Ethnoracial Impact on Blood-Based Biomarker Detection of Alzheimer's in Primary Care Patients

种族对初级保健患者阿尔茨海默病血液生物标志物检测的影响

• 批准号: 10333341
• 负责人: Charisse N Winston
• 金额: $ 9.71万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN DIEGO
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-02-01 至 2024-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10333341
• 关键词: Address; African American; African American population; Algorithms; Alzheimer disease detection; Alzheimer' s Disease; Alzheimer' s disease risk; Alzheimer’s disease biomarker; Amyloid beta-Protein; Antibodies; Astrocytes; Attenuated; Autopsy; Award; Behavioral; Biological; Biological Markers; Biology; Cell Separation; Clinical; Complement; Data; Diagnosis; Diagnostic; Disease; Enzyme-Linked Immunosorbent Assay; Ethnic Origin; Funding; Future; Home; Human; Immunoassay; In Vitro; Individual; Infrastructure; Institution; Interleukin-10; Laboratories; Lead; Learning; Mass Spectrum Analysis; Membrane; Membrane Proteins; Mentors; Mentorship; Methods; Minority Groups; Nerve Degeneration; Neuroglia; Neurons; Not Hispanic or Latino; Oligodendroglia; Pathologic; Pathology; Patient Care; Patients; Phase; Physiological; Plasma; Preventive measure; Primary Health Care; Productivity; Prognostic Marker; Proteins; Proteomics; Publishing; ROC Curve; Race; Reagent; Reporting; Research; Risk; Sampling; Scientist; Screening procedure; Seeds; Shapes; Surface; Symptoms; Testing; Therapeutic Intervention; Time; Training; Transmission Electron Microscopy; United States National Institutes of Health; Vesicle; Work; advanced dementia; base; biobank; biomarker discovery; biomarker identification; blood-based biomarker; cell type; cohort; cost effective; cytokine; cytotoxicity; diagnostic biomarker; diagnostic value; ethnic difference; exosome; in vivo; insight; interdisciplinary approach; macrophage; magnetic beads; member; nanoparticle; novel; novel marker; primary care setting; prognostic; prognostic value; racial and ethnic; racial and ethnic disparities; racial difference; racial disparity; relating to nervous system; targeted treatment; tau Proteins; tau-1; therapeutic development; tool; treatment strategy; validation studies

Project Summary/Abstract If no preventative measures are developed, the number of individuals suffering from Alzheimer’s Disease (AD) is expected to triple by 2050; many of whom will be members of a minority group. Ethnic and racial disparities in Alzheimer’s disease exist; however, these disparities are severely understudied, especially amongst African Americans. The consequent need for less invasive and more cost-effective tools to identify stages of AD at an earlier and perhaps more treatable time-point has fueled research into plasma biomarkers. Neural (NDEs) and astrocyte-derived exosomes (ADEs) have demonstrated biomarker potential for detecting stages of AD and predicting the conversion of MCI to AD. Although the field has been focused on NDEs and ADEs, there are surprisingly no published reports demonstrating the biomarker potential of microglial derived exosomes (MDEs). Any potential value of plasma exosome cargo to accurately identify stages of MCI and predict the conversion of MCI to AD, will require additional validation studies that specifically account for ethnic and racial differences amongst its patient cohorts. Understanding how ethnic and racial factors modify AD risk can yield new insights into race-dependent biological mechanisms, which in turn, can inform future diagnostic and therapeutic interventions. With the existing infrastructure at my home institution (UCSD), reagents and combined expertise of my mentor and collaborators, I will use a multidisciplinary approach to accomplish my research objectives. In the mentored phase of this proposal, I will be trained in unbiased, Mass spectrometry (MS)-based proteomic profiling for novel biomarker identification. My mentored studies will also involve the purification and characterization of MDEs. Lastly, I will also use these samples to study the diagnostic and prognostic utility of ADE and MDE cargo proteins (e.g. Aβ and p-tau) to predict conversion of MCI to AD. During the independent phase, I will apply the methods and perspectives learned in the mentored phase of this application to cross-validate the biomarker potential of plasma exosomes in a live cohort of African American patients who are at risk for developing AD. Successful completion of this study will significantly advance the field of exosome biology in neurodegeneration and may lead to the identification of novel biological targets for therapeutic development of AD. The training and mentorship that I will receive because of this funding award will undoubtedly contribute to my productivity as an independent scientist. Moreover, the K99/R00 mechanism will provide with the support necessary to advance of establishing an NIH- R01 funded, independent laboratory where I plan to continue my studies in racial disparities, exosome biology and biomarker discovery.

项目概要/摘要 如果不采取预防措施，患有阿尔茨海默病（AD）的人数 预计到 2050 年将增加两倍；其中许多人将是少数族裔和种族差异的成员。 阿尔茨海默病的患病率确实存在；然而，人们对这些差异的研究严重不足，特别是在非洲人中 美国人因此需要侵入性较小且更具成本效益的工具来及时识别 AD 的阶段。 更早且可能更容易治疗的时间点推动了对血浆生物标记物（NDE）和神经标记物的研究。 星形胶质细胞衍生的外泌体 (ADE) 已被证明是检测 AD 阶段和 预测 MCI 到 AD 的转换 尽管该领域一直专注于 NDE 和 ADE，但也存在一些问题。 令人惊讶的是，没有发表的报告证明小胶质细胞衍生的外泌体的生物标志物潜力 (MDE) 血浆外泌体货物对于准确识别 MCI 阶段和预测的任何潜在价值。 将 MCI 转换为 AD，将需要专门考虑民族和种族的额外验证研究 了解种族和种族因素如何改变 AD 风险可以产生不同的结果。 对种族依赖性生物机制的新见解，这反过来又可以为未来的诊断和治疗提供信息 利用我所在机构（加州大学圣地亚哥分校）的现有基础设施、试剂和 结合我的导师和合作者的专业知识，我将使用多学科的方法来完成我的任务 在本提案的指导阶段，我将接受公正的质谱分析培训。 基于 MS 的蛋白质组学分析用于新型生物标志物鉴定。 最后，我还将使用这些样品来研究诊断和表征。 ADE 和 MDE 货物蛋白（例如 Aβ 和 p-tau）在预测 MCI 向 AD 转化方面的预后效用。 在独立阶段，我将应用在本次指导阶段学到的方法和观点 应用交叉验证血浆外泌体在非裔美国人活体队列中的生物标志物潜力 成功完成这项研究将显着促进有 AD 风险的患者。 外泌体生物学领域在神经退行性疾病中的应用，并可能导致新的生物靶标的鉴定 我将因这项资助而获得 AD 的培训和治疗指导。 毫无疑问，K99/R00 机制将有助于提高我作为独立科学家的生产力。 将提供必要的支持以推进建立 NIH-R01 资助的独立实验室 我计划在那里继续我的种族差异、外泌体生物学和生物标志物发现方面的研究。