Plasma neuronal-derived exosomes are biomarkers of HIV cognitive impairment

血浆神经元来源的外泌体是 HIV 认知障碍的生物标志物

• 批准号: 10577822
• 负责人: Lynn PULLIAM
• 金额: $ 58.94万
• 依托单位: NORTHERN CALIFORNIA INSTITUTE/RES/EDU
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-05-15 至 2025-02-28
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10577822
• 关键词: Acquired Immunodeficiency Syndrome; Affect; Aftercare; Age; Aging; Alzheimer' s Disease; Amyloid beta-Protein; Antibodies; Antigens; Basic Science; Biological Assay; Biological Markers; Brain; Cell surface; Cells; Chronic; Cognition; Cognitive; Cohort Studies; Communicable Diseases; Diagnosis; Discipline; Funding; Goals; HIV; HIV Infections; HIV Seronegativity; HIV diagnosis; HIV-associated cognitive impairment; HIV-associated neurocognitive disorder; HMGB1 gene; Hand; Health; Image; Impaired cognition; Impairment; Incubated; Individual; Injury; Label; Light; Liquid substance; Longitudinal cohort; Mass Spectrum Analysis; Monitor; Neural Cell Adhesion Molecule L1; Neurocognitive Deficit; Neurology; Neurons; Neurosciences Research; Oligonucleotides; Parents; Pathogenesis; Pathologic; Persons; Plasma; Probability; Procedures; Prognosis; Proteins; Radiology Specialty; Recovery; Techniques; Technology; Testing; Time; United States National Institutes of Health; Virus Replication; Woman; Women' s Interagency HIV Study; aged; biomarker selection; brain health; clinical diagnosis; cohort; differential expression; exosome; extracellular vesicles; improved; interdisciplinary approach; interest; men; microvesicles; mild cognitive impairment; neural; neurocognitive disorder; neurofilament; neuroimaging; neuroimaging marker; neuroinflammation; novel therapeutics; peripheral blood; protein biomarkers

Cognitive impairment in chronic well-controlled HIV infection continues to affect from 30%-60% of individuals. Mechanisms are still unknown but probably associated with continued neuroinflammation. Biomarkers for cognitive impairment have been inconsistent although neuroimaging has emerged as a possibility. Unfortunately, imaging is expensive with limited access. Exosomes are small microvesicles shed from most all cells under normal and pathologic conditions. The cellular cargo packaged into exosomes can represent the state of the parent cell. We have isolated neuron-derived exosomes (NDE) in plasma using a 2-step isolation procedure and a cell surface neuron specific antibody. We have shown in a recently completed R21 using mass spectroscopy that NDE are rich in over 50 neuronal proteins. In addition, using proximity extension analysis (PEA) for neurology biomarkers, we identified an additional 28 proteins that were present. At least 7 proteins were statistically significantly differentially expressed in HIV infection alone, neurocognitive impairment in HIV+ women versus men and 1 protein that was significantly correlated with age and impairment. Several NDE proteins correlate with cognitive domains and several differentiate HIV cognitive impairment from Alzheimer’s disease. Our overall hypothesis is that NDE can be used to diagnose cognitive impairment in HIV infection and that men and women have different proteins in NDE that will influence diagnosis and treatment. We further plan to differentiate mild cognitive impairment with that associated with a pre-Alzheimer’s mild cognitive impairment (MCI) diagnosis. To test this hypothesis, we propose the following Specific Aims: (1) Select and verify a set of neuronal exosome proteins that predict and diagnose HIV cognitive impairment with aging in women and men, (2) Determine whether neuronal exosome cargo can differentiate HIV-associated cognitive impairment from mild MCI/Alzheimer’s disease (3) Correlate HIV NDE protein targets and cognitive domains associated with neuroimaging markers of injury and (4) Establish a rapid ultrasensitive assay using verified neuronal exosome target proteins for diagnosis of HIV cognitive impairment in a longitudinal cohort. We will utilize a multidisciplinary approach that includes basic research of protein targets correlated with cognitive domains and clinical diagnosis using neuroimaging correlation with selected biomarker proteins. These results will have major impact on treatment and cure of HIV in the brain as fluid biomarkers are discovered and the health of the neuron can be assessed in “real time.”

慢性良好控制的HIV感染的认知障碍继续影响30％-60％ 个人。机制仍然未知，但可能与持续有关 神经炎症。认知障碍的生物标志物并不一致 神经影像已经成为一种可能性。不幸的是，成像很昂贵，有限 使用权。外泌体是在正常和病理下大多数细胞中脱离的小微泡 状况。包装到外泌体中的细胞货物可以代表母细胞的状态。 我们使用2步隔离程序在血浆中具有孤立的神经衍生的外泌体（NDE） 和细胞表面神经元特异性抗体。我们已经在最近完成的R21中显示 NDE富含50多个神经元蛋白的质谱法。另外，使用接近度 神经病学生物标志物的扩展分析（PEA），我们确定了另外的28种蛋白质 在场。在HIV中，至少7种蛋白质在统计学上的表达显着差异 仅感染，艾滋病毒+女性与男性中的神经认知障碍和1个蛋白质 与年龄和障碍显着相关。几种NDE蛋白与认知相关 领域和几个区分HIV认知障碍与阿尔茨海默氏病。我们的 总体假设是NDE可用于诊断HIV感染中的认知障碍 男性和女性在NDE中具有不同的蛋白质，会影响诊断和 治疗。我们进一步计划将轻度认知障碍与与 前Alzheimer的轻度认知障碍（MCI）诊断。为了检验这一假设，我们提出了 以下特定目的：（1）选择并验证一组预测的神经元外泌体蛋白 并诊断男女衰老的艾滋病毒认知障碍，（2）确定是否是否 神经元外泌体货物可以区分与中间的HIV相关认知障碍 MCI/阿尔茨海默氏病（3）相关的HIV NDE蛋白靶标和认知领域 与损伤的神经成像标记有关，（4）建立快速的超敏化测定法 使用经过验证的神经元外部靶蛋白来诊断A 纵向队列。我们将利用一种多学科方法，包括 蛋白质靶标与认知领域和使用神经成像相关 与选定的生物标志物蛋白的相关性。这些结果将对治疗产生重大影响 当发现液体生物标志物，神经元的健康状况可以使大脑中的艾滋病毒治愈 可以进行“实时评估”。