Sex Differences in the Molecular Determinants of Alzheimer's Disease Risk: Prodromal Endophenotype
阿尔茨海默病风险分子决定因素的性别差异:前驱内表型
基本信息
- 批准号:9770740
- 负责人:
- 金额:$ 114.13万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2018
- 资助国家:美国
- 起止时间:2018-09-01 至 2023-05-31
- 项目状态:已结题
- 来源:
- 关键词:AddressAgeAge FactorsAlzheimer&aposs DiseaseAlzheimer&aposs disease modelAlzheimer&aposs disease riskAmyloid depositionAnimal ModelApolipoprotein EAutomobile DrivingBioenergeticsBioinformaticsBiological MarkersBiologyBrainBrain imagingComplexDataData ScienceData SetDevelopmentDiseaseElectronic Medical Records and Genomics NetworkFemaleGenotypeGoalsHaplotypesHumanHuman BiologyImageIncidenceInterventionLate Onset Alzheimer DiseaseLifeMagnetic Resonance ImagingMetabolicMissionMitochondriaMitochondrial DNAModelingMolecularMolecular BiologyMultimodal ImagingMusNeurodegenerative DisordersNuclearOutcomePathway interactionsPeripheralPhasePositron-Emission TomographyPrecision HealthPrevalenceProteomeRecording of previous eventsResearchRiskRisk FactorsS PhaseSex DifferencesStructureSystemSystems AnalysisSystems BiologyTestingTreatment EfficacyWomanagedaging brainanimal model developmentapolipoprotein E-4basedesigndisorder preventionendophenotypefluorodeoxyglucose positron emission tomographygenotypic sexglucose metabolisminnovationmenmetabolomemetabolomicsmiddle agemitochondrial genomemultimodalitynovelpre-clinicalprecision medicinepreventprogramssexsymposiumtherapeutic targettranscriptome
项目摘要
PROJECT SUMMARY / ABSTRACT
The mission for the Sex Differences in the Molecular Determinants of Alzheimer's Disease Risk: Prodromal
Endophenotype project is to determine the complex interaction between chromosomal sex and the major risk
factors for late onset Alzheimer’s (LOAD): age, APOE*4 genotype and maternal history of AD. As LOAD accounts
for the greatest incidence and prevalence of the disease, determining molecular mechanisms relevant to LOAD
has the potential for greatest impact. Further, targeting early stage transitions of risk have the greatest potential
for therapeutic efficacy. Thus, research proposed herein focuses on the prodromal / preclinical stage of LOAD
and the sex differences that underlie early risks of LOAD progression. Elucidation of sex differences in the
mechanisms driving prodromal LOAD will lead to identification of therapeutic targets to change the trajectory of
the disease to prevent, delay and potentially reverse course of developing LOAD.
To achieve this goal, we have assembled an integrative research team with expertise spanning sex
differences in: human brain imaging endophenotypes that emerge during pre-clinical / prodromal phase of LOAD,
molecular mechanisms of complex interactions across sex, age, ApoE and mitochondrial bioenergetics and
innovative translational AD animal model development, data science and computational systems biology
bioinformatics to identify sex specific endophenotypes and therapeutic targets for precision health,
Our proposed program of research is organized and integrated across three specific aims designed to
determine the complex mechanisms and pathways underlying sex differences in the prodromal LOAD
endophenotype. Translationally, we have anchored our approach in the complex biology of humans and
integrated that complexity into an innovative animal model that combine LOAD risk factors of age, sex, APOE*4
genotype and maternal mitochondrial DNA inheritance. Aim 1 will establish sex differences in brain prodromal
endophenotype using brain PET and MRI imaging in parallel with innovative 31P-MRS imaging of mitochondrial
function in human brain. Aim 2 is designed to mechanistically determine the systems biology pathways and
networks that emerge during the prodromal phase of LOAD. With UI-JAX Model-AD, we will develop a novel and
translationally valid model of LOAD that addresses each of the 4 LOAD risk factors including maternal inheritance
of AD through inheritance of the maternal mitochondrial genome and bioenergetic capacity (LOADm4: aged
mtDNA-hAPP-hAPOEe4). In Aim 3, multi-scale data from Aims 1 and 2 will be analyzed using an innovative and
sensitive computational systems biology approach to detect sex differences in the prodromal transition state of
LOAD risk and therapeutic targets to mitigate risk.
Outcomes of our analyses will elucidate molecular mechanisms that emerge in midlife and that increase risk
of developing AD later in life. Collectively, these data will provide therapeutic targets for sex-based precision
medicine interventions during the prodromal phase of LOAD, when the potential to reverse, prevent and delay
LOAD progression is greatest.
Research proposed herein address goals of the National Alzheimer's Project Act (NAPA) to prevent and
effectively treat AD by 2025 and the NIA Alzheimer's Disease Research Summit 2015 key objectives of sex
and metabolic determinants of AD.
项目摘要/摘要
项目成果
期刊论文数量(0)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
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ROBERTA EILEEN BRINTON其他文献
ROBERTA EILEEN BRINTON的其他文献
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{{ truncateString('ROBERTA EILEEN BRINTON', 18)}}的其他基金
Translational Research in Alzheimer's Disease and related Dementias (TRADD)
阿尔茨海默病和相关痴呆症的转化研究 (TRADD)
- 批准号:
10709167 - 财政年份:2023
- 资助金额:
$ 114.13万 - 项目类别:
Novel Intranasal Formulations of Allopregnanolone, a Regenerative Therapeutic for Alzheimer's Disease
Allopregnanolone 的新型鼻内制剂,一种阿尔茨海默病的再生疗法
- 批准号:
10698555 - 财政年份:2023
- 资助金额:
$ 114.13万 - 项目类别:
PhytoSERM Efficacy to Prevent Menopause Associated Decline in Brain Metabolism and Cognition: A Double-Blind, Randomized, Placebo-Controlled Phase 2 Clinical Trial
PhytoSERM 预防更年期相关脑代谢和认知能力下降的功效:双盲、随机、安慰剂对照 2 期临床试验
- 批准号:
10560591 - 财政年份:2022
- 资助金额:
$ 114.13万 - 项目类别:
PhytoSERM for Menopausal Hot Flashes and Sustained Brain Health
PhytoSERM 针对更年期潮热和持续大脑健康
- 批准号:
10547639 - 财政年份:2022
- 资助金额:
$ 114.13万 - 项目类别:
PhytoSERM Efficacy to Prevent Menopause Associated Decline in Brain Metabolism and Cognition: A Double-Blind, Randomized, Placebo-Controlled Phase 2 Clinical Trial
PhytoSERM 预防更年期相关脑代谢和认知能力下降的功效:双盲、随机、安慰剂对照 2 期临床试验
- 批准号:
10344556 - 财政年份:2022
- 资助金额:
$ 114.13万 - 项目类别:
PhytoSERM for Menopausal Hot Flashes and Sustained Brain Health
PhytoSERM 针对更年期潮热和持续大脑健康
- 批准号:
10707107 - 财政年份:2022
- 资助金额:
$ 114.13万 - 项目类别:
Regulatory and Human Study Operations (RHSO) Core C
监管和人体研究运营 (RHSO) 核心 C
- 批准号:
10689308 - 财政年份:2021
- 资助金额:
$ 114.13万 - 项目类别:
Regulatory and Human Study Operations (RHSO) Core C
监管和人体研究运营 (RHSO) 核心 C
- 批准号:
10491851 - 财政年份:2021
- 资助金额:
$ 114.13万 - 项目类别:
Regulatory and Human Study Operations (RHSO) Core C
监管和人体研究运营 (RHSO) 核心 C
- 批准号:
10270190 - 财政年份:2021
- 资助金额:
$ 114.13万 - 项目类别:
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