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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

基本信息

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
项目类别：
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&apos s Disease Alzheimer&apos s disease model Alzheimer&apos 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

项目摘要

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.

项目摘要斯坦福大学阿尔茨海默氏症研究中心通过提供以下服务来支持国家阿尔茨海默氏症项目法案作为一个共享资源，以促进对阿尔茨海默病的研究，认知障碍与路易体大脑的变化和认知老化。显然，在母公司斯坦福大学ADRC的范围内，本行政补充文件恭敬地要求为斯坦福大学ADRC神经病理学核心提供补充资金，以负责推导， 20个新的人诱导多能干细胞（iPSC）系的表征和库，并评估在iPSC衍生的神经元和小胶质细胞培养物中的生物标志物用于AD和PD。我们特别支持和将ADRC的目标4扩展为“提供参与者生物标本和高含量生物标本通过产生新的iPSC系，其可以分化成神经元和神经胶质培养物，并重现 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中分离出60个新的人iPSC克隆在AD中具有确定的临床表型和遗传特征的人皮肤成纤维细胞系谱系（AD-痴呆，AD-轻度认知损害）和路易体谱系（帕金森病，路易体痴呆），与健康对照组相匹配。我们使用非整合重编程方法来开发这些iPSC克隆。所有克隆将根据NIH标准进行严格的质量控制测试。指南(2)iPSC神经元和小胶质细胞的AD/ADRD表型表征。我们将区分细胞系转化为皮质神经元和小胶质细胞， AD和PD相关神经病理学的表型和表达组（目标2.1），以及试验裂解物和用于确定的AD生物标志物的培养基上清液，包括tau、过度磷酸化的tau、A β 1-40和A β 1-42， α-突触核蛋白聚集体，并将分析结果与相应样本中的脑脊液生物标志物进行比较来自同一捐助者（目标2.2）。(3)将iPSC细胞系储存并分配至NCRAD生物库（目标3a）。我们将跨中心合作，创新新资源的开发，如直接转化为神经元和人类类器官（与UC San Diego的iPSC Core合作）以及小胶质细胞和嵌合体模型（与UC Irvine的iPSC Core合作）（Aim 3b）。当成功完成时，本补充中提出的工作将从20个新的iPSC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共享所有线路存储库，斯坦福大学及其他地方的研究社区。该资源将扩大斯坦福大学ADRC 组织资源库，并允许科学界与先进的预测人类细胞模型系统

项目成果

期刊论文数量（79）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Six Recurrent Amyloid-Related Imaging Abnormality Episodes in a Patient Treated With Aducanumab.

DOI：
10.1001/jamaneurol.2021.3933
发表时间：
2022-01-01
期刊：
JAMA NEUROLOGY
影响因子：
29
作者：
Hall, Jacob N.;Mormino, Elizabeth;Ng, Amanda;Boumis, Athanasia;Gaudioso, Jennifer L.;Davidzon, Guido A.;Sha, Sharon J.
通讯作者：
Sha, Sharon J.

Phenotypic Heterogeneity among GBA p.R202X Carriers in Lewy Body Spectrum Disorders.

DOI：
10.3390/biomedicines10010160
发表时间：
2022-01-12
期刊：
Biomedicines
影响因子：
4.7
作者：
Napolioni V;Fredericks CA;Kim Y;Channappa D;Khan RR;Kim LH;Zafar F;Couthouis J;Davidzon GA;Mormino EC;Gitler AD;Montine TJ;Schüle B;Greicius MD
通讯作者：
Greicius MD

Risk of Parkinson Disease and Secondary Parkinsonism in Myocardial Infarction Survivors.

DOI：
10.1161/jaha.121.022768
发表时间：
2022-03
期刊：
JOURNAL OF THE AMERICAN HEART ASSOCIATION
影响因子：
5.4
作者：
Sundboll, Jens;Szepligeti, Szimonetta Komjathine;Szentkuti, Peter;Adelborg, Kasper;Horvath-Puho, Erzsebet;Pedersen, Lars;Henderson, Victor W.;Sorensen, Henrik Toft
通讯作者：
Sorensen, Henrik Toft

Common X-Chromosome Variants Are Associated with Parkinson Disease Risk.

DOI：
10.1002/ana.26051
发表时间：
2021-07
期刊：
Annals of neurology
影响因子：
11.2
作者：
Le Guen Y;Napolioni V;Belloy ME;Yu E;Krohn L;Ruskey JA;Gan-Or Z;Kennedy G;Eger SJ;Greicius MD
通讯作者：
Greicius MD

Generalizability of cognitive results from clinical trial participants to an older adult population: Addressing external validity.