Discovering Centrally Linked Peripheral Molecular Signatures of Alzheimer's Disease

发现阿尔茨海默病的中心连锁外周分子特征

基本信息

批准号：
10555727
负责人：
NILUFER ERTEKIN-TANER
金额：
$ 97.58万
依托单位：
MAYO CLINIC JACKSONVILLE
依托单位国家：
美国
项目类别：
财政年份：
2023
资助国家：
美国
起止时间：
2023-03-15 至 2028-02-29
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10555727
关键词：
African American Aging Alzheimer&apos s Disease Alzheimer&apos s disease brain Alzheimer&apos s disease pathology Alzheimer&apos s disease related dementia Alzheimer’s disease biomarker American Autopsy Biological Biological Markers Blood Blood Vessels Blood specimen Brain Brain region Cell Nucleus Cerebrospinal Fluid Clinic Clinical Cognition Cognitive Collaborations Communities Complex Data Diagnosis Diagnostic Disease Disease Progression Early Diagnosis Epigenetic Process Ethnic Population Florida Functional disorder Future Gene Expression Profile Genes Genetic Genome Image Individual Knowledge Latino Link Longitudinal cohort Measures Molecular Molecular Profiling Multiomic Data Natural Immunity Outcome Participant Pathway Analysis Pathway interactions Pattern Peripheral Phenotype Population Population Heterogeneity Proteins Proteome RNA Resources Sampling Symptoms Synapses Testing Therapeutic Therapeutic Intervention Transcript Translations advanced analytics artificial neural network biomarker discovery blood-based biomarker brain cell cell type cohort comparative cost effective disease phenotype disorder subtype lipidome metabolome methylome multi-ethnic multiple omics myelination neuroimaging neuropathology novel patient stratification peripheral blood personalized medicine precision medicine preservation prognostic random forest transcriptome transcriptome sequencing transcriptomic profiling translational approach translational study validation studies

项目摘要

SUMMARY ABSTRACT Discovering Alzheimer’s disease (AD) biomarkers for early diagnosis, tracking of disease progression and timely therapeutic interventions is a significant need. Despite the utility of existing neuroimaging and cerebrospinal fluid biomarkers, there is an urgent need to develop cost-effective and blood-based biomarkers to apply at the population level. Large-scale multi-omics studies identified a multitude of molecular perturbations in AD. These discoveries support the rationale for discovery of peripheral biomarkers that capture the full spectrum of central changes that occur in this disease. Our proposal aims to leverage combined blood and brain multi-omics data in well-characterized cohorts to identify peripheral molecular signatures which reflect the central molecular perturbations that occur in AD brains. We hypothesize that blood molecular signatures can serve as centrally- linked peripheral biomarkers (CLPBM) since many brain multi-omics changes can also be observed in blood and vice versa. As they are linked with brain molecular perturbations, such CLPBM can provide mechanistic information on potential drivers of disease and its progression. CLPBM can also be expected to aid in patient stratification according to biological subtypes and disease stage, ultimately paving the way for personalized medicine. There are, however, no sizable studies that simultaneously analyze brain and blood samples from the same individuals to discover centrally-linked peripheral molecular signatures (CLPMS) that can serve as future centrally-linked peripheral biomarkers (CLPBM). In Project 1, we leverage three studies with complementary strengths, Mayo Clinic Study of Aging, Alzheimer’s Disease Neuroimaging Initiative and Mayo Clinic Florida post- mortem African American and Latino American cohorts, to accomplish our specific aims to: 1. Discover brain region-specific CLPMS through molecular profiling (transcriptome, genome, methylome, proteome, metabolome/lipidome) in up to 5 brain regions and in matched blood samples. 2. Identify cell-type specific CLPMS through single nucleus transcriptome profiling across 5 brain regions and in matched blood samples. 3. Establish CLPMS in diverse populations by profiling of same -omics measures across the same brain regions from LA and AA participants. 4. Discover CLPMS that reflect biological subtypes and temporal progression of AD through use of advanced analytics approaches of the molecular data. We expect to identify brain region and cell-type specific CLPMS, which reflect the heterogeneous neuropathology in AD; associate with or drive antemortem clinical, neuroimaging and cognitive progression and outcomes of AD; define biological subtypes and predict molecular stage of AD in multi-ethnic populations. Findings from Project 1, together with those from Projects 2 and 3, collectively comprising >20,000 multi-omics and >48,000 AD phenotypes from >3,700 multi- ethnic participants will be analyzed applying our well-defined Roadmap to Translation approach to prioritize CLPMS for translation to precision medicine biomarkers for AD. Further, the data, outcomes and knowledge from this Project will be shared broadly and serve as an unprecedented resource for the research community.

摘要摘要发现阿尔茨海默氏病（AD）生物标志物，用于早期诊断，跟踪疾病进展和及时治疗干预是一个重要需求。尽管现有的神经影像学和脑脊液具有实用性生物标志物，迫切需要开发具有成本效益和血液的生物标志物以适用人口水平。大规模的多委员会研究确定了AD中的大量分子扰动。这些发现支持发现周围生物标志物的基本原理，这些生物标志物捕获了中央的完整范围这种疾病发生的变化。我们的建议旨在利用血液和大脑多词的联合数据特征良好的队列以鉴定外周分子特征，反映了中央分子在广告大脑中发生的扰动。我们假设血液分子特征可以作为集中的连接的外围生物标志物（CLPBM），由于许多大脑多词的变化也可以在血液中观察到反之亦然。由于它们与脑分子扰动有关，因此这种CLPBM可以提供机械有关疾病及其进展的潜在驱动因素的信息。也可以期望CLPBM有助于患者根据生物学亚型和疾病阶段的分层，最终为个性化铺平了道路药品。但是，没有相当大的研究简单地分析了大脑和血液样本相同的个体可以发现可以用作未来的中心连接的外围分子特征（CLPM）中央连接的外围生物标志物（CLPBM）。在项目1中，我们利用三项完善研究优势，梅奥诊所衰老，阿尔茨海默氏病神经影像学计划和梅奥诊所佛罗里达州 Mortem非裔美国人和拉丁美洲裔美国人队列，以实现我们的具体目标：1。发现大脑通过分子分析（转录组，基因组，甲基组，蛋白质组，多达5个大脑区域和匹配的血液样本中的代谢组/脂肪组）。 2。确定细胞类型特异性通过单核转录组分析的CLPM在5个大脑区域和匹配的血液样本中进行。 3。通过分析相同大脑区域的相同态度测量，在潜水员种群中建立CLPM 来自洛杉矶和AA参与者。 4。发现反映生物学亚型和暂时进展的CLPM 通过使用分子数据的先进分析方法来广告。我们希望识别大脑区域和细胞类型的特异性CLPM，反映了AD中的异质神经病理；与或驾驶 Anemontem临床，神经影像学和认知进展以及AD的结果；定义生物亚型并预测多种族种群中AD的分子阶段。项目1的发现以及项目2和3，共同完成> 20,000个多媒体和> 48,000 AD表型的项目将分析种族参与者，将我们定义明确的路线图应用于翻译方法以优先考虑 Clpms转化为Precision Medicine生物标志物的AD。此外，数据，结果和知识该项目将广泛共享，并作为研究界的前所未有的资源。