Stanford Alzheimer's Disease Research CenterAdmin Supp: Developing iPSC models for AD and PD

斯坦福阿尔茨海默病研究中心管理补充：开发 AD 和 PD 的 iPSC 模型

• 批准号: 10653524
• 负责人: Victor Henderson
• 金额: $ 34.52万
• 依托单位: STANFORD UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-06-01 至 2025-03-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10653524
• 关键词: Administrative Supplement; Alzheimer' s Disease; Alzheimer' s disease model; Alzheimer' s disease related dementia; Alzheimer’s disease biomarker; Award; Biological Markers; Biological Models; Biology; Biopsy; Brain; Caring; Cell Culture Techniques; Cell Differentiation process; Cell Line; Cell model; Cells; Cerebrospinal Fluid; Chimera organism; Clinical; Clone Cells; Cognitive aging; Collaborations; Communities; Culture Media; Data; Dementia; Dementia with Lewy Bodies; Deposition; Derivation procedure; Development; Diagnosis; Disease; Disease model; Fibroblasts; Funding; Genes; Genomics; Genotype; Guidelines; Human; Image; Immune; Impaired cognition; In Vitro; Karyotype determination procedure; LRRK2 gene; Length; Lewy Bodies; Lewy Body Disease; Light; Link; Medical Genetics; Methods; Microglia; Mission; Modeling; Mycoplasma; National Institute of Neurological Disorders and Stroke; Nature; Neuroglia; Neurons; Optics; Organoids; Parents; Parkinson Disease; Participant; Phenotype; Physiology; Prevention approach; Proteomics; Protocols documentation; Quality Control; Research; Research Personnel; Resolution; Resource Sharing; Resources; Sampling; Skin; Source; Sterility; Testing; Time; United States National Institutes of Health; Work; alpha synuclein; base; biobank; cell repository; cellular imaging; chemokine; clinical phenotype; clinical translation; comparative; cytokine; data repository; epigenomics; familial Alzheimer disease; genetic variant; genome sequencing; genomic variation; glucosylceramidase; hyperphosphorylated tau; improved; induced pluripotent stem cell; innovation; metabolomics; mild cognitive impairment; molecular phenotype; multiplexed imaging; neurofilament; neuropathology; novel; pluripotency; polygenic risk score; repository; screening; stem cell model; tau Proteins; tau-1; tissue resource; tool; transcriptomics; whole genome

PROJECT SUMMARY The Stanford Alzheimer's Disease Research Center supports the National Alzheimer's Project Act by serving as a shared resource to promote research on Alzheimer's disease, cognitive impairment linked to Lewy body changes in the brain, and cognitive aging. Clearly, within the scope of the parent Stanford ADRC, this Administrative Supplement respectfully requests supplemental funding for the Stanford ADRC Neuropathology Core to take responsibility for the derivation, characterization, and banking of 20 new human induced pluripotent stem cell (iPSC) lines and to assess biomarkers in iPSC-derived neuronal and microglia cultures for AD and PD. In particular, we support and expand Aim 4 of the parent ADRC to “make available participant biospecimens and high-content biospecimen data” by generating new iPSC lines that can be differentiated into neuronal and glia cultures and recapitulate many molecular and phenotypic aspects of AD and PD. The Aims of this study are: (1) the derivation of 60 new human iPSC clones from 20 existing ADRC human skin fibroblasts lines with defined clinical phenotypes and genetic characterization within the AD spectrum (AD-dementia, AD-mild cognitive impairment) and Lewy body spectrum (Parkinson’s disease, dementia with Lewy bodies), matched with healthy controls. We use non-integrating reprogramming methods to develop these iPSC clones. All clones will undergo rigorous quality control testing in accordance with NIH guidelines. (2) AD/ADRD phenotypic characterization of iPSC neurons and microglia. We will differentiate cell lines into cortical neurons and microglia using established protocols, develop multiplex imaging phenotyping and expression panels for AD and PD-related neuropathology (Aim 2.1), and test lysates and media supernatant for established AD biomarkers, including tau, hyperphosphorylated tau, A1-40, and A1-42, alpha-synuclein aggregates and compare analyses to cerebrospinal fluid biomarkers in corresponding samples from the same donor (Aim 2.2). (3) Banking and distribution of iPSC lines to the NCRAD biobank (Aim 3a). We will collaborate across centers to innovate the development of new resources, such as directly transformed neurons and human organoids (in collaboration with UC San Diego’s iPSC Core) and the development of microglia and chimera models (in collaboration with UC Irvine’s iPSC Core) (Aim 3b). When successfully completed, the work proposed in this supplement will yield 60 new iPSC clones from 20 clinically and genetically well-characterized ADRC participants, and we will share all lines with the NCRAD repository, the research community at Stanford and beyond. This resource will expand the Stanford ADRC tissue resource repertoire and allow the scientific community to work with advanced predictive human cellular model systems.

项目概要 斯坦福阿尔茨海默病研究中心通过服务支持国家阿尔茨海默病项目法案 作为促进阿尔茨海默病、路易体相关认知障碍研究的共享资源 大脑的变化和认知老化。 显然，在母斯坦福 ADRC 的范围内，本行政补充文件谨请 为斯坦福 ADRC 神经病理学核心提供补充资金，以负责推导， 20 个新的人类诱导多能干细胞 (iPSC) 系的表征和库并进行评估 我们特别支持和开发 iPSC 衍生的神经和小胶质细胞培养物中的 AD 和 PD 生物标志物。 将母公司 ADRC 的目标 4 扩展为“提供参与者生物样本和高含量生物样本 数据”，通过生成新的 iPSC 系来分化为神经和神经胶质细胞培养物并概括 AD 和 PD 的许多分子和表型方面。 本研究的目的是：（1）从 20 个现有的 ADRC 中衍生出 60 个新的人类 iPSC 克隆 AD 内具有明确临床表型和遗传特征的人类皮肤成纤维细胞系 谱（AD-痴呆、AD-轻度认知障碍）和路易体谱（帕金森病、 路易体痴呆），与健康对照相匹配，我们使用非整合重编程方法。 为了开发这些 iPSC 克隆，所有克隆都将根据 NIH 进行严格的质量控制测试。 (2) iPSC 神经元和小胶质细胞的 AD/ADRD 表型特征。 使用既定方案将细胞系转化为皮质神经元和小胶质细胞，开发多重成像 AD 和 PD 相关神经病理学的表型和表达组（目标 2.1），以及测试裂解物和 已确定的 AD 生物标志物的培养基上清液，包括 tau、过度磷酸化 tau、A1-40 和 A1-42， α-突触核蛋白聚集并与相应样品中的脑脊液生物标志物进行比较分析 来自同一供体（目标 2.2） (3) 将 iPSC 系储存并分配至 NCRAD 生物库（目标 3a）。 我们将跨中心协作，创新开发新资源，例如直接转化 神经元和人类类器官（与加州大学圣地亚哥分校的 iPSC 核心合作）以及 小胶质细胞和嵌合体模型（与加州大学欧文分校的 iPSC Core 合作）（目标 3b）。 成功完成后，本补充材料中提出的工作将从 20 个克隆中产生 60 个新的 iPSC 克隆。 临床和遗传特征良好的 ADRC 参与者，我们将与 NCRAD 共享所有产品线 存储库、斯坦福大学及其他研究社区。该资源将扩展斯坦福 ADRC。 组织资源库，使科学界能够利用先进的预测性人类细胞 模型系统。

项目成果

Plasma Vitamin B12 Levels, High-Dose Vitamin B12 Treatment, and Risk of Dementia.

血浆维生素 B12 水平、高剂量维生素 B12 治疗和痴呆风险。

• 发表时间: 2021
• 作者: Arendt, Johan Frederik Håkonsen;Horváth;Sørensen, Henrik Toft;Nexø, Ebba;Pedersen, Lars;Ording, Anne Gulbech;Henderson, Victor W
• 通讯作者: Henderson, Victor W

Restoring metabolism of myeloid cells reverses cognitive decline in ageing.

恢复骨髓细胞的新陈代谢可以逆转衰老过程中认知能力的下降。

• 发表时间: 2021-02
• 影响因子: 64.8
• 作者: Minhas, Paras S;Latif;McReynolds, Melanie R;Durairaj, Aarooran S;Wang, Qian;Rubin, Amanda;Joshi, Amit U;He, Joy Q;Gauba, Esha;Liu, Ling;Wang, Congcong;Linde, Miles;Sugiura, Yuki;Moon, Peter K;Majeti, Ravi;Suematsu, Makoto
• 通讯作者: Suematsu, Makoto

Motivation to Participate in Precision Health Research and Acceptability of Texting as a Recruitment and Intervention Strategy Among Vietnamese Americans: Qualitative Study.

越南裔美国人参与精准健康研究的动机以及短信作为招募和干预策略的接受度：定性研究。

• 发表时间: 2021
• 影响因子: 5
• 作者: Ta Park, Van;Kim, Amber;Cho, In Hyang;Nam, Bora;Nguyen, Khue;Vuong, Quyen;Periyakoil, Vyjeyanthi S;Hong, Y Alicia
• 通讯作者: Hong, Y Alicia

Predicting future amyloid biomarkers in dementia patients with machine learning to improve clinical trial patient selection.

通过机器学习预测痴​​呆症患者未来的淀粉样蛋白生物标志物，以改善临床试验患者的选择。

• 发表时间: 2021
• 作者: Reith, Fabian H;Mormino, Elizabeth C;Zaharchuk, Greg
• 通讯作者: Zaharchuk, Greg

Rapid Deployment of Whole Slide Imaging for Primary Diagnosis in Surgical Pathology at Stanford Medicine: Responding to Challenges of the COVID-19 Pandemic.

斯坦福大学医学院在外科病理学中快速部署全玻片成像进行初步诊断：应对 COVID-19 大流行的挑战。

• 发表时间: 2023-03-01
• 影响因子: 4.6
• 作者: Rojansky, Rebecca;Jhun, Iny;Dussaq, Alex M;Chirieleison, Steven M;Nirschl, Jeffrey J;Born, Don;Fralick, Jennifer;Hetherington, William;Kerr, Alison M;Lavezo, Jonathan;Lawrence, Daniel B;Lummus, Seth;Macasaet, Ronald;Montine, Thomas J;Ryan, E
• 通讯作者: Ryan, E