Core F: Biomarker

核心 F：生物标志物

• 批准号: 10164700
• 负责人: Celeste Marie Karch
• 金额: $ 26.41万
• 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/10164700
• 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; Apolipoprotein E; 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; 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; Magnetic Resonance Imaging; Medical Genetics; Microglia; Molecular; Molecular Analysis; Mutation; Neurodegenerative Disorders; Neurons; Oligodendroglia; Organoids; Parkinson Disease; Participant; Pathogenesis; Pathologic; Pathology; Phase; Population; Positron-Emission Tomography; Process; Program Research Project Grants; Research; Research Personnel; Resources; Sampling; Services; Skin; Somatic Cell; TREM2 gene; Variant; Work; age related; autosomal dominant Alzheimer' s disease; biobank; brain tissue; cell type; cohort; data management; data sharing; 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：生物标志物项目摘要 神经退行性疾病是由多因素过程引起的，这些过程导致多效性变化 连接一系列生物过程的分子网络，导致大脑的蛋白质聚集，并 最终，认知的远程下降，这是大多数与年龄相关的痴呆疾病的特征。 神经退行性疾病，例如阿尔茨海默氏病（AD），特发性帕金森氏病（PD）和 额颞叶变性（FTLD）是通过相关的常见或稀有变体的机制发生的 疾病风险是直接遗传或偶尔出现的。人类体细胞和干细胞模型具有 成为建模病理基因表达复杂性的强大系统，特别是在 疾病的早​​期阶段，在非塑性人类基因组的背景下。此外，人类干细胞可以 分化为在疾病中受影响的单个细胞类型，例如神经元，星形胶质细胞，小胶质细胞和 少突胶质细胞以及3D“迷你脑”器官。为此，我们建立了 AD和相关痴呆症的干细胞模型。该系列包括200多个人类成纤维细胞 骑士ADRC和主要遗传的阿尔茨海默氏症网络（Dian）和诱导多能干细胞 （IPSC）来自30多个在应用程序，PSEN1，PSEN2，GRN，MAPT和风险的人的线 MAPT，APOE，TREM2，RAB10和PLD3中的变体。我们的长期目标是开发一组工具和 广告和相关痴呆症的生物标志物。为此，我们将继续建立人类的生物座席 体细胞模型。这些细胞将促进基本疾病机制的研究，允许 发现新型生物标志物，并促进了药物发现平台。我们将重点关注细胞收集 建立在骑士ADRC中的三个主要优势领域：（1）潜水员种族背景的贡献 AD的分子和细胞生物标志物； （2）大家族开始时年龄的遗传和分子修饰符 具有浓密的发作广告家族史； （3）比较分子和细胞生物标志物 常见和独特的常见体显性广告和零星，晚期AD。最后，我们会做 可为更广泛的研究社区提供人类的体细胞和干细胞系，以革新我们 了解AD和相关痴呆症。