UC Irvine MODEL-AD

加州大学欧文分校模型-AD

• 批准号: 10708160
• 负责人: Kim Green
• 金额: $ 923.15万
• 依托单位: UNIVERSITY OF CALIFORNIA-IRVINE
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-09-15 至 2027-08-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10708160
• 关键词: ATAC-seq; Academia; Affect; Aging; Alzheimer' s Disease; Alzheimer' s disease model; Alzheimer' s disease risk; Alzheimer' s disease therapy; Amyloid Beta A4 Precursor Protein; Amyloid beta-Protein; Animal Model; Animals; Apolipoprotein E; Award; Behavioral; Biochemical; Biochemistry; Bioinformatics; Biological Markers; Brain; Brain imaging; California; Cell Nucleus; Cells; Clustered Regularly Interspaced Short Palindromic Repeats; Communities; Data; Data Set; Databases; Deposition; Development; Diet; Disease; Disease Progression; Disease model; Electrophysiology (science); Ensure; Evaluation; Funding; Gene Expression; Generations; Genes; Genetic; Genetic Risk; Genome; Goals; Histology; Human; Image; Individual; Industry; Infrastructure; International; Intervention; Investigation; Knowledge Portal; Late Onset Alzheimer Disease; Liquid substance; Longevity; Medical; Methods; Modeling; Mouse Strains; Mus; Mutation; Names; Nomenclature; Outcome; Pathology; Pathway interactions; Persons; Phase; Phenocopy; Phenotype; Physiology; Plasma; Population; Proteomics; Protocols documentation; Reproducibility; Research; Research Personnel; Resources; Rodent; Sampling; Series; Societies; Synapses; Technology; Testing; The Jackson Laboratory; Therapeutic; Tissues; United States National Institutes of Health; Universities; Validation; Variant; Work; apolipoprotein E-4; base; biomarker validation; cognitive testing; combat; data management; data modeling; design; disorder subtype; economic impact; effective therapy; efficacious treatment; environmental stressor; forging; gene replacement; genome wide association study; human disease; human model; imaging modality; improved; insight; lipidomics; member; metabolome; metabolomics; microbiome; model organism; mouse model; neuroimaging; neurovascular; novel; open source; programs; response; risk variant; screening; single-cell RNA sequencing; socioeconomics; tau Proteins; therapeutic evaluation; therapeutically effective; transcriptome sequencing; transcriptomics; ultra high resolution; web site

ABSTRACT The goal of the University of California, Irvine MODEL-AD U54 Center is to develop novel mouse models of late- onset Alzheimer’s disease (LOAD), to deeply phenotype these and to make all data and mouse strains available to enable researchers to select the optimal mouse model and timepoints for therapeutic and intervention testing, as well as testing of hypotheses concerning mechanisms of LOAD. During the past five years, we have generated and deeply phenotyped mice with one component of our base genetic platform in which the Aß region of the App gene was converted from the rodent to the human sequence, and we have recently introduced the second component, a humanized MAPT (TAU) locus produced via gene-replacement. We have also used CRISPR and genome replacement to model and validate nine GWAS identified LOAD risk loci and have characterized mice with each of these both on a wild-type and 5xFAD background to determine their effects on plaque generation and damage exerted on the brain in response to pathology. In this continuation, we will use the results of these analyses to identify the combinations of LOAD risk variants most likely to phenocopy LOAD and introduce them on two complementary hAb-KI, hTAU, hAPOE4 platform lines, designed to mimic sub-types of AD that have been recently defined. To ensure translationability, we have an expanded focus on biomarkers and alignment with human phenotypes. To that end we have established a new Core – the Neuroimaging and neurovascular core (NIVC), which will provide brain imaging modalities currently employed in human AD subjects to align phenotypes in our mice with human disease progression. We have also expanded our fluid biomarker analysis efforts to include CSF, as well as plasma lipidomics and metabolomics to be compared to human AD plasma signatures. Similarly, our bioinformatics and data management efforts have been expanded to include single cell and nucleus RNA-seq and ATAC-seq, as well as spatial transcriptomics to enable alignment of data from our models with human AD signatures, but also to understand the mechanisms underlying disease progression in our mice. We are utilizing a comprehensive approach to evaluate our mice across their lifespans, which includes behavioral/cognitive assessment, electrophysiological analysis, super-resolution synaptic imaging, neuroimaging, bulk and single-cell RNA-seq, single cell level spatial transcriptomic analysis, unbiased proteomics, and microbiome and metabolome investigations. The UCI MODEL-AD Center will leverage the resources of our NIA-funded Alzheimer’s Disease Research Center combined with AMP-AD and other human AD datasets to facilitate comparisons to the human condition to identify the best mouse models to evaluate further. All data and models will be made available without restrictions, via The Jackson Labs, and data will be explorable via the modeladexplorer.org website, and raw data freely available for download via the AD Knowledge Portal.

摘要

项目成果

Systematic Phenotyping and Characterization of the 3xTg-AD Mouse Model of Alzheimer's Disease.

• DOI: 10.3389/fnins.2021.785276
• 发表时间: 2021
• 期刊: Frontiers in neuroscience
• 影响因子: 4.3
• 作者: Javonillo DI;Tran KM;Phan J;Hingco E;Kramár EA;da Cunha C;Forner S;Kawauchi S;Milinkeviciute G;Gomez-Arboledas A;Neumann J;Banh CE;Huynh M;Matheos DP;Rezaie N;Alcantara JA;Mortazavi A;Wood MA;Tenner AJ;MacGregor GR;Green KN;LaFerla FM
• 通讯作者: LaFerla FM

Proteomic Data Advance Targeted Drug Development for Neurogenerative Diseases.

• DOI: 10.1016/j.biopsych.2023.02.003
• 发表时间: 2023-05-01
• 期刊: Biological psychiatry
• 影响因子: 10.6

hdWGCNA identifies co-expression networks in high-dimensional transcriptomics data.

• DOI: 10.1016/j.crmeth.2023.100498
• 发表时间: 2023-06-26
• 期刊: Cell reports methods

Neuroimaging of Mouse Models of Alzheimer's Disease.

• DOI: 10.3390/biomedicines10020305
• 发表时间: 2022-01-28
• 期刊: Biomedicines
• 影响因子: 4.7
• 作者: Jullienne A;Trinh MV;Obenaus A
• 通讯作者: Obenaus A

Model organism development and evaluation for late-onset Alzheimer's disease: MODEL-AD.

• DOI: 10.1002/trc2.12110
• 发表时间: 2020
• 期刊: Alzheimer's & dementia (New York, N. Y.)
• 作者: Oblak AL;Forner S;Territo PR;Sasner M;Carter GW;Howell GR;Sukoff-Rizzo SJ;Logsdon BA;Mangravite LM;Mortazavi A;Baglietto-Vargas D;Green KN;MacGregor GR;Wood MA;Tenner AJ;LaFerla FM;Lamb BT;and The MODEL‐AD;Consortium
• 通讯作者: Consortium