Establishment of a causal link between AD and L1 retrotransposons
AD 和 L1 反转录转座子之间因果关系的建立
基本信息
- 批准号:10704226
- 负责人:
- 金额:$ 78.47万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2022
- 资助国家:美国
- 起止时间:2022-09-15 至 2027-07-31
- 项目状态:未结题
- 来源:
- 关键词:AccelerationAgingAlzheimer&aposs DiseaseAlzheimer&aposs disease modelAlzheimer&aposs disease pathologyAlzheimer&aposs disease patientAstrocytesAutopsyBiological ModelsBrainCRISPR/Cas technologyCell AgingCell DeathCellsChronicCollectionCytoplasmDNADataDiseaseDisease ProgressionElementsEvolutionGene ExpressionGenomeGenomicsGoalsHumanImmune systemImmunologic StimulationIndividualInflammationInflammatoryInterferon ActivationInterferonsL1 ElementsLinkMeasuresMicrogliaModelingMolecularNeurogliaNeuronsNucleosidesOrganoidsOutcome StudyPathogenesisPathway interactionsPhenotypeProtective AgentsProtocols documentationRNA-Directed DNA PolymeraseRetrotransposonReverse Transcriptase InhibitorsReverse TranscriptionSeriesSingle-Stranded DNASiteSterilitySynapsesSyndromeTestingTherapeuticage effectbrain cellcell typecytokinedesignexperimental studyhuman diseasehuman modelhuman tissueimprovedinduced pluripotent stem cellinsightmutantneural networkneurotoxicneurotoxicitynoveloverexpressionprematureresponsesynaptogenesistau aggregationtau-1transcriptomicswhole genome
项目摘要
Abstract
Our overall goal is to determine a potential causal link between L1, an active retrotransposon element, in
human brain cells and Alzheimer's Disease (AD). L1s are involved in numerous human diseases with different
molecular and cellular mechanisms. L1 expression was also found to be upregulated in AD postmortem human
tissues, leading to the speculation that L1s could contribute, at least partially, to the mechanisms leading to AD
in humans. However, despite all these correlations, there is no experimental-based causal link between L1s
and AD so far. Here, we hypothesized that L1 expression in AD-derived brain cells can contribute to AD
pathology, using both cell-autonomous and non-cell-autonomous mechanisms. Accumulation of L1-derived
ssDNA molecules in the cytoplasm of glial cells might be responsible for a chronic low-level stimulation of the
immune system, aka “sterile” inflammation, and can aggravate molecular and cellular phenotypes in neurons
derived from AD patients. Moreover, a cell autonomous mechanism, triggered by L1 ssDNA accumulation in
neurons could accelerate and exacerbate molecular and cellular phenotypes related to AD pathogenesis.
Thus, the combinatory impact of L1 expression in the different cell types could causally contribute to AD. To
experimentally test this hypothesis, we will use induced pluripotent stem cells (iPSC) from controls and AD to
overexpress L1 ssDNA molecules and analyze their impact on different neuronal types individually or in
combination using a brain organoid model system. The use of iPSC-derived cells and organoid model is
perfectly suited as we can isolate the aging effect and capture the entire genome of AD individuals in relevant
cell types. We have designed the following specific aims to test our hypothesis: Aim 1: Determine the impact
of L1 retrotransposons in AD-derived astrocytes. We will measure alterations in transcriptomics,
cytokines/interferon release levels and interferon-stimulated gene (ISGs) expression in AD/isogenic-derived
astrocytes upon L1 ssDNA overexpression. We will also evaluate neurotoxicity using astrocyte conditioned
media from AD-derived astrocytes overexpressing L1 ssDNA. Aim 2: Determine the impact of L1
retrotransposons in AD-derived cortical neurons. We will measure Tau aggregation and phosphorylation,
and synaptic loss, all early hallmarks of the AD progression. Aim 3: To model AD progression with a brain
organoid model. We will use our optimized protocol to generate brain cortical organoids (BCO) infused with
human microglia from AD- and control individuals. BCO with L1 ssDNA but treated with nucleoside reverse
transcriptase inhibitors (NRTI) as a protective agent, will be compared. Our proposal aims to demonstrate an
eventual causal contribution of L1-derived ssDNA to molecular, cellular and network phenotypes in brain cells
and organoids derived from AD individuals. Our data will reveal unexplored pathways with immediate
therapeutic relevance that could lead to transformative treatments for AD and other aging-related syndromes.
摘要
项目成果
期刊论文数量(0)
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会议论文数量(0)
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Alysson R. Muotri其他文献
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Mirian A. F. Hayashi
Alysson R. Muotri的其他文献
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{{ truncateString('Alysson R. Muotri', 18)}}的其他基金
Impact of prenatal inflammation on developing human brain
产前炎症对人类大脑发育的影响
- 批准号:
10705556 - 财政年份:2022
- 资助金额:
$ 78.47万 - 项目类别:
A new brain organoid model for NeuroHIV and the impact of opioids
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- 批准号:
10693976 - 财政年份:2022
- 资助金额:
$ 78.47万 - 项目类别:
Establishment of a causal link between AD and L1 retrotransposons
AD 和 L1 反转录转座子之间因果关系的建立
- 批准号:
10519029 - 财政年份:2022
- 资助金额:
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A new brain organoid model for NeuroHIV and the impact of opioids
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10529106 - 财政年份:2022
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Impact of prenatal inflammation on developing human brain
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- 批准号:
10387980 - 财政年份:2022
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$ 78.47万 - 项目类别:
The impact of hiPSC-derived microglia in human brain development in health and disease
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- 批准号:
10279492 - 财政年份:2021
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Investigation of Pitt-Hopkins Syndrome pathophysiology using a human model
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10553718 - 财政年份:2021
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Investigation of Pitt-Hopkins Syndrome pathophysiology using a human model
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10208365 - 财政年份:2021
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10458040 - 财政年份:2021
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- 批准号:
10661578 - 财政年份:2021
- 资助金额:
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