubicin Early Intervention Embryo Environmental Exposure Enzyme-Linked Immunosorbent Assay Exhibits Exposure to Family Female Fibroblasts Functional disorder Future Genetic Predisposition to Disease Genus Hippocampus Goals Grant Health Heart Mitochondria Human In Vitro Indirect Calorimetry Life Life Style Longitudinal Studies Measurable Measures Metabolism Methods Mitochondria Mitochondrial DNA Monitor Mus Names Neurons Nuclear Proteins Open Reading Frames Organ Oxygen Consumption Peptides Plasma Population Research Preventive Intervention Production Proteins Public Health RNA, Ribosomal, 16S Reaction Time Research Role Rotenone Site Staging Technology Tissues Toxic Environmental Substances Toxin Translating Vascular Endothelial Cell assay development human disease humanin in vivo innovation mitochondrial dysfunction mouse model novel tool

项目摘要

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. We 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. We propose 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. Our goals in this project include continued development and characterization of ELISA assays for humanin and SHLPs in humans and mice. Our preliminary data demonstrates abnormalities in their levels in human diseases states associated with mitochondrial dysfunction and in mice subjected to acute doxorubicin exposure. We will also examine the in vitro effects of the mitochondrial toxins Rotenone and Doxorubicin on cell lines and primary cultures in terms of their effect on the expression and production of mitochondrial peptides, and correlate this to measures of mitochondrial function. Finally we will determine 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. We will assess changes in circulating levels of MDPs following toxin exposure and correlated them 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.