Astrocyte-specific exosomes as a platform for biomarker discovery in multiple sclerosis

星形胶质细胞特异性外泌体作为多发性硬化症生物标志物发现的平台 急性和慢性神经炎症是MS病理学的主要驱动因素，其难以在体内量化。 因此，对于可靠地反映这些过程的生物标志物存在显著未满足的需求。星形胶质细胞高度 CNS病理学的敏感指标和MS中广泛病理过程的主动驱动因素。 大多数细胞、星形胶质细胞分泌一类称为外来体的超小微泡。因为外泌体的成分 随着亲本细胞功能状态的变化，星形胶质细胞外泌体的货物可以提供一个窗口， 星形胶质细胞的特定激活状态。我们已经开发出一种策略， 来自患者血浆的外泌体，基于谷氨酸/天冬氨酸转运蛋白（GLAST）的组合表达 和胶质细胞酸性蛋白（GFAP）。在这项提议中，我们正在探索星形胶质细胞来源的外泌体作为一种新的生物学方法。 在MS急性脱髓鞘和继发性进展中发现生物标志物的平台。在具体目标1中，我们 将全面验证GLAST +/GFAP+外泌体是星形胶质细胞衍生的。具体目标2： 探索血浆来源的GLAST +/GFAP+外泌体为两种不同的MS提供生物标志物的效用 疾病状态-急性白色物质脱髓鞘和MS进展。为此，我们将分析外泌体 伴有钆增强白色病变和继发性进展性MS患者的miRNA含量 MS和确定特定于每种条件的miRNA签名。基于外泌体的识别 损伤形成和MS进展的生物标志物将构成MS患者护理的重大进步 和临床试验。在后续研究中，我们将在更大的MS患者队列中验证这些生物标志物。

Astrocyte-specific exosomes as a platform for biomarker discovery in multiple sclerosis. Acute and chronic neuroinflammation are major drivers of MS pathology, which are difficult to quantify in vivo. Thus, there is a significant unmet need for biomarkers that reliably reflect these processes. Astrocytes are highly sensitive indicators of CNS pathology and active drivers of a wide range of pathological processes in MS. Like most cells, astrocytes secrete a class of ultrasmall microvesicles termed exosomes. Because exosomal content changes with the functional state of the parent cell, the cargo of astrocyte exosomes may provide a window into the specific activation states of astrocytes. We have developed a strategy for isolating astrocytespecific exosomes from patient plasma, based on the combined expression of glutamate/aspartate transporter (GLAST) and glial fibrillary acidic protein (GFAP). In this proposal, we are exploring astrocyte-derived exosomes as a platform for biomarker discovery in acute demyelination and secondary progression in MS. In specific aim 1, we will comprehensively validate that GLAST+/GFAP+ exosomes are astrocyte-derived. In specific aim 2, we will explore the utility of plasma-derived GLAST+/GFAP+ exosomes to provide biomarkers for two distinct MS disease states – acute white matter demyelination and MS progression. To this end, we will profile the exosomal miRNA content of MS patients with gadolinium-enhancing white matter lesions and with secondary progressive MS and determine the miRNA signatures that are specific to each condition. Identifying exosome-based biomarkers for lesion formation and MS progression would constitute a major advancement for MS patient care and clinical trials. In follow-up studies, we will validate these biomarkers in larger MS patient cohorts.