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。

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.