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: 10626828
• 负责人: Michel Benjamin Chonchol
• 金额: $ 60.27万
• 依托单位: UNIVERSITY OF COLORADO DENVER
• 依托单位国家: 美国
• 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: https://reporter.nih.gov/project-details/10626828
• 关键词: Acceleration; Adipocytes; Adult; Aging; Automobile Driving; Biological; Blood; Blood Cells; Bone Marrow; Cardiovascular Diseases; Cardiovascular system; Cells; Cessation of life; Chronic; Chronic Kidney Failure; Clinical; Clonal Evolution; Clonal Expansion; Cognitive; DNA; Data; Dementia; Development; Disease; Disease Progression; Elderly; Epidemiology; Event; Fatty acid glycerol esters; Femur; Genes; Genetic; Goals; Growth; Hematopoiesis; Hematopoietic; Hematopoietic stem cells; Human; Impaired cognition; Impairment; Incidence; Individual; Inflammatory; Interleukin-6; Intervention Trial; Kidney; Kidney Diseases; Knowledge; Link; Magnetic Resonance Imaging; Malignant Neoplasms; Modeling; Mutation; Participant; Pathogenesis; Pathologic; Patient Recruitments; Patients; Play; Prevalence; Prognosis; Quality of life; Renal function; Resources; Risk Factors; Role; Shapes; Somatic Mutation; Testing; Vascular Diseases; Vertebral column; Work; age related; aged; blood pressure intervention; clinical risk; cognitive function; cohort; environmental stressor; functional decline; genomic data; global health; high risk; inflammatory marker; insight; leukemia; metabolomics; mild cognitive impairment; mortality; mutant; novel; prospective; recruit; systemic inflammatory response; targeted sequencing

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.

项目摘要 慢性肾脏疾病（CKD）主要是与年龄有关的疾病，与加速有关 认知功能下降。尽管流行病学证据将轻度认知障碍（MCI）和 随着肾功能下降的痴呆，我们仍然对涉及其因素的不完全理解 发病机理表明还有其他未知与年龄相关的因果风险因素驱动 MCI，痴呆和肾功能下降的发展和进展。最近的数据表明衰老 人类在造血干细胞中积累白血病相关的体细胞突变。这些突变 似乎为突变细胞提供了竞争性的增长优势，从而可以进行性克隆膨胀 已被定义为克隆造血（CH），其特征是慢性全身性恶化 炎。 CH与几种病理状况有关，包括心血管疾病，但是 尚未探索它与认知和肾脏终点的关联。另外，基础 驾驶CH的机制仍有待确定。因此，我们的主要目标是建立一个协会 在CH与MCI，痴呆和肾脏疾病进展之间。鉴于CH和老化之间的相互作用 骨髓（BM）脂肪微环境的相关变化，该应用的关键次要目标是 确定BM脂肪在CH进化中的作用。我们还将检查血液代谢物特征 与临床上有意义的认知和CKD终点以及较高BM脂肪含量的较高风险相关。 我们的初步数据表明，CKD患者的CH发生了显着出现。另外，我们已经表明 BM脂肪细胞会产生局部炎症特征，包括促进CH的白介素-6增加。 这些发现为我们的假设提供了有力的前提，即CH与MCI，痴呆和CKD相关联， BM脂肪在CH开发中起着重要作用。我们将利用 收缩压干预试验（SPRINT），包括评估认知的纵向数据 功能和CKD，生物测量和DNA促进CH的评估。在6,000个冲刺的子集中 50岁或50岁以上的参与者在基线时具有正常肾功能，我们将在基线时确定CH 我们针对的测序面板和分析管道，用于召唤躯体突变，并评估CH是否是否 确定那些患认知和肾功能障碍风险最高的人。我们提出3个目标；目标1：到 评估CH与代谢组学与事件MCI和痴呆症事件之间的前瞻性关联 在基线时具有正常肾功能的Sprint参与者中。目标2：评估潜在的 CH与代谢组学与肾脏疾病进展事件之间的关联 基线时具有正常肾功能的参与者。目标3：定义BM Fat和Clonal之间的链接 CKD中的造血。了解与CH和相关的疾病相关的危险因素 机制可能会发现减轻MCI，痴呆和肾脏疾病进展的新方法。