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.”

慢性控制良好的艾滋病毒感染中的认知障碍继续影响30%-60% 个人的。机制尚不清楚，但可能与持续的 神经炎症认知障碍的生物标志物一直不一致， 神经成像已经成为一种可能。不幸的是，成像是昂贵的， access.外来体是在正常和病理条件下从大多数细胞脱落的小微泡。 条件包装到外泌体中的细胞货物可以代表亲本细胞的状态。 我们使用两步分离程序分离了血浆中的神经元来源的外泌体（NDE 和细胞表面神经元特异性抗体。我们在最近完成的R21中使用 NDE富含超过50种神经元蛋白质。此外，利用邻近 通过对神经学生物标志物的扩展分析（PEA），我们确定了另外28种蛋白质， 都在场至少有7个蛋白质在HIV中差异表达， 单独感染，HIV+女性与男性相比的神经认知障碍， 与年龄和损伤显著相关。几种NDE蛋白与认知功能相关 领域和几个区分艾滋病毒认知障碍从阿尔茨海默病。我们 总体假设是NDE可用于诊断HIV感染的认知障碍 男性和女性在NDE中有不同的蛋白质，这将影响诊断， 治疗我们计划进一步区分轻度认知功能障碍与 阿尔茨海默病前期轻度认知障碍（MCI）诊断。为了验证这一假设，我们建议 具体目的如下：（1）选择并验证一组神经元外泌体蛋白， 并诊断艾滋病毒认知障碍与年龄的妇女和男子，（2）确定是否 神经元外泌体货物可以区分HIV相关的认知障碍和轻度认知障碍。 MCI/阿尔茨海默病（3）HIV NDE蛋白靶点与认知领域的相关性 与损伤的神经影像学标志物相关;（4）建立一种快速的超灵敏检测方法 使用经验证的神经元外泌体靶蛋白诊断HIV认知障碍， 纵向队列我们将利用多学科的方法，包括基础研究， 与认知领域相关的蛋白质靶点和使用神经成像的临床诊断 与所选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 和治愈艾滋病毒在大脑中的液体生物标志物被发现，神经元的健康， 在“真实的时间”中进行评估。