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Metabolic markers for mitochondrial function

线粒体功能的代谢标志物

基本信息

批准号：
8485608
负责人：
Cynthia Therese McMurray
金额：
$ 43.29万
依托单位：
UNIVERSITY OF CALIF-LAWRENC BERKELEY LAB
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：
2011-09-20 至 2016-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8485608
关键词：
1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine 1-Methyl-4-phenylpyridinium Abbreviations Address Adenosine Triphosphate Affect Age Amino Acids Animal Model Animals Biological Markers Biology Blood Blood - brain barrier anatomy Brain Calcium Cells Chronic Chronic Disease Clinical Markers Complex Cytosol Defect Detection Disease Early Diagnosis Environment Environmental Exposure Exposure to Functional disorder Heterogeneity Human Individual Injury Intervention Lead Link Mass Spectrum Analysis Measurable Measurement Measures Metabolic Metabolic Diseases Metabolic Marker Methodology Mitochondria Modeling Monoamine Oxidase Nanostructures Noise Oxidation-Reduction Oxidative Phosphorylation Pattern Preventive Intervention Production Property Propionic Acids Resolution Respiration Rodent Rotenone Sampling Signal Transduction Sorting - Cell Movement Staging Symptoms Synaptosomes System Techniques Technology Testing Tissues Toxic Environmental Substances Toxic effect Toxicant exposure Toxin Ubiquitin Urine Variant base brain cell cell motility cell type dopamine transporter functional decline in vivo mitochondrial dysfunction mouse model multicatalytic endopeptidase complex nervous system disorder new technology oxidative damage prevent response tool

项目摘要

ABSTRACT Mitochondrial (MT) dysfunction is a factor in numerous chronic diseases and the toxicity related to environmental exposures, but early deficits in MT function are difficult to detect. Current clinical markers for mitochondrial dysfunction typically detect only advanced symptoms of tissue injury and disease, yet the sensitivity to detect mild MT dysfunction and heterogeneity within tissue has hampered robust identification of meaningful biomarkers at early stages. Mitochondrial biology is variable; and chronic, low level MT dysfunction may be below the detection sensitivity of many techniques. We need new tools to enhance the mechanistic understanding of environmentally-induced mitochondrial toxicity at early stages to enable prevention and intervention. To address this problem, we have developed and applied a new technology for single cell mass spectrometry, called Nanostructure-Initiator Mass Spectrometry (NIMS). NIMS has both the single cell resolution (1-10 ¿m) and the high sensitivity (attomolar) needed to detect early biomarkers of MT dysfunction as metabolic "signatures" in individual cells. NIMS offers a number of advantages over standard mass spectrometry, including (1) ultra-high sensitivity, (2) high selectivity, and (3) single cell resolution to reduce sample complexity. We apply NIMS to identify metabolic signatures for early MT dysfunction in the brain and blood of diseased animals or animals treated with environmental toxins at "subclinical" levels. In Aim 1, we use NIMS to generate metabolic signatures for MT decline. In Aim 2, we will functionally test whether the biomarker reflects functional changes in MT or MT within the context of the cell. NIMS can be applied to any tissue and any cell type, to quantitatively sort out complex changes that occur in dynamic cellular environments, and minimizes the inherent system heterogeneity that has confounded efforts in detecting meaningful markers of MT decline.

摘要