Biomarkers for Niemann-Pick C Disease

生物医学的一个主要目标是识别生物液中的疾病生物标记物，这些标记物可用于疾病筛查、早期诊断和治疗方法的监测。到目前为止，溶酶体储存疾病(LSD)的这种生物标记物的开发还没有成功。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，也是绝对必要的，特别是对于那些具有神经退行性表型的LSD。 大多数生物标记物研究都集中在比较正常和疾病状态下的血浆蛋白。这种方法的主要问题是血浆蛋白质组的复杂性，即可以在血浆中发现的循环蛋白质。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记蛋白：外切体。 外切体是唯一适合于LSD病生物标记物的鉴定方法。它们是从晚期内体的膜中提取的小囊泡，内体中含有通常在内体中发现的一组蛋白质。许多细胞分泌外切体，因此很可能从细胞分泌物中分离和鉴定其中所含的蛋白质。由于LSD经常出现内体/溶酶体隔间的异常，我们假设Exosome将反映派生/分离LSD的细胞所表现出的疾病缺陷所特有的蛋白质和脂肪变化。 在这里，我们建议：1)测试来自Neimann-Pick C1细胞的外切体将具有独特的蛋白质和/或脂肪识别符(生物标记物)的预测，这些生物标记物将使它们与正常细胞的那些细胞区分开来；2)评估这些潜在的生物标记物是否可以在包括血浆、尿液和脑脊液在内的生物液中检测到；以及3)测试葡萄糖代谢的变化与NPC1疾病严重程度相关并可用于监测疾病进展的预测。 简而言之，这种新的方法可以促进LSD生物标志物的有效发现，并为我们提供下一步开发可以在临床试验中以有意义的方式评估的治疗方法。

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.