Biomarkers for Niemann-Pick C Disease

生物医学的一个主要目标是鉴定生物流体中的疾病生物标志物，其可用于疾病筛查、早期诊断和治疗方法的监测。迄今为止，溶酶体贮积病（LSD）的此类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是需要的，并且对于评估疾病干预的安全性和有效性是绝对必要的，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集中在比较正常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，即可以在血浆中循环发现的蛋白质。我们已经建立了一种新的方法来识别血浆和其他液体（如尿液）中的疾病生物标志物。这种独特的方法消除了血浆蛋白质组分析中固有的困难，首先在一个不太复杂的系统中识别潜在的生物标志物蛋白：外泌体。 外泌体是唯一适用于鉴定LSD疾病生物标志物。它们是来自晚期内体膜的小囊泡，含有通常在内体中发现的蛋白质的子集。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LSD通常在内体/溶酶体区室中存在异常，因此我们假设外泌体将反映它们所来源/分离的细胞所表现出的疾病缺陷特异性的蛋白质和脂质变化。 在此，我们建议：1）测试来自Neimann-Pick C1细胞的外来体将具有独特的蛋白质和/或脂质标识符的预测2）评估这些潜在的生物标志物在生物流体（包括血浆、尿液和CSF）中是否可检测;和3）测试葡萄糖代谢的变化与NPC 1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，并为我们开发可以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。

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.