A Diagnostic Platform for Extracellular Vesicle-Derived Biomarkers - Towards Early Detection of Alzheimer's Disease

细胞外囊泡衍生生物标志物的诊断平台 - 迈向阿尔茨海默病的早期检测

• 批准号: 10629620
• 负责人: Kristen Dellinger
• 金额: $ 14.07万
• 依托单位: NORTH CAROLINA AGRI & TECH ST UNIV
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-05-01 至 2027-04-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10629620
• 关键词: Address; Affect; Affinity; Alzheimer disease detection; Alzheimer disease screening; Alzheimer' s Disease; Alzheimer' s disease care; Alzheimer' s disease diagnosis; Alzheimer' s disease model; Alzheimer' s disease patient; Alzheimer’s disease biomarker; Amyloid beta-42; Amyloid beta-Protein; Area; Binding; Biological; Biological Assay; Biological Markers; Biomedical Research; Biosensing Techniques; Biosensor; Blood; Blood specimen; Caring; Cerebrospinal Fluid; Characteristics; Clinical; Clinical assessments; Cognitive; Cognitive Therapy; Complex; Coupled; Dementia; Detection; Development; Devices; Diagnosis; Disease; Early Diagnosis; Early Intervention; Effectiveness of Interventions; Endowment; Engineering; Environment; Enzyme-Linked Immunosorbent Assay; Executive Dysfunction; Exhibits; Experimental Designs; Foundations; Goals; Gold; Human; Impaired cognition; Individual; Institutionalization; Language; Long-Term Care; Molecular; Monitor; Neurofibrillary Tangles; Neurons; North Carolina; Optics; Participant; Patients; Pharmacologic Substance; Positioning Attribute; Protein Isoforms; Proteins; Raman Spectrum Analysis; Rapid screening; Recording of previous events; Research; Research Support; Sampling; Screening procedure; Senile Plaques; Sensitivity and Specificity; Serum; Societies; Source; Specificity; Spectrum Analysis; Spinal Puncture; Surface; Symptoms; Technology; Time; Treatment outcome; Underrepresented Populations; United States National Institutes of Health; Universities; Update; Visuospatial; Western Blotting; Work; biochip; care costs; clinical diagnostics; clinical practice; cost effective; design; detection limit; diagnostic criteria; diagnostic platform; diagnostic screening; early detection biomarkers; economic cost; effective intervention; extracellular vesicles; graduate student; improved; induced pluripotent stem cell; multidisciplinary; novel; patient prognosis; point of care; pre-clinical; predictive marker; prognostic tool; rational design; routine practice; routine screening; screening; societal costs; tau Proteins; tau-1; tool; undergraduate student

A Diagnostic Platform for Extracellular Vesicle-Derived Biomarkers: Towards Early Detection of Alzheimer’s Disease PROJECT SUMMARY. Alzheimer’s disease (AD) poses a growing burden on our society, with cases expected to reach 12.7 million by 2050. While research supports biomarkers for early detection, most Alzheimer’s patients are diagnosed after exhibiting clinical symptoms. At this stage, the advanced progression of senile plaques and neurofibrillary tangles pose significant challenges to effective interventions. Moreover, established biomarkers, such as amyloid beta-42/amyloid beta-40 and phosphorylated tau, are currently limited to analysis in cerebrospinal fluid, making their potential for routine screening nearly impossible. Thus, there is a critical need for novel, non-invasive approaches to rapidly screen for preclinical Alzheimer’s to facilitate the application of early interventions, such as physical, pharmaceutical, and cognitive therapies. Recent work has demonstrated the potential of circulating extracellular vesicles as a promising source of biomarkers to monitor and diagnose various diseases, including AD. However, accessible technologies to accurately detect AD-associated extracellular vesicles and their constituents are not currently in clinical practice. Moreover, concentrations in blood are present in the low pico- to femtomolar range, limiting conventional detection by ELISA and Western blot. This proposal aims to address these critical needs and focuses on developing a new platform to detect tau in neuron-derived extracellular vesicles (NDEVs). We hypothesize that ultrasensitive detection (< 5 pg/mL) of NDEV-tau can be achieved by optimizing our surface-enhanced Raman spectroscopy (SERS) nanotag technology using a rational design-of-experiment approach. If our hypothesis is correct, we expect this work to serve as the foundation for developing a point-of-care device that can be used for routine screening of pre-symptomatic AD. With this goal in mind, we will focus on the following specific aims: (1) Synthesize ‘SERS nanotags’ with a high affinity for NDEV-tau and identify the characteristics for effective binding; (2) Assess NDEV-tau sensitivity and specificity using the SERS platform in spiked human serum. Ultimately, we expect to establish the limit of detection and sample volumes needed for accurate tau detection. By engineering SERS-active substrates for ultrasensitive detection of NDEV-tau, we can then build upon this platform to enhance the multiplexing of several AD-associated biomarkers in complex biological samples. Our long-term goal is to develop SERS-based bioanalysis to drastically improve current standards in molecular detection for AD in both clinical and research settings.

细胞外囊泡衍生生物标志物的诊断平台： 迈向阿尔茨海默病的早期检测 项目摘要。 阿尔茨海默病 (AD) 给我们的社会带来了越来越大的负担，预计病例数将达到 1,270 万 到 2050 年。虽然研究支持通过生物标志物进行早期检测，但大多数阿尔茨海默病患者都会被诊断出来 出现临床症状后。在此阶段，老年斑进展严重， 神经原纤维缠结对有效干预提出了重大挑战。此外，还设立了 生物标志物，例如淀粉样蛋白 β-42/淀粉样蛋白 β-40 和磷酸化 tau，目前仅限于 脑脊液中的分析，使得它们几乎不可能进行常规筛查。因此，有 迫切需要新颖的非侵入性方法来快速筛查临床前阿尔茨海默病，以促进 早期干预措施的应用，例如物理、药物和认知疗法。最近的 工作证明了循环细胞外囊泡作为生物标志物的有前途的来源的潜力 监测和诊断各种疾病，包括 AD。然而，可用技术准确地 检测 AD 相关的细胞外囊泡及其成分目前尚未进入临床实践。 此外，血液中的浓度处于低皮摩尔至飞摩尔范围内，限制了传统的 通过ELISA和Western blot检测。该提案旨在解决这些关键需求，并重点关注 开发一个新平台来检测神经元源性细胞外囊泡 (NDEV) 中的 tau 蛋白。我们假设 通过优化我们的表面增强技术可以实现 NDEV-tau 的超灵敏检测（< 5 pg/mL） 拉曼光谱 (SERS) 纳米标签技术采用合理的实验设计方法。如果我们的 假设是正确的，我们希望这项工作能够成为开发即时护理设备的基础 可用于症状前 AD 的常规筛查。带着这个目标，我们将重点 以下具体目标：(1) 合成对 NDEV-tau 具有高亲和力的“SERS 纳米标签”，并鉴定 有效结合的特征； (2) 使用SERS平台评估NDEV-tau的敏感性和特异性 在加标的人血清中。最终，我们希望确定检测的限度和所需的样本量 用于准确的 tau 检测。通过设计用于超灵敏检测 NDEV-tau 的 SERS 活性底物， 然后，我们可以在该平台的基础上增强多种 AD 相关生物标志物的复用 复杂的生物样品。我们的长期目标是开发基于 SERS 的生物分析，以彻底解决 提高临床和研究环境中 AD 分子检测的现行标准。