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：
10538975
负责人：
David Pitt
金额：
$ 25.13万
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/10538975
关键词：
Acute Adipocytes Age Alzheimer&apos s Disease Amyotrophic Lateral Sclerosis Antibodies Astrocytes Biological Markers Blood Tests Cells Central Nervous System Diseases Cerebrospinal Fluid Chronic Clinical Trials Demyelinating Diseases 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 Human Inflammation Lesion Lymphocyte Measures MicroRNAs Multiple Sclerosis Multiple Sclerosis Lesions Oligodendroglia Parents Pathologic Processes Pathology Patient Care Patients Plasma Population Process Relapse Relapsing-Remitting Multiple Sclerosis Sampling Secondary Progressive Multiple Sclerosis Specificity Testing Vesicle base biomarker discovery 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是多发性硬化症中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，很难在体内量化。这是对生物标志物的重要需求，可以可靠地反映这些过程。星形胶质细胞高 MS中CNS病理学的敏感指标和各种病理过程的活跃驱动因素。喜欢大多数细胞，星形胶质细胞秘密一类称为外泌体的超质微泡。因为外泌体含量随着父单元的功能状态的变化，星形胶质细胞外泌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。我们已经制定了一种隔离星形胶质细胞的策略基于谷氨酸/天冬氨酸转运蛋白（GLAST）的组合表达的患者血浆外泌体和神经胶质原纤维酸性蛋白（GFAP）。在此提案中，我们正在探索星形胶质细胞衍生的外泌体作为一个 MS中急性脱髓鞘和继发进展的生物标志物发现平台。在特定目标1中，我们将全面验证Glast+/GFAP+外泌体是星形胶质细胞衍生的。在特定的目标2中，我们将探索等离子衍生的Glast+/GFAP+外泌体的实用性，可为两个不同的MS提供生物标志物疾病状态 - 急性白质脱髓鞘和MS进展。为此，我们将介绍外泌体 MS患者具有增强毒品病变和继发性进行性的MS患者的miRNA含量 MS并确定特定于每种条件的miRNA签名。识别基于外泌体的病变形成和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，我们将在较大的MS患者队列中验证这些生物标志物。