A microchip to analyze trafficking leukocytes in Alzheimer’s disease patients

用于分析阿尔茨海默病患者白细胞运输的微芯片

• 批准号: 9047117
• 负责人: Timothy S McConnell
• 金额: $ 16.4万
• 依托单位: ISOPLEXIS, INC.
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-06-01 至 2016-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9047117
• 关键词: Alzheimer' s Disease; Antibodies; Biological Assay; Biological Markers; Blood - brain barrier anatomy; Brain; Cardiovascular system; Cells; Cerebrospinal Fluid; Chronic; Clinical; Development; Devices; Diagnosis; Early Diagnosis; Effector Cell; Encephalitis; Engineering; Enzyme-Linked Immunosorbent Assay; Generic Drugs; Goals; Hand; Heterogeneity; Human; Image; Immune; Immune response; Immunologic Surveillance; Impaired cognition; Inflammation; Inflammatory; Inflammatory Response; Lead; Leukocyte Trafficking; Leukocytes; Liquid substance; Manuals; Marketing; Measurement; Measures; Memory impairment; Methods; Monitor; Nerve Degeneration; Neuraxis; Neurodegenerative Disorders; Outcome; PTPRC gene; Pathogenesis; Pathology; Patients; Pharmacologic Substance; Phase; Prevalence; Process; Protein Analysis; Proteins; Public Health; Research; Sampling; Serum; Staging; Surface; System; Technology; Testing; Therapeutic; Time; TimeLine; Universities; Work; chemokine; controlled release; cytokine; design; immune function; instrument; meetings; microchip; migration; minimally invasive; molecular marker; nano; nanostructured; nervous system disorder; non-invasive monitor; operation; potential biomarker; pre-clinical; protein function; protein profiling; prototype; public health relevance; research and development; screening; single cell proteins; tool

 DESCRIPTION (provided by applicant): Alzheimer's disease (AD) is one of the most common neurodegenerative diseases that lead to detrimental outcomes such as progressive memory deficit and cognitive impairment. Although it is expected that the prevalence of AD will double over the next 30 years, currently no widely-accepted molecular biomarkers for early detection or non-invasive monitoring of AD. There has been increasing evidence that immune responses and brain inflammation are involved in the pathogenesis of neurodegenerative disorders in the central nervous system (CNS). The immune cells participating in the inflammatory response in the deep brain often get into cerebrospinal fluid (CSF), so called the "circulatory" system of CNS, and these cells carry the information about deep brain inflammatory pathology. On the other hand, while the blood-brain barrier (BBB) restricts the entry of immune cells into the CNS, a small number of immune cells can traverse into the CNS during pathophysiological states to participate in immune surveillance. Excessive migration or abnormal functioning of these immune cells contribute to the development of neurodegenerative pathology. It has been hypothesized that these trafficking leukocytes in CSF are potential cell markers to detect and measure inflammatory neurodegenerative disease. However, it remains challenging due to (i) the paucity of trafficking leukocytes (~1 cell/microliter) and (2) the high degree of cellular heterogeneity with diverse immune effector functions/proteins secreted by cells (up to 40). IsoPlexis has a prototype hand-held technology that for the first time provides the ability to measure many (up to 45) of these key effector proteins at the single cell level. At the same time, this device in its envisioned form requires much less amount of cell input (~1000) representing a major advantage over the existing single-cell instruments (e.g., flow cytometer) for the specific application toward the analysis of rare trafficking leukocytes. It will also be far less costly tha existing single-cell instruments, representing a significant market advantage. Thus, we plans to develop a fully integrated system that incorporates the enrichment of trafficking leukocytes using nanorough surfaces and single-cell effector protein analysis on the same microdevice to truly enable the opportunity for wide-spread use of trafficking leukocytes as the biomarker for early stage diagnosis and monitoring of inflammatory neurodegenerative diseases (specifically AD). To reach this goal, we propose: 1. Incorporating a cell capture module in the IsoPlexis microdevice to perform on-chip separation of low abundance leukocytes followed by highly multiplexed immune function analysis. 2. Develop an integrated carrier device to perform reliable operation of the integrated microchip for measuring rare trafficking leukocytes from CSF. We expect to develop a unique and minimally invasive approach to quantitatively measure inflammatory conditions in deep brain for early diagnosis and therapeutic monitoring of AD using CSF. This approach will also have broad impact on preclinical or clinical uses for routine screening or monitoring of inflammatory neurodegenerative diseases.

 描述（由适用提供）：阿尔茨海默氏病（AD）是最常见的神经退行性疾病之一，导致有害结果，例如渐进的记忆力不足和认知障碍。尽管预计AD的患病率将在未来30年内翻一番，但目前没有广泛的分子生物标志物用于早期检测或非侵入性监测AD。越来越多的证据表明，免疫复杂和脑感染与中枢神经系统（CNS）中神经退行性疾病的发病机理有关。参与深脑炎症反应的免疫电池通常会进入脑脊液（CSF），即CNS的“循环”系统，这些细胞带有有关深脑炎症病理学的信息。另一方面，尽管血脑屏障（BBB）限制了免疫细胞进入中枢神经系统的进入，但在病理生理状态下，少数免疫核管可以进入中枢神经系统，以参与免疫监护。这些免疫细胞的过度迁移或异常功能有助于神经退行性病理的发展。据推测，CSF中的这些运输白细胞是检测和测量炎症性神经退行性疾病的潜在细胞标记。但是，由于（i）运输白细胞（〜1个细胞/微晶）和（2）具有潜水员免疫效应子功能/蛋白质的高度细胞异质性（最多40）。 Isoplexis具有一项原型手持技术，该技术首次提供了在单细胞水平上测量这些关键效应蛋白的许多（最多45）的能力。同时，该设备以其设想的形式所需的细胞输入（〜1000）所需的量要比现有的单细胞仪器（例如流式细胞仪）代表主要优势，以分析稀有运输白细胞的特定应用。现有的单细胞仪器的成本也要低得多，这代表了市场优势。因此，我们计划开发一个完全集成的系统，该系统使用纳米菌表面和对同一微电位的单细胞效应蛋白分析结合了贩运白细胞的富集，从而真正有机会将贩运的白细胞用作生物标记物作为早期诊断和监测易发性神经变性的生物标志物的广泛使用，以实现生物标记（为了达到此目标，我们提出：1。将细胞捕获模块纳入等级微电位，以在低抽象白细胞的片上进行片间分离，然后进行高度多重的免疫功能分析。 2。开发一个集成的载体设备，以执行集成微芯片的可靠操作，以测量CSF的稀有运输白细胞。我们期望开发一种独特的侵入性方法，以定量测量深脑的炎症状况，以便使用CSF对AD进行早期诊断和治疗监测。这种方法还将对临床前或临床用途产生广泛的影响，以常规筛查或监测炎症性神经退行性疾病。