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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

基本信息

批准号：
10645224
负责人：
David Pitt
金额：
$ 20.94万
依托单位：
YALE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-07-01 至 2024-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10645224
关键词：
Acute Adipocytes Age Alzheimer&apos s Disease Amyotrophic Lateral Sclerosis Antibodies Aspartate Astrocytes Biological Markers Blood Tests Cells Central Nervous System Diseases Cerebrospinal Fluid Chronic Clinical Trials Demyelinations Disease Disease Progression Enhancing Lesion Enzyme-Linked Immunosorbent Assay Epithelial Cells Exhibits Follow-Up Studies GLAST Protein Gadolinium Gender Glial Fibrillary Acidic Protein Glutamate-Ammonia Ligase Glutamates Human Inflammation Lesion Lymphocyte Measures MicroRNAs Multiple Sclerosis Multiple Sclerosis Lesions Oligodendroglia Parents Pathologic Processes Pathology Patient Care Patients Plasma Population Process Relapsing-Remitting Multiple Sclerosis Sampling Secondary Progressive Multiple Sclerosis Specificity Testing Vesicle biomarker discovery biomarker validation brain cell cell type cohort differential expression disability exosome in vivo interstitial cell microvesicles multiple sclerosis patient nanoparticle nervous system disorder neuroinflammation peripheral blood potential biomarker response white matter

项目摘要

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.

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。