Integrating the exposome and methylome to inform brain molecular changes in ADRD across established diverse cohorts.
Integrating the exposome and methylome to inform brain molecular changes in ADRD across established diverse cohorts.
批准号:
10657846
负责人:
NILUFER ERTEKIN-TANER
金额:
$98.9万
依托单位:
依托单位国家:
美国
项目类别:
财政年份:
2020
资助国家:
美国
项目状态:
已结题
起止时间:
2020-09-01 至 2024-08-31
关键词:
AddressAdministrative SupplementAffectAfrican AmericanAge FactorsAlcohol consumptionAllelesAlzheimer&aposs disease related dementiaAlzheimer&aposs disease riskAmericanAmyloidAmyloid beta-ProteinAutopsyAwardBrainBrain DiseasesBrain regionCell NucleusCellsCerebellumCerebrovascular DisordersChIP-seqClinicCohort StudiesCollaborationsCollecting CellCollectionCommunitiesComplementary DNADNADNA MethylationDataData AnalysesDiagnosisDiseaseDisease OutcomeEducationEthnic OriginEthnic groupFreezingGene ExpressionGeneticGenomic SegmentGenotypeGoalsHealthIndividualKnowledge PortalLatin AmericanLatinoLife StyleMeasuresMethylationMicrogliaMolecularMolecular ProfilingMultiomic DataNatural ImmunityNeurodegenerative DisordersNeurogliaNeuronsNot Hispanic or LatinoOutcomeParentsParticipantPathogenesisPathologyPhenotypePlayPopulationPopulation HeterogeneityProcessProgressive Supranuclear PalsyProteomeProteomicsPublicationsRaceRecordsResearchRoleSamplingSmokingSuperior temporal gyrusSystemTemporal LobeTissuesapolipoprotein E-4basebrain cellbrain healthbrain tissueburden of illnesscell typecohortcomorbiditycomparativedementia riskdesigndisorder riskepigenomeepigenomicsethnic minorityinsightlipidomicsmembermetabolomemetabolomicsmethylomemulti-ethnicmultiple omicsneuropathologynovelparent grantpathological agingracial and ethnicsexsocialsocial health determinantstau Proteinstherapeutic targettranscriptometranscriptome sequencingtranscriptomics
中文摘要
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英文摘要
Project Summary
This is an application for an administrative supplement to enhance the outcome of the parent grant: U01
AG046139 “A Systems Approach to Targeting Innate Immunity in AD”. This Administrative Supplement aims to
expand the multiomics profiling in this cohort and enable curation of exposome variables from existing
brain bank records. The design of our unique study cohort in the parent award enables us to perform comparative
analysis of control (no pathology), PathAg, (Pathologic Aging, amyloid+), AD (tau+, amyloid+) and PSP
(progressive supranuclear palsy, tau+) providing a framework to identify therapeutic targets that play a role in
the transition to different disease neuropathologic stages of AD. Further, comparisons between two brain regions
(TCX=affected and CER=largely spared in AD) and between AD and PSP can help distinguish whether the
molecular changes identified are likely a cause or consequence of pathology. We have collected multiomics
measures in ~350 study participants, including genetic (WGS), transcriptomic (RNAseq) and epigenomic (ChIP-
Seq) data. In collaboration with other consortia members, proteomic, metabolomic and lipidomic measures
were/will also be collected. The study cohort in the parent award is focused on non-Hispanic White (NHW)
individuals. Through the AMP-AD diversity initiative supplement, we expanded this study to understudied
racial/ethnic minority cohorts comprising African American (AA) and Latin American (LA) participants. These
efforts have generated complementary genetic, transcriptomic and proteomic measures on >200 diverse
individuals. However, complementary DNA methylation data is currently lacking from both the parent (NHW)
and the diversity supplement (AA, LA) cohorts. The samples in both cohorts are from the Mayo Clinic brain bank
and have undergone in-depth neuropathological examination. A similarly in-depth review of available records to
curate data on demographic, lifestyle (education, smoking and alcohol consumption), comorbid diseases,
as well as specific neuropathological findings indicative of cerebrovascular disease is currently lacking. We
hypothesize that the exposome interacts with the epigenome to drive gene expression changes which may
underlie regional, cellular and ethno-racial vulnerabilities to neuropathology and ultimately neurodegenerative
disease. The goal of this Supplement is to extract and collect exposome and DNA methylation data respectively
for participants in the Mayo Clinic AMP-AD cohorts. Our specific aims are: 1. Identify exposome variables in an
established post-mortem cohort of multi-ethnic participants with existing and new (methylome) brain multi-omics
data. 2. Discover differentially methylated regions in brain associated with AD/ADRD diagnosis, neuropathology,
and exposome phenotypes. 3. Identify impacts of AD, related neuropathologies and exposome phenotypes on
the DNA methylation profile of key brain cell types in AD. We expect to identify differentially methylated
regions (DMRs) that reveal the molecular mechanisms underlying brain regional and cellular
vulnerabilities in AD and their interactions with exposome and race/ethnicity that may drive this.
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DOI:
10.1002/trc2.12297
发表时间:
2022
期刊:
ALZHEIMERS & DEMENTIA-TRANSLATIONAL RESEARCH & CLINICAL INTERVENTIONS
影响因子:
4.8
作者:
[Roach, Jared C, Hodes, John F, Funk, Cory C, Shankle, William R, Merrill, David A, Hood, Leroy, Bramen, Jennifer]
通讯作者:
Bramen, Jennifer
DOI:
10.1002/trc2.12191
发表时间:
2021
期刊:
Alzheimer's & dementia (New York, N. Y.)
影响因子:
--
作者:
[McEwen SC, Merrill DA, Bramen J, Porter V, Panos S, Kaiser S, Hodes J, Ganapathi A, Bell L, Bookheimer T, Glatt R, Rapozo M, Ross MK, Price ND, Kelly D, Funk CC, Hood L, Roach JC]
通讯作者:
Roach JC
DOI:
10.1186/s13024-016-0137-9
发表时间:
2016-11-25
期刊:
Molecular neurodegeneration
影响因子:
15.1
作者:
[Ma L, Allen M, Sakae N, Ertekin-Taner N, Graff-Radford NR, Dickson DW, Younkin SG, Sevlever D]
通讯作者:
Sevlever D
DOI:
10.3233/jad-220886
发表时间:
2023
期刊:
JOURNAL OF ALZHEIMERS DISEASE
影响因子:
4
作者:
[Meysami, Somayeh, Raji, Cyrus A., Glatt, Ryan M., Popa, Emily S., Ganapathi, Aarthi S., Bookheimer, Tess, Slyapich, Colby B., Pierce, Kyron P., Richards, Casey J., Lampa, Melanie G., Gill, Jaya M., Rapozo, Molly K., Hodes, John F., Tongson, Ynez M., Wong, Claudia L., Kim, Mihae, Porter, Verna R., Kaiser, Scott A., Panos, Stella E., Dye, Richelin, V, Miller, Karen J., Bookheimer, Susan Y., Martin, Neil A., Kesari, Santosh, Kelly, Daniel F., Bramen, Jennifer E., Siddarth, Prabha, Merrill, David A.]
通讯作者:
Merrill, David A.
DOI:
10.1111/jnc.13583
发表时间:
2016-10
期刊:
Journal of neurochemistry
影响因子:
4.7
作者:
[Golde TE]
通讯作者:
Golde TE
共 59 条
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依托单位:
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