BIOMARKER DISCOVERY AND VALIDATION IN PSP
PSP 中生物标志物的发现和验证
基本信息
- 批准号:9750090
- 负责人:
- 金额:$ 94.4万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2018
- 资助国家:美国
- 起止时间:2018-08-01 至 2023-04-30
- 项目状态:已结题
- 来源:
- 关键词:AffectAlgorithmsAreaBasal GangliaBiochemical ProcessBioinformaticsBiologicalBiological AssayBiological MarkersBlindedBrainBrain regionCell DeathCellsCerebrospinal FluidCerebrospinal Fluid ProteinsClinicalClinical TrialsCollectionComplexDataData DiscoveryDiagnosisDiagnosticDiagnostic ProcedureDiseaseEnrollmentEnsureEvaluationExhibitsFourier TransformFunctional disorderGlobus PallidusGoalsImpairmentIndividualLabelLongevityMass Spectrum AnalysisMediatingMedical HistoryMetabolicMethodsMonitorMotorNeurodegenerative DisordersNeuronsParkinson DiseaseParkinsonian DisordersPathogenesisPathologicPathway interactionsPatientsPennsylvaniaPeptidesPerformancePharmacotherapyProgressive Supranuclear PalsyProteinsProteomeProteomicsQuality of lifeReactionReproducibilityResolutionResourcesSamplingSet proteinTechniquesTechnologyTestingTime ManagementUniversitiesValidationbasebiomarker discoverybiomarker validationbrain tissuecandidate markercandidate validationclinical practicecohortcostdaily functioningdiagnostic biomarkerdifferential expressiondisorder controlexperimental studynervous system disorderneuroimagingoutcome forecastpatient responseprogramsprospectiveprotein aggregationprotein biomarkersproteomic signaturetau Proteinsvalidation studies
项目摘要
ABSTRACT
Progressive supranuclear palsy (PSP) is a devastating atypical parkinsonian disorder that currently lacks
meaningful symptomatic therapies, reduces lifespan and greatly impairs daily function and quality of life. It is
often difficult to distinguish from Parkinson disease (PD) clinically, which is crucial for appropriate and timely
management, prognosis and clinical trial enrollment. Despite a critical need for a reliable diagnostic marker for
parkinsonian disorders, there is currently no biomarker that can be used in routine clinical practice to
distinguish between PSP and PD. The purpose of this project is to discover cerebrospinal fluid (CSF)
biomarkers that reliably distinguish between PSP, PD and healthy individuals. The difficulty of identifying
reliable biomarkers can be attributed to the variability of clinical samples, low abundance of proteins that are
involved in the pathogenesis of PSP and PD, and the lack of reproducibility in validating biomarker candidates.
To overcome these limitations, we propose use of a large CSF cohort with greater statistical power for true
discovery, and deep proteome analysis to reveal PSP biomarkers that are involved in PSP pathogenesis, but
are present at low abundance. In addition, multiplexed sample analysis by isobaric tandem mass tagging
(TMT) with a common reference for data normalization will ensure robust analytical precision of quantitative
proteomic data for discovery from a larger set of samples. Moreover, additional proteomic analysis of brain
tissue will be used to select those biomarkers that show differential expression in CSF as well as the globus
pallidus, a representative brain region used to pathologically define PSP. These discovery platforms will utilize
a bioinformatics approach to select the most plausible candidates for targeted validation studies followed by an
intensive validation of the discovered biomarker candidates. To achieve these goals, we propose four aims:
Specific Aim 1: To prospectively collect CSF on patients with clinically well-characterized PSP. Specific Aim
2: To discover proteins that are differentially expressed in patients with PSP compared to controls and PD. We
plan to carry out a quantitative proteomic analysis of CSF and globus pallidus samples from patients with PSP,
PD and from controls by employing TMT-based multiplexing technology. With this approach, we expect to
obtain a more comprehensive coverage of a larger number of proteins quantified across the analyzed samples.
Specific Aim 3: To prioritize PSP biomarker candidates based on an integrative analysis of alterations in CSF
and globus pallidus. By integrating the expression changes in CSF and brain tissue with a network approach
that takes advantage of the known biological pathways that have been described in PSP, our proposal will be
able to select reliable PSP biomarker candidates for validation by targeted PRM experiments. Specific Aim 4:
To validate candidate protein biomarkers in a larger cohort using targeted parallel reaction monitoring (PRM)
mass spectrometry using CSF samples from a PSP cohort at Johns Hopkins University, the University of
Pennsylvania, UCSF and PDBP. Biomarkers that are selected by algorithms based on these PRM experiments
will finally be confirmed using blinded PDBP CSF samples from PSP and will be compared to CSF samples
from PD. Through the approaches outlined above, we expect to discover and validate reliable PSP biomarkers
that are distinguishable from PD in a reproducible manner.
摘要
进行性核上性瘫痪(PSP)是一种破坏性的非典型帕金森病,目前缺乏
有意义的对症治疗,缩短寿命,极大地损害日常功能和生活质量。它是
临床上常常难以与帕金森病(PD)相鉴别,这对恰当和及时地治疗帕金森病至关重要
管理、预后和临床试验招募。尽管迫切需要一种可靠的诊断标记物
帕金森病,目前还没有可用于常规临床实践的生物标记物
区分PSP和PD。这个项目的目的是发现脑脊液(CSF)
可靠区分PSP、PD和健康个体的生物标志物。辨认的困难
可靠的生物标志物可以归因于临床样本的变异性,低丰度的蛋白质
参与了PSP和PD的发病机制,以及在验证候选生物标记物时缺乏重复性。
为了克服这些限制,我们建议使用具有更大统计能力的大型脑脊液队列来进行TRUE
发现,并进行深入的蛋白质组分析,以揭示参与PSP发病机制的PSP生物标记物,但
以较低的丰度存在。此外,用等压串联质量标记法进行多路样品分析
(TMT)具有数据归一化的公共参考将确保可靠的定量分析精度
从更大的样本集合中发现蛋白质组学数据。此外,对大脑进行了额外的蛋白质组学分析
组织将被用来选择那些在脑脊液和球部显示差异表达的生物标记物
苍白球,一个具有代表性的大脑区域,用于从病理上定义PSP。这些发现平台将利用
一种生物信息学方法来选择最可信的候选对象进行靶向验证研究,然后
对已发现的生物标志物候选进行密集验证。为了实现这些目标,我们提出了四个目标:
具体目标1:前瞻性收集临床特征良好的PSP患者的脑脊液。特定目标
2:发现PSP患者与对照组和PD患者相比差异表达的蛋白质。我们
计划对PSP患者的脑脊液和苍白球样本进行定量蛋白质组学分析,
PD和通过使用基于TMT的多路复用技术来自对照。通过这种方法,我们希望
更全面地覆盖更多在分析样本中量化的蛋白质。
具体目标3:基于对脑脊液改变的综合分析,确定PSP生物标志物候选的优先顺序
和苍白球。通过将脑脊液和脑组织的表达变化与网络方法相结合
这利用了PSP中描述的已知生物途径,我们的建议将是
能够通过目标PRM实验选择可靠的PSP生物标记物候选进行验证。具体目标4:
使用靶向平行反应监测(PRM)验证较大队列中的候选蛋白质生物标记物
使用约翰·霍普金斯大学PSP队列中的脑脊液样本进行质谱分析
宾夕法尼亚州,加州大学旧金山分校和PDBP。由基于这些PRM实验的算法选择的生物标志物
最终将使用来自PSP的盲法PDBP脑脊液样本进行确认,并将其与脑脊液样本进行比较
从警局来的。通过以上概述的方法,我们期望发现和验证可靠的PSP生物标志物
以可重现的方式与PD区分。
项目成果
期刊论文数量(0)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
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Ted M. Dawson其他文献
Molecular mediating prion-like α-synuclein fibrillation from toxic PFFs to nontoxic species
分子介导从有毒 PFF 到无毒物种的类朊病毒 α-突触核蛋白纤维颤动
- DOI:
- 发表时间:
2020 - 期刊:
- 影响因子:4.7
- 作者:
Longgang Jia;Yuqing Liu;Wenliang Wang;Ying Wang;Haiqing Liu;Fufeng Liu;Rong Chen;Valina L. Dawson;Ted M. Dawson;Fuping Lu;Lei Liu;Yanping Wang;Xiaobo Mao - 通讯作者:
Xiaobo Mao
Parthanatos: Mechanisms, modulation, and therapeutic prospects in neurodegenerative disease and stroke
PARP 依赖性细胞死亡(Parthanatos):在神经退行性疾病和中风中的机制、调节及治疗前景
- DOI:
10.1016/j.bcp.2024.116174 - 发表时间:
2024-10-01 - 期刊:
- 影响因子:5.600
- 作者:
Liu Yang;Lauren Guttman;Valina L. Dawson;Ted M. Dawson - 通讯作者:
Ted M. Dawson
α-Synuclein pathology as a target in neurodegenerative diseases
α-突触核蛋白病理作为神经退行性疾病的靶点
- DOI:
10.1038/s41582-024-01043-w - 发表时间:
2024-11-28 - 期刊:
- 影响因子:33.100
- 作者:
Hyejin Park;Tae-In Kam;Valina L. Dawson;Ted M. Dawson - 通讯作者:
Ted M. Dawson
Preclinical studies and transcriptome analysis in a model of Parkinson’s disease with dopaminergic ZNF746 expression
- DOI:
10.1186/s13024-025-00814-3 - 发表时间:
2025-02-28 - 期刊:
- 影响因子:17.500
- 作者:
Ji Hun Kim;Sumin Yang;Hyojung Kim;Dang-Khoa Vo;Han-Joo Maeng;Areum Jo;Joo-Heon Shin;Joo-Ho Shin;Hyeon-Man Baek;Gum Hwa Lee;Sung-Hyun Kim;Key-Hwan Lim;Valina L. Dawson;Ted M. Dawson;Jae-Yeol Joo;Yunjong Lee - 通讯作者:
Yunjong Lee
Molecular Mediation of Prion-like α-Synuclein Fibrillation from Toxic PFFs to Nontoxic Species
类朊病毒 α-突触核蛋白纤维化从有毒 PFF 到无毒物种的分子介导
- DOI:
10.1021/acsabm.0c00684 - 发表时间:
2020 - 期刊:
- 影响因子:4.7
- 作者:
Longgang Jia;Yuqing Liu;Wenliang Wang;Ying Wang;Haiqing Liu;Fufeng Liu;Rong Chen;Valina L. Dawson;Ted M. Dawson;Fuping Lu;Lei Liu;Yanping Wang;Xiaobo Mao - 通讯作者:
Xiaobo Mao
Ted M. Dawson的其他文献
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{{ truncateString('Ted M. Dawson', 18)}}的其他基金
Biomarker Discovery and Validation in Parkinson's Disease
帕金森病生物标志物的发现和验证
- 批准号:
9269667 - 财政年份:2017
- 资助金额:
$ 94.4万 - 项目类别:
Biology of Parkin and It's Role in Parkinson's Disease
帕金生物学及其在帕金森病中的作用
- 批准号:
8882845 - 财政年份:2014
- 资助金额:
$ 94.4万 - 项目类别:
Biology of Parkin and Its Role in Parkinson's Disease
帕金生物学及其在帕金森病中的作用
- 批准号:
8540519 - 财政年份:2012
- 资助金额:
$ 94.4万 - 项目类别:
Johns Hopkins Medicine Biomarker Discovery in Parkinson's Disease
约翰霍普金斯大学医学帕金森病生物标志物的发现
- 批准号:
9116479 - 财政年份:2012
- 资助金额:
$ 94.4万 - 项目类别:
Johns Hopkins Medicine Biomarker Discovery in Parkinson's Disease
约翰霍普金斯大学医学帕金森病生物标志物的发现
- 批准号:
9143805 - 财政年份:2012
- 资助金额:
$ 94.4万 - 项目类别:
Johns Hopkins Medicine Biomarker Discovery in Parkinson's Disease
约翰霍普金斯大学医学帕金森病生物标志物的发现
- 批准号:
8472291 - 财政年份:2012
- 资助金额:
$ 94.4万 - 项目类别:
Johns Hopkins Medicine Biomarker Discovery in Parkinson's Disease
约翰霍普金斯大学医学帕金森病生物标志物的发现
- 批准号:
8740577 - 财政年份:2012
- 资助金额:
$ 94.4万 - 项目类别:
Johns Hopkins Medicine Biomarker Discovery in Parkinson's Disease
约翰霍普金斯大学医学帕金森病生物标志物的发现
- 批准号:
8554394 - 财政年份:2012
- 资助金额:
$ 94.4万 - 项目类别:
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