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病研究中心通过服务来支持《国家阿尔茨海默氏症计划法》作为促进对阿尔茨海默氏病的研究的空气资源，认知障碍与Lewy身体有关大脑的变化和认知衰老。显然，在父母斯坦福德ADRC的范围内，此行政支持宗教请求斯坦福德ADRC神经病理学核心的补充资金，负责该派生，表征和银行的20个新人类诱导的多能干细胞（IPSC）线并评估尤其是AD和PD的IPSC衍生的神经元和小胶质细胞培养物的生物标志物。扩展AIM 4 4 4 4 4 4 4 数据“通过生成新的IPSC线条文化文化和概括性 AD和PD的许多分子和表型方面。该研究的目的是：（1）来自20个现有ADRC的60个新人IPSC克隆的推导人类皮肤成纤维细胞线具有定义的临床表态表型和AD内的遗传特征光谱（Ad-Denemia，广告认知障碍）和Lewy身体谱（帕金森氏病， Lewy身体的痴呆症，与健康对照相匹配。为了开发所有克隆。指南（2）AD/ADRD的表型表征，我们将分化使用ESing ESing建立的方案进入皮质神经元和小胶质细胞，开发多重成像与AD PD相关神经病理学（AIM 2.1）的表型和表达面板，并测试裂解物和用于已建立的AD生物标志物的媒体上清液，包括Tau，高磷酸化的Tau，A1-40和A1-42， α-核蛋白聚集体并将分析与Corresspong样品中的脑脊液生物标志物进行比较来自同一捐助者（AIM 2.2）。我们将在整个中心合作开发新资源，例如直接转化神经元和人体器官（与加州大学圣地亚哥分校的IPSC核心合作）和发展小胶质细胞和嵌合体模型（与UC Irvine的IPSC Core合作）（AIM 3B）。成功完成后，此补充剂中提出的工作将产生20个新的IPSC克隆。临床和遗传良好的ADRC参与者，我们将与Ncrad共享所有线条存储库，斯坦福大学及以后的研究社区。组织资源研究，使科学界能够与先进的预测性人类细胞一起工作模型系统。

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）

Sleep duration, insomnia, and Parkinson disease.

DOI：
10.1097/gme.0000000000001954
发表时间：
2022-02-07
期刊：
Menopause (New York, N.Y.)
影响因子：
0
作者：
Henderson VW
通讯作者：
Henderson VW

Molecular signatures underlying neurofibrillary tangle susceptibility in Alzheimer's disease.

DOI：
10.1016/j.neuron.2022.06.021
发表时间：
2022-09-21
期刊：
NEURON
影响因子：
16.2
作者：
Otero-Garcia, Marcos;Mahajani, Sameehan U.;Wakhloo, Debia;Tang, Weijing;Xue, Yue-Qiang;Morabito, Samuel;Pan, Jie;Oberhauser, Jane;Madira, Angela E.;Shakouri, Tamara;Deng, Yongning;Allison, Thomas;He, Zihuai;Lowry, William E.;Kawaguchi, Riki;Swarup, Vivek;Cobos, Inma
通讯作者：
Cobos, Inma

Longitudinal Coaching and Decision Support Provided by a Patient-Family Liaison Promotes Goal-Concordant Care.

患者家庭联络员提供的纵向指导和决策支持促进目标一致的护理。