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Biomarkers for Niemann-Pick C Disease

尼曼-匹克 C 病的生物标志物

基本信息

批准号：
8460498
负责人：
YIANNIS A IOANNOU
金额：
$ 33.97万
依托单位：
ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI
依托单位国家：
美国
项目类别：
财政年份：
2010
资助国家：
美国
起止时间：
2010-05-01 至 2014-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8460498
关键词：
Biological Biological Markers Cell secretion Cells Ceramidase Clinical Trials Complex Defect Development Disease Disease Progression Early Diagnosis Endosomes Enzymes Exhibits Farber&apos s lipogranulomatosis Fingerprint Functional disorder Gluconeogenesis Glycolysis Goals Human Intervention Label Link Lipids Liquid substance Lysosomal Storage Diseases Maps Mass Spectrum Analysis Measures Membrane Metabolic Metabolic Pathway Monitor Nerve Degeneration Normal Cell Nuclear Pore Complex Oxidative Phosphorylation Pathogenesis Pathway interactions Patients Plasma Plasma Proteins Proteins Proteome Proteomics Safety Sampling Severity of illness Source Sphingomyelinase Symptoms System Testing Therapeutic Urine Vesicle glucose metabolism late endosome mouse model neurodegenerative phenotype neuropathology novel strategies prototype screening therapy development

项目摘要

A major goal in biomedicine is the identification of disease biomarkers in biological fluids that can be used in disease screening, early diagnosis, and monitoring of therapeutic approaches. The development of such biomarkers for lysosomal storage diseases (LSDs) has not been successful thus far. However, the availability of these biomarkers is needed and absolutely necessary to evaluate the safety and efficacy of disease interventions, especially for those LSDs with a neurodegenerative phenotype. Most biomarker studies have focused on comparing plasma proteins between a normal and a disease state. The major problem with this approach is the complexity of the plasma proteome, i.e. the proteins that can be found circulating in plasma. We have established a novel approach for identifying disease biomarkers in plasma and other fluids such as urine. This unique approach eliminates the difficulties inherent in analysis of the plasma proteome by first identifying potential biomarker proteins in a less complex system: the exosome. Exosomes are uniquely suited for the identification of the LSD disease biomarkers. They are small vesicles derived from the membranes of late endosomes that contain a subset of proteins normally found in endosomes. Many cells secrete exosome and thus it is likely that the proteins contained within them can be isolated and identified from cellular secretions. Because LSDs often present with abnormalities in endosomal/lysosomal compartments, we hypothesize that exosome will reflect protein and lipid changes specific to the disease defect exhibited by the cell from which they are derived/isolated. Here, we propose to: 1) test the prediction that exosomes from Neimann-Pick C1 cells will have unique protein and/or lipid identifiers (biomarkers) that will distinguish them from those of normal cells; and 2) evaluate whether these potential biomarkers are detectable in biological fluids including plasma, urine and CSF; and 3) test the prediction that changes in glucose metabolism correlate with NPC1 disease severity and can be used to monitor disease progression. In short, this new approach could facilitate the efficient discovery of LSD biomarkers and provide us with the next step in developing therapies that can be evaluated a in meaningful way in clinical trials.

生物医学的一个主要目标是识别生物液体中的疾病生物标志物，这些标志物可用于疾病筛查、早期诊断和治疗方法监测。迄今为止，此类溶酶体贮积病（lsd）生物标志物的开发尚未取得成功。然而，这些生物标志物的可用性对于评估疾病干预的安全性和有效性是必要的，特别是对于那些具有神经退行性表型的lsd。