The role of blood and brain 5-hydroxymethylcytosine in linking vascular risk factors to ADRD in older White and Black persons
血液和脑 5-羟甲基胞嘧啶在老年白人和黑人血管危险因素与 ADRD 之间的联系中的作用
基本信息
- 批准号:10315659
- 负责人:
- 金额:$ 327.52万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2021
- 资助国家:美国
- 起止时间:2021-08-15 至 2024-07-31
- 项目状态:已结题
- 来源:
- 关键词:AddressAffectAgeAgingAlzheimer&aposs DiseaseAlzheimer&aposs disease brainAlzheimer&aposs disease pathologyAlzheimer&aposs disease related dementiaAlzheimer&aposs disease riskAmyloidAutopsyBiologicalBloodBlood PressureBlood VesselsBlood specimenBody mass indexBrainBrain PathologyCause of DeathCerebrovascular DisordersChemicalsChronicClinicalClinical DataCognitionCognitiveCohort StudiesCollectionCommunitiesCytosineDNADataDementiaDiabetes MellitusDiseaseElderlyEpigenetic ProcessFreezingGene ActivationGenetic TranscriptionGenomic DNAGlycosylated hemoglobin AGoalsHumanImpaired cognitionIndividualInterventionKnowledgeLife StyleLinkMapsMeasuresMethodsModificationNeurofibrillary TanglesParticipantPathologicPathologyPatientsPerformancePersonsPharmaceutical PreparationsPhenotypePlayPrefrontal CortexPreventionProcessPublic HealthRaceResearchResearch PriorityResourcesRoleScienceSensitivity and SpecificitySerumSocietiesTechniquesTissue SampleTissuesValidationVascular Diseasesaging brainbaseblack menblack womenblood resourcebrain tissuecell free DNAcerebrovascularclinical carecohortdementia caredementia riskdemethylationepigenomeexperimental studygenome-wideimprovedminimally invasivenanonovelpopulation healthprimary outcomeracial minorityresponsesealsecondary analysissextoolvascular factorvascular risk factor
项目摘要
PROJECT SUMMARY/ ABSTRACT
Alzheimer’s Disease (AD) is a chronic and disabling condition, the 6th leading cause of death in the US, and a
major cause of personal, societal, and global burden. Yet, our understanding of pathobiologic mechanisms
underlying dementia and cognitive impairment in aging remains incomplete, and this gap in knowledge hinders
scientific advancement and improved clinical care and prevention. Vascular conditions such as diabetes
mellitus (DM) are common, especially among minority racial groups, and recognized as increasing dementia
risk. Because these factors are modifiable by treatment and lifestyle approaches, research linking vascular
factors to Alzheimer’s Disease/ Alzheimer’s Disease-Related Dementias (AD/ADRD) is more important than
ever. Emerging data suggests that the epigenome likely plays a role in this link, and novel methods to study
the epigenome are now available. 5-hydroxymethylcytosine (5hmC) is an epigenetic modification of cytosine
for which we can now measure genome-wide changes in circulating cell-free DNA (cfDNA) in blood and
genomic DNA (gDNA) in tissues. Our group has developed a highly sensitive and selective analytic approach
to capture and sequence 5hmC-containing DNA fragments in order to map genome-wide distributions, and
have successfully used this approach to develop 5hmC scores which distinguish between patients with and
without different conditions, including in recent studies of AD and DM. In response to the pressing need to
better understand the pathobiologic underpinnings of AD/ADRD, we propose a collaborative project with the
overall goal of elucidating epigenetic mechanisms linking vascular risk factors to AD/ADRD clinical and
pathological phenotypes, in older Whites and Blacks. The proposed study will leverage available resources
from two community-based cohort studies, including research participants from which to collect blood
specimens, as well as extensive longitudinal clinical data and postmortem neuropathologic data, and
biospecimens (e.g., frozen brain tissue samples). Among White and Black persons, we will collect new
genome-wide 5hmC data to generate serum-specific (Aims 1 and 4) and brain-specific 5hmC scores (Aims 2
and 4), using discovery and validation experiments in different sets of persons, that distinguishes between
persons with and without dementia. We will then link the blood and brain 5hmC data to AD/ADRD clinical and
pathologic phenotypes, including incident dementia and cognitive decline (Aims 1 and 4), cerebrovascular and
AD pathology (Aim 2). We will further examine if relations are differential by vascular risk factors (DM, blood
pressure [BP], and body mass index [BMI]) and by other factors (e.g., sex; Aims1-4), and if generalizable to
Black persons (Aim 4). Because vascular risk factors are common and modifiable, this study which will
elucidate 5hmC mechanisms in AD/ADRD and vascular diseases among White and Black older persons, will
fill a major gap in scientific knowledge about dementia and provide important data to inform future research
and to ultimately improve clinical dementia care and prevention.
项目总结/摘要
阿尔茨海默病(AD)是一种慢性和致残性疾病,是美国第六大死亡原因,
是个人、社会和全球负担的主要原因。然而,我们对病理生物学机制的理解
老年痴呆症和认知障碍的基础仍然不完整,这种知识的差距阻碍了
科学进步和改善临床护理和预防。糖尿病等血管疾病
糖尿病(DM)是常见的,特别是在少数民族群体中,并被认为是增加痴呆症
风险由于这些因素可以通过治疗和生活方式来改变,
阿尔茨海默病/阿尔茨海默病相关痴呆(AD/ADRD)的因素比
史以来新出现的数据表明,表观基因组可能在这一联系中发挥作用,
表观基因组现在是可用的。5-羟甲基胞嘧啶(5 hmC)是胞嘧啶的表观遗传修饰
我们现在可以测量血液中循环无细胞DNA(cfDNA)的全基因组变化,
基因组DNA(gDNA)。我们的团队开发了一种高度敏感和选择性的分析方法
捕获并测序含5 hmC的DNA片段,以绘制全基因组分布图,以及
已经成功地使用这种方法来开发5 hmC评分,该评分可以区分患有和
没有不同的条件,包括在最近的研究AD和DM。为了满足迫切需要,
为了更好地了解AD/ADRD的病理生物学基础,我们提出了一个与
总体目标是阐明将血管危险因素与AD/ADRD临床和临床表现联系起来的表观遗传机制,
病理表型,在老年白人和黑人。拟议的研究将利用现有资源
来自两项基于社区的队列研究,包括采集血液的研究参与者
标本,以及广泛的纵向临床数据和死后神经病理学数据,以及
生物样本(例如,冷冻脑组织样品)。在白色和黑色的人,我们将收集新的
全基因组5 hmC数据,以生成血清特异性(目的1和4)和脑特异性5 hmC评分(目的2
和4),使用不同人群的发现和验证实验,区分
患有和不患有痴呆症的人。然后,我们将血液和脑5 hmC数据与AD/ADRD临床和
病理表型,包括偶发性痴呆和认知下降(目的1和4),脑血管和
AD病理学(目的2)。我们将进一步检查是否有血管危险因素(糖尿病,血液)的差异
血压[BP]和体重指数[BMI])和其他因素(例如,性别;目标1 -4),如果可推广到
黑人(目标4)。由于血管危险因素是常见的和可改变的,这项研究将
阐明白色和黑人老年人AD/ADRD和血管疾病中的5 hmC机制,将
填补了关于痴呆症的科学知识的重大空白,并为未来的研究提供了重要数据。
并最终改善痴呆症的临床护理和预防。
项目成果
期刊论文数量(3)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
PETCH-DB: a Portal for Exploring Tissue-specific and Complex disease-associated 5-Hydroxymethylcytosines.
- DOI:10.1093/database/baad042
- 发表时间:2023-06-10
- 期刊:
- 影响因子:0
- 作者:
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Zoe Arvanitakis其他文献
Zoe Arvanitakis的其他文献
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{{ truncateString('Zoe Arvanitakis', 18)}}的其他基金
Brain cPLA2 as a mechanism for neuroinflammation in AD/ADRD with and without APOE4
大脑 cPLA2 作为 AD/ADRD 神经炎症的机制,有或没有 APOE4
- 批准号:
10464564 - 财政年份:2022
- 资助金额:
$ 327.52万 - 项目类别:
Vascular Cognitive and Motor Decline: Impact of aPL
血管认知和运动衰退:aPL 的影响
- 批准号:
8336938 - 财政年份:2011
- 资助金额:
$ 327.52万 - 项目类别:
Vascular Cognitive and Motor Decline: Impact of aPL
血管认知和运动衰退:aPL 的影响
- 批准号:
8881036 - 财政年份:2011
- 资助金额:
$ 327.52万 - 项目类别:
Vascular Cognitive and Motor Decline: Impact of aPL
血管认知和运动衰退:aPL 的影响
- 批准号:
8728095 - 财政年份:2011
- 资助金额:
$ 327.52万 - 项目类别:
Vascular Cognitive and Motor Decline: Impact of aPL
血管认知和运动衰退:aPL 的影响
- 批准号:
8526334 - 财政年份:2011
- 资助金额:
$ 327.52万 - 项目类别:
Vascular Cognitive and Motor Decline: Impact of aPL
血管认知和运动衰退:aPL 的影响
- 批准号:
8234526 - 财政年份:2011
- 资助金额:
$ 327.52万 - 项目类别:
Oxidative Stress, Aging and Alzheimer's Disease
氧化应激、衰老和阿尔茨海默病
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7556333 - 财政年份:2005
- 资助金额:
$ 327.52万 - 项目类别:
Oxidative Stress, Aging and Alzheimer's Disease
氧化应激、衰老和阿尔茨海默病
- 批准号:
7007680 - 财政年份:2005
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$ 327.52万 - 项目类别:
Oxidative Stress, Aging and Alzheimer's Disease
氧化应激、衰老和阿尔茨海默病
- 批准号:
7367080 - 财政年份:2005
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$ 327.52万 - 项目类别:
Oxidative Stress, Aging and Alzheimer's Disease
氧化应激、衰老和阿尔茨海默病
- 批准号:
6868496 - 财政年份:2005
- 资助金额:
$ 327.52万 - 项目类别:
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