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

星形胶质细胞特异性外切体作为多发性硬化症生物标记物发现的平台。 急性和慢性神经炎是MS病理的主要驱动因素，在体内很难量化。 因此，对可靠反映这些过程的生物标记物的需求尚未得到满足。星形胶质细胞高度 多发性硬化患者中枢神经系统病理的敏感指标和多种病理过程的活跃驱动因素 大多数细胞、星形胶质细胞都会分泌一类被称为外体的超小微泡。因为胞外体内容物 随着亲本细胞功能状态的变化，星形胶质细胞外切体的货物可能会提供一个窗口 星形胶质细胞的特定激活状态。我们已经开发了一种分离星形胶质细胞特异性的策略 基于谷氨酸/天冬氨酸转运体(GLAST)联合表达的患者血浆外切体 和胶质纤维酸性蛋白(GFAP)。在这个提案中，我们正在探索星形细胞衍生的外切体作为一种 MS急性脱髓鞘和继发性进展的生物标记物发现平台 将全面验证GLAST/GFAP外切体是星形胶质细胞来源的。在具体目标2中，我们将 探索血浆来源的GLAST/GFAP外切体为两种不同的多发性硬化症提供生物标志物的作用 疾病状态-急性白质脱髓鞘和多发性硬化症进展。为此，我们将介绍Exosomal 多发性硬化症患者脑白质Gd增强和继发性进展期的miRNA含量 Ms，并确定特定于每种情况的miRNA签名。鉴定基于外切体的 病变形成和多发性硬化症进展的生物标志物将构成多发性硬化症患者护理的重大进步 和临床试验。在后续研究中，我们将在更大的多发性硬化症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.