Clonal hematopoiesis, mild cognitive impairment and kidney function decline
克隆性造血、轻度认知障碍和肾功能下降
基本信息
- 批准号:10626828
- 负责人:
- 金额:$ 60.27万
- 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:2022-06-01 至 2027-03-31
- 项目状态:未结题
- 来源:
- 关键词:AccelerationAdipocytesAdultAgingAutomobile DrivingBiologicalBloodBlood CellsBone MarrowCardiovascular DiseasesCardiovascular systemCellsCessation of lifeChronicChronic Kidney FailureClinicalClonal EvolutionClonal ExpansionCognitiveDNADataDementiaDevelopmentDiseaseDisease ProgressionElderlyEpidemiologyEventFatty acid glycerol estersFemurGenesGeneticGoalsGrowthHematopoiesisHematopoieticHematopoietic stem cellsHumanImpaired cognitionImpairmentIncidenceIndividualInflammatoryInterleukin-6Intervention TrialKidneyKidney DiseasesKnowledgeLinkMagnetic Resonance ImagingMalignant NeoplasmsModelingMutationParticipantPathogenesisPathologicPatient RecruitmentsPatientsPlayPrevalencePrognosisQuality of lifeRenal functionResourcesRisk FactorsRoleShapesSomatic MutationTestingVascular DiseasesVertebral columnWorkage relatedagedblood pressure interventionclinical riskcognitive functioncohortenvironmental stressorfunctional declinegenomic dataglobal healthhigh riskinflammatory markerinsightleukemiametabolomicsmild cognitive impairmentmortalitymutantnovelprospectiverecruitsystemic inflammatory responsetargeted sequencing
项目摘要
PROJECT SUMMARY
Chronic kidney disease (CKD) is a predominantly age-related disorder and is associated with accelerated
cognitive function decline. Despite epidemiological evidence linking mild cognitive impairment (MCI) and
dementia with kidney function decline, we still have an incomplete understanding of the factors involved in their
pathogenesis suggesting that there are other unidentified age-related causal risk factors that drive the
development and progression of MCI, dementia, and kidney function decline. Recent data indicates that aging
humans accumulate leukemia associated somatic mutations in hematopoietic stem cells. These mutations
appear to provide a competitive growth advantage to the mutant cells, allowing progressive clonal expansion
which has been defined as clonal hematopoiesis (CH) and it is characterized by worsening chronic systemic
inflammation. CH is associated with several pathological conditions including cardiovascular disease, however,
its association with cognitive and kidney endpoints has not been explored. In addition, the underlying
mechanisms driving CH remain to be determined. Hence, our primary objective is to establish an association
between CH with MCI, dementia, and kidney disease progression. Given the interplay between CH and aging
related changes in the bone marrow (BM) fat microenvironment, a key secondary goal of this application is to
determine the role of BM fat in the evolution of CH. We will also examine blood metabolite signatures
associated with higher risk for clinically meaningful cognitive and CKD endpoints and higher BM fat content.
Our preliminary data demonstrated a significant occurrence of CH in patients with CKD. Also, we have shown
that BM adipocytes produce a local inflammatory signature including increased interleukin-6 that promotes CH.
These findings provide a strong premise for our hypothesis that CH associates with MCI, dementia and CKD,
and that BM fat plays a significant role in CH development. We will leverage the unique resources of the
Systolic blood Pressure Interventional Trial (SPRINT), including longitudinal data on assessment of cognitive
function and CKD, biospecimens, and DNA enabling assessment of CH. In a subset of 6,000 SPRINT
participants aged 50 or older with normal kidney function at baseline, we will determine CH at baseline using
our targeted sequencing panel and analytic pipeline for somatic mutation calling and assess whether CH
identifies those at highest risk for cognitive and kidney function impairment. We propose 3 aims; Aim 1: To
evaluate the prospective associations between CH and metabolomics with incident MCI and dementia events
among SPRINT participants with normal kidney function at baseline. Aim 2: To evaluate the prospective
associations between CH and metabolomics with kidney disease progression events among SPRINT
participants with normal kidney function at baseline. Aim 3: To define a link between BM fat and clonal
hematopoiesis in CKD. Understanding the disease related risk factors associated with CH and the related
mechanisms may uncover new ways to reduce the burden of MCI, dementia and kidney disease progression.
项目总结
项目成果
期刊论文数量(0)
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科研奖励数量(0)
会议论文数量(0)
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Michel Benjamin Chonchol其他文献
Michel Benjamin Chonchol的其他文献
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{{ truncateString('Michel Benjamin Chonchol', 18)}}的其他基金
Clonal hematopoiesis, mild cognitive impairment and kidney function decline
克隆性造血、轻度认知障碍和肾功能下降
- 批准号:
10464393 - 财政年份:2022
- 资助金额:
$ 60.27万 - 项目类别:
Feasibility study of empagliflozin in patients with autosomal dominant polycystic kidney disease
恩格列净治疗常染色体显性多囊肾病的可行性研究
- 批准号:
10534531 - 财政年份:2022
- 资助金额:
$ 60.27万 - 项目类别:
Feasibility study of empagliflozin in patients with autosomal dominant polycystic kidney disease
恩格列净治疗常染色体显性多囊肾病的可行性研究
- 批准号:
10684097 - 财政年份:2022
- 资助金额:
$ 60.27万 - 项目类别:
Inspiratory muscle strength training for lowering systolic blood pressure in midlife and older adults with chronic kidney disease
吸气肌力量训练可降低患有慢性肾病的中年和老年人的收缩压
- 批准号:
10669712 - 财政年份:2021
- 资助金额:
$ 60.27万 - 项目类别:
Inspiratory muscle strength training for lowering systolic blood pressure in midlife and older adults with chronic kidney disease
吸气肌力量训练可降低患有慢性肾病的中年和老年人的收缩压
- 批准号:
10313126 - 财政年份:2021
- 资助金额:
$ 60.27万 - 项目类别:
Nicotinamide riboside supplementation for treating arterial stiffness and elevated systolic blood pressure in patients with moderate to severe CKD.
补充烟酰胺核苷可治疗中度至重度 CKD 患者的动脉僵硬度和收缩压升高。
- 批准号:
10640074 - 财政年份:2019
- 资助金额:
$ 60.27万 - 项目类别:
Nicotinamide riboside supplementation for treating arterial stiffness and elevated systolic blood pressure in patients with moderate to severe CKD.
补充烟酰胺核苷可治疗中度至重度 CKD 患者的动脉僵硬度和收缩压升高。
- 批准号:
10400032 - 财政年份:2019
- 资助金额:
$ 60.27万 - 项目类别:
Nicotinamide riboside supplementation for treating arterial stiffness and elevated systolic blood pressure in patients with moderate to severe CKD.
补充烟酰胺核苷可治疗中度至重度 CKD 患者的动脉僵硬度和收缩压升高。
- 批准号:
9762288 - 财政年份:2019
- 资助金额:
$ 60.27万 - 项目类别:
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