Core B - Biomarkers

核心 B - 生物标志物

• 批准号: 10331682
• 负责人: Berislav V Zlokovic
• 金额: $ 23.96万
• 依托单位: UNIVERSITY OF SOUTHERN CALIFORNIA
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-09-30 至 2027-03-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10331682
• 关键词: Alzheimer' s Disease; Alzheimer' s disease risk; Amyloid beta-42; Amyloid beta-Protein; Arizona; Biological Assay; Biological Markers; Blood - brain barrier anatomy; Body mass index; Budgets; Centrifugation; Cerebrovascular system; Clinic; Clinical; Cognitive; Collaborations; Collection; Communities; Custom; Data; Detection; Development; Enrollment; Ensure; Enzyme-Linked Immunosorbent Assay; Funding Opportunities; Genetic Risk; Genotype; Glycosylated hemoglobin A; Goals; Guidelines; High Density Lipoproteins; Homozygote; Human; Human Resources; Huntington Disease; Image; Impaired cognition; Individual; Information Systems; Institutes; Instruction; Knock-in; Knowledge; Laboratories; Leadership; Low-Density Lipoproteins; MMP9 gene; Magnetic Resonance Imaging; Measurement; Measures; Medical Research; Molecular; Mus; Pathology; Pericytes; Plasma; Procedures; Proteins; Publications; Pulse Pressure; Quality Control; Reporting; Research; Research Institute; Research Personnel; Resources; Risk; Sampling; Schedule; Scientist; Services; Site; Spinal Puncture; Standardization; Technology; Testing; Tight Junctions; Time; Training; Transgenic Organisms; Triglycerides; Tube; Universities; Vascular Dementia; Venipunctures; Washington; apolipoprotein E-3; apolipoprotein E-4; clinical research site; contrast enhanced; data dissemination; data management; dementia risk; experience; genetic risk factor; imaging informatics; improved; multiplex assay; neurogenetics; neurovascular unit; novel; open data; programs; tau Proteins; vascular injury; vascular risk factor

CORE B – PROJECT SUMMARY/ABSTRACT The Biomarker Core B will continue to provide services, resources and expertise in blood-brain barrier (BBB) and neurovascular unit (NVU) and AD (Aβ, tau, pTau) biomarkers in CSF and plasma for Projects 1-3 and all P01 investigators. This includes biomarkers in individuals at high genetic risk for AD (APOE4 carriers) and in those at the lower risk for AD (APOE3 homozygotes) (Projects 1 and 2), and in novel APOE knock-inflox/flox (KIF) mouse lines with and without A and tau pathology (Project 3). The core will provide the essential, quantified molecular measures relatable to the imaging and cognitive measures collected as part of this program. During the initial P01’s budget period, Core B has developed and tested a novel panel of 37 BBB/NVU biomarkers measured simultaneously with A and tau biomarkers in >800 CSF human samples. The data have been used by Projects 1 and 2 in several high impact publications by P01 Investigators. The CSF BBB/NVU and AD biomarkers have been validated by site-specific analysis from multiple P01 sites. For Projects 1 and 2, Core B has recently tested a group of biomarkers in human plasma (e.g., sPDGFR, A40/A40, total tau, pTau-181), and is developing additional BBB/NVU biomarkers in plasma (e.g., BBB tight junction proteins, S100B, sTREM2). For Project 3, Core B has developed and validated all proposed 30 BBB/NVU biomarkers in the mouse CSF and plasma, using transgenic pericyte-deficient, APOE knock-in, 5xFAD and/or P301S tau lines. The mouse BBB/NVU and AD biomarkers are analogous to the respective human biomarkers, which allows us to directly compare findings in humans (Projects 1 and 2) and mice (Project 3). Existing strengths of Core B include: 1) decades of experience and knowledge in studying the BBB, NVU, and cerebrovascular system; 2) several years of experience working with MSD (Mesoscale Discovery Technology) scientists to develop the first reliable simultaneous measurements of multiple BBB/NVU biomarkers in biofluid samples in humans and mice including development of new MSD assays for sPDGFR, CypA, MMP9, sLRP1; 3) established and validated collaboration with all clinical site co-Is participating in this P01 including USC ADRC (Chui, Schneider, Ringman, Joe, Yassine), Huntington Medical Research Institute Pasadena (Harrington), Washington University Knight ADRC (Morris, Fagan, Benzinger), Banner Alzheimer’s Institute (Reiman)/ Mayo Clinic Arizona (Caselli), as well as with Project 1- 3 Investigators – laboratories of Drs. Zlokovic, Nation, Pa, Toga, Thompson, Jacobs, Coba, Holtzman and Griffin. For most BBB/NVU biomarkers in human (Project 1, 2) and mouse (Project 3) biofluids, Core B will use MSD multiplex or singleplex platforms; and for a few biomarkers ELISA and Sima (see Res. Plan Fig. 2). Under the leadership of Dr. Zlokovic and the resources available at the Zilkha Neurogenetic Institute at USC, Core B will continue to 1) coordinate biofluid collection, processing, and delivery, 2) assay CSF and plasma for BBB/NVU and AD biomarkers and conduct APOE genotyping, 3) provide technological developments, and 4) facilitate data management, requests and distribution to projects to support the scientific goals of the P01.

核心B - 项目摘要/摘要 生物标志物B将继续提供血脑屏障（BBB）的服务，资源和专业知识 在CSF和等离子体中，针对项目1-3的CSF和等离子体中的神经血管单元（NVU）和AD（Aβ，TAU，PTAU）和所有生物标志物 P01调查人员。这包括具有AD高遗传风险（APOE4载体）和IN的个体的生物标志物 AD（APOE3纯合子）（项目1和2）的风险较低的人，在新型的Apoe敲击Inflox/Flox（KIF）中 带有A和TAU病理学的小鼠线（项目3）。核心将提供必不可少的，量化的 与该程序的一部分收集的成像和认知度量相关的分子测量。期间 最初的P01预算期，Core B已开发并测试了一个37 BBB/NVU生物标志物的新颖面板 仅在> 800 csf人类样品中用A和Tau生物标志物进行测量。数据已使用 P01调查人员在几个高影响力出版物中进行的项目1和2。 CSF BBB/NVU和AD 生物标志物已通过多个P01位点的特定地点分析来验证。对于项目1和2，核心B 最近测试了人血浆中的一组生物标志物（例如SPDGFR，A40/A40，Total Tau，PTAU-181）， 并正在在血浆中开发其他BBB/NVU生物标志物（例如BBB紧密连接蛋白，S100B，Strem2）。 对于项目3，Core B已开发并验证了所有提议的30 BBB/NVU生物标志物 和等离子体，使用转基因周细胞不足，apoe敲入，5xfad和/或p301s tau线。鼠标 BBB/NVU和AD生物标志物类似于各自的人类生物标志物，这使我们能够直接 比较人类（项目1和2）和小鼠（项目3）的发现。核心B的现有优势包括：1） 数十年来研究BBB，NVU和脑血管系统方面的经验和知识； 2）几年 与MSD（中尺度发现技术）科学家一起开发第一个可靠的经验 人类和小鼠中生物流体样品中多个BBB/NVU生物标志物的简单测量 开发SPDGFR，CYPA，MMP9，SLRP1的新MSD分析； 3）已建立和验证 与所有临床站点共同参加此P01，包括USC ADRC（Chui，Schneider，Ringman， 乔，Yassine），亨廷顿医学研究所帕萨迪纳（哈灵顿），华盛顿大学骑士 ADRC（Morris，Fagan，Benzinger），Alzheimer Institute（Reiman）/ Mayo Clinic Arizona（Caselli）（Caselli） 与项目1-3的研究人员一样 - 博士实验室。 Zlokovic，Nation，PA，Toga，Thompson，Jacobs，Coba， 霍尔茨曼和格里芬。对于人类（项目1、2）和小鼠（项目3）生物流体的大多数BBB/NVU生物标志物， Core B将使用MSD多路复用或单个Plex平台；以及一些生物标志物Elisa和Sima（请参阅Res。计划。 图2）。在Zlokovic博士的领导下，以及Zilkha神经源性研究所可用的资源 USC，核心B将继续至1）协调生物流体收集，处理和交付，2）分析CSF和等离子体 对于BBB/NVU和AD生物标志物并进行APOE基因分型，3）提供技术发展，并 4）促进数据管理，请求和分配项目，以支持P01的科学目标。