Biomarkers for Niemann-Pick C Disease

尼曼-匹克 C 病的生物标志物

• 批准号: 7887409
• 负责人: YIANNIS A IOANNOU
• 金额: $ 42.38万
• 依托单位: ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI
• 依托单位国家: 美国
• 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/7887409
• 关键词: Biological; Biological Markers; Cell secretion; Cells; Clinical Trials; Complement component C1s; Complex; Defect; Development; Disease; Disease Progression; Early Diagnosis; Endosomes; Exhibits; Goals; Intervention; Lipids; Liquid substance; Lysosomal Storage Diseases; Membrane; Monitor; Normal Cell; Plasma; Plasma Proteins; Proteins; Proteome; Safety; Screening procedure; Severity of illness; System; Testing; Therapeutic; Urine; Vesicle; glucose metabolism; late endosome; neurodegenerative phenotype; novel strategies; public health relevance; therapy development

DESCRIPTION (provided by applicant): 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 LDSs 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. PUBLIC HEALTH RELEVANCE: A major goal in biomedicine is the identification of disease biomarkers in biological fluids that can be used as screening, early diagnosis, and monitoring of therapeutic approaches. The availability of such biomarkers for lysosomal storage as is are currently lacking and are needed to evaluate the safety and efficacy of disease intervention and provide us with the next step in developing therapies that can be objectively evaluated in clinical trials.

描述（由申请人提供）：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，这些生物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，此类溶酶体贮积症（LSD）生物标志物的开发尚未成功。 然而，这些生物标志物的可用性对于评估疾病干预措施的安全性和有效性是必要的，并且绝对是必要的，特别是对于那些具有神经退行性表型的 LSD。 大多数生物标志物研究都集中于比较正常状态和疾病状态之间的血浆蛋白。这种方法的主要问题是血浆蛋白质组的复杂性，即血浆中循环的蛋白质。 我们建立了一种新方法来识别血浆和其他液体（例如尿液）中的疾病生物标志物。 这种独特的方法首先在不太复杂的系统（外泌体）中识别潜在的生物标志物蛋白质，从而消除了血浆蛋白质组分析中固有的困难。 外泌体特别适合识别 LSD 疾病生物标志物。 它们是源自晚期内体膜的小囊泡，含有通常在内体中发现的蛋白质子集。 许多细胞分泌外泌体，因此很可能可以从细胞分泌物中分离和鉴定其中包含的蛋白质。 由于 LDS 在内体/溶酶体区室中经常出现异常，因此我们假设外泌体将反映其衍生/分离的细胞所表现出的疾病缺陷特有的蛋白质和脂质变化。 在这里，我们建议：1）测试来自 Neimann-Pick C1 细胞的外泌体将具有独特的蛋白质和/或脂质标识符（生物标志物）的预测，这些标识符将它们与正常细胞的外泌体区分开来； 2) 评估这些潜在的生物标志物是否可以在血浆、尿液和脑脊液等生物体液中检测到； 3) 测试葡萄糖代谢变化与 NPC1 疾病严重程度相关的预测，并可用于监测疾病进展。 简而言之，这种新方法可以促进 LSD 生物标志物的有效发现，并为我们开发可在临床试验中以有意义的方式进行评估的疗法提供下一步。 公共卫生相关性：生物医学的一个主要目标是识别生物体液中的疾病生物标志物，可用于筛查、早期诊断和监测治疗方法。 目前缺乏此类用于溶酶体储存的生物标志物，需要这些生物标志物来评估疾病干预的安全性和有效性，并为我们下一步开发可在临床试验中客观评估的疗法提供依据。