Core F: Biomarker

核心 F：生物标志物

• 批准号: 10622642
• 负责人: Celeste Marie Karch
• 金额: $ 50.5万
• 依托单位: WASHINGTON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-05-15 至 2025-04-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10622642
• 关键词: 3-Dimensional; Affect; Age; Alzheimer' s Disease; Alzheimer' s disease model; Alzheimer' s disease related dementia; Alzheimer' s disease risk; Alzheimer’s disease biomarker; Architecture; Area; Astrocytes; Biological Assay; Biological Markers; Biological Models; Biological Process; Biopsy; Brain; Budgets; C9ORF72; Cell Line; Cells; Charge; Clinical; Cognition; Collaborations; Collection; Communities; Database Management Systems; Dermal; Disease; Electronics; European; Family; Family history of; Fibroblasts; Frontotemporal Lobar Degenerations; Future; Gene Expression; Genetic; Genomics; Goals; Grant; Human; Human Genome; Idiopathic Parkinson Disease; Image; Individual; Induced pluripotent stem cell derived neurons; Inherited; Laboratories; Late Onset Alzheimer Disease; Link; Liquid substance; Microglia; Molecular; Molecular Analysis; Mutation; Neurodegenerative Disorders; Neurons; Oligodendroglia; Organoids; Parkinson Disease; Participant; Pathogenesis; Pathologic; Pathology; Phase; Population; Positron-Emission Tomography; Process; Productivity; Program Research Project Grants; Qualifying; Research; Research Personnel; Resources; Sampling; Services; Skin; Somatic Cell; TREM2 gene; Variant; Work; age related; autosomal dominant Alzheimer' s disease; biobank; brain magnetic resonance imaging; brain tissue; cell type; cohort; data management; data sharing; demented; disorder risk; drug discovery; ethnic diversity; genetic architecture; genome editing; human stem cells; induced pluripotent stem cell; neuropathology; novel; novel marker; presenilin-1; presenilin-2; protein aggregation; rare variant; risk variant; specific biomarkers; statistics; stem cell model; stem cells; tool; transcriptome

Core F: Biomarker Project Summary Neurodegenerative diseases result from multifactorial processes that cause pleiotropic changes in the molecular networks that link a host of biological processes, leading to protein aggregation in the brain, and ultimately to the relentless decline in cognition that characterizes most age-related dementing illnesses. Neurodegenerative diseases, such as Alzheimer disease (AD), idiopathic Parkinson's disease (PD), and frontotemporal lobar degeneration (FTLD) occur by mechanisms in which common or rare variants associated with disease risk are directly inherited or arise sporadically. Human somatic and stem cell models have emerged as a powerful system for modeling the complexities of pathological gene expression, particularly in the early phase of disease, in the context of a non-neoplastic human genome. Further, human stem cells can be differentiated into individual cell types affected in disease, such as neurons, astrocytes, microglia, and oligodendrocytes, as well as 3D “mini-brain” organoids. To this end, we have established a biorepository of stem cell models of AD and related dementias. The collection includes more than 200 human fibroblasts from the Knight ADRC and the Dominantly Inherited Alzheimer Network (DIAN) and induced pluripotent stem cell (iPSC) lines from more than 30 individuals carrying mutations in APP, PSEN1, PSEN2, GRN, MAPT, and risk variants in MAPT, APOE, TREM2, RAB10 and PLD3. Our long-term goal is to develop a set of tools and biomarkers for AD and related dementias. To do this, we will continue to build a biorepository of human somatic and stem cell models. These cells will facilitate the study of basic disease mechanisms, allow for discovery of novel biomarkers, and facilitate drug discovery platforms. We will focus on cell collection that builds on three major areas of strength in the Knight ADRC: (1) contributions of diverse ethnic backgrounds to molecular and cellular biomarkers of AD; (2) genetic and molecular modifiers of age at onset in large families with a dense family history of late onset AD; and (3) comparison of the molecular and cellular biomarkers that are common and unique between autososomal dominant AD and sporadic, late onset AD. Finally, we will make available the human somatic and stem cell lines to the broader research community to revolutionize our understanding of AD and related dementias.

核心F：生物标志物项目总结 神经退行性疾病由多因素过程引起，所述多因素过程引起神经系统的多效性变化。 分子网络，连接一系列生物过程，导致蛋白质在大脑中聚集， 最终导致认知能力的持续下降，而这正是大多数与年龄相关的痴呆症的特征。 神经退行性疾病，如阿尔茨海默病（AD）、特发性帕金森病（PD）和阿尔茨海默病（AD）。 额颞叶变性（FTLD）的发生机制，其中常见或罕见的变异相关 疾病风险是直接遗传的或偶发的。人体和干细胞模型 作为一个强大的系统，用于模拟病理基因表达的复杂性，特别是在 疾病的早期阶段，在非肿瘤人类基因组的背景下。此外，人类干细胞可以 分化成受疾病影响的单个细胞类型，如神经元、星形胶质细胞、小胶质细胞，以及 少突胶质细胞以及3D“迷你脑”类器官。为此，我们建立了一个生物储存库， AD和相关痴呆的干细胞模型。该集合包括200多个来自 Knight ADRC和显性遗传阿尔茨海默病网络（DIAN）和诱导多能干细胞 来自30多个携带APP、PSEN 1、PSEN 2、GRN、MAPT和风险突变的个体的iPSC（多能干细胞）系 MAPT、APOE、TREM 2、RAB 10和PLD 3中的变体。我们的长期目标是开发一套工具， AD和相关痴呆的生物标志物。为了做到这一点，我们将继续建立一个人类生物储存库， 体细胞和干细胞模型。这些细胞将有助于研究基本的疾病机制， 发现新的生物标志物，并促进药物发现平台。我们将专注于细胞收集， 建立在骑士ADRC的三个主要优势领域：（1）不同种族背景的贡献， AD的分子和细胞生物标志物;（2）大家族中发病年龄的遗传和分子修饰物 具有迟发性AD的密集家族史;和（3）比较 在常染色体显性AD和散发性迟发性AD之间是常见和独特的。最后，我们将 将人类体细胞和干细胞系提供给更广泛的研究界，以彻底改变我们的 了解AD和相关痴呆症。