Core B - Biomarkers

核心 B - 生物标志物

基本信息

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
项目类别：
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&apos s Disease Alzheimer&apos 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

项目摘要

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 Biomarker Core B将继续提供血脑屏障（BBB）方面的服务、资源和专业知识项目 1-3 和所有项目的脑脊液和血浆中的神经血管单元 (NVU) 和 AD（Aβ、tau、pTau）生物标志物 P01 研究人员，其中包括 AD 高遗传风险个体（APOE4 携带者）和个体的生物标志物。 AD 风险较低的人群（APOE3 纯合子）（项目 1 和 2）以及新型 APOE 敲入 inflox/flox (KIF) 具有和不具有 A 和 tau 病理学的小鼠品系（项目 3）将提供必要的、量化的信息。与作为该计划的一部分收集的成像和认知测量相关的分子测量。在最初的 P01 预算期间，Core B 开发并测试了包含 37 个 BBB/NVU 生物标志物的新型面板在超过 800 个 CSF 人类样本中与 A 和 tau 生物标志物同时测量。数据已被使用。由 P01 调查员的几份高影响力出版物中的项目 1 和 2 提出。对于项目 1 和 2，核心 B，生物标志物已通过多个 P01 站点的位点特异性分析得到验证。最近测试了人类血浆中的一组生物标志物（例如 sPDGFR、A40/A40、总 tau、pTau-181），并正在开发血浆中的其他 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 开发并验证了小鼠脑脊液中所有提议的 30 个 BBB/NVU 生物标志物和血浆，使用转基因周细胞缺陷、APOE 敲入、5xFAD 和/或 P301S tau 系。 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）的研究结果，核心 B 的现有优势包括：1）。数十年研究 BBB、NVU 和脑血管系统的经验和知识 2) 几年；与 MSD（中尺度发现技术）科学家合作开发第一个可靠的经验同时测量人类和小鼠生物体液样本中的多种 BBB/NVU 生物标志物，包括开发针对 sPDGFR、CypA、MMP9、sLRP1 的新 MSD 检测方法 3) 已建立并得到验证；与参与本 P01 的所有临床中心合作，包括 USC ADRC（Chui、Schneider、Ringman、 Joe，Yassine），亨廷顿医学研究所帕萨迪纳（哈灵顿），华盛顿大学奈特 ADRC（Morris、Fagan、Benzinger）、班纳阿尔茨海默病研究所 (Reiman)/亚利桑那州梅奥诊所 (Caselli) 以及与项目 1-3 研究者一样 - Zlokovic、Nation、Pa、Toga、Thompson、Jacobs、Coba 博士的实验室， Holtzman 和 Griffin 对于人类（项目 1、2）和小鼠（项目 3）生物体液中的大多数 BBB/NVU 生物标志物， Core B 将使用 MSD 多重或单一平台；对于一些生物标志物 ELISA 和 Sima（参见 Res. Plan）图 2) 在 Zlokovic 博士的领导下以及 Zilkha 神经遗传学研究所的可用资源南加州大学核心 B 将继续 1) 协调生物体液的收集、处理和输送，2) 检测脑脊液和血浆用于 BBB/NVU 和 AD 生物标志物并进行 APOE 基因分型，3) 提供技术开发，以及 4) 促进数据管理、请求和项目分发，以支持 P01 的科学目标。