Biomarkers for Niemann-Pick C Disease

描述（由申请人提供）：生物医学的主要目标是识别生物液体中的疾病生物标志物，用于疾病筛查，早期诊断和治疗方法的监测。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。大多数生物标志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，即可以在血浆中循环的蛋白质。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：外泌体。外泌体特别适合于LSD疾病生物标志物的鉴定。它们是来自晚期核内体膜的小泡，含有通常在核内体中发现的一组蛋白质。许多细胞分泌外泌体，因此很可能从细胞分泌物中分离和鉴定出其中所含的蛋白质。由于lds经常在内体/溶酶体区室中出现异常，我们假设外泌体反映了它们来源于/分离的细胞所表现出的疾病缺陷的特异性蛋白质和脂质变化。

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.