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.

项目概要 慢性肾病（CKD）是一种主要与年龄相关的疾病，并且与加速肾病相关 认知功能下降。尽管流行病学证据表明轻度认知障碍（MCI）与 肾功能衰退导致的痴呆，我们对其影响因素仍不完全了解 发病机制表明还有其他未确定的与年龄相关的因果危险因素驱动 MCI、痴呆和肾功能衰退的发生和进展。最新数据表明，老龄化 人类在造血干细胞中积累与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生长优势，允许逐步克隆扩增 其被定义为克隆性造血（CH），其特征是慢性全身性恶化 炎。 CH 与包括心血管疾病在内的多种病理状况有关，然而， 其与认知和肾脏终点的关联尚未被探索。此外，底层 驱动 CH 的机制仍有待确定。因此，我们的首要目标是建立一个协会 CH 与 MCI、痴呆和肾脏疾病进展之间的关系。鉴于 CH 与衰老之间的相互作用 骨髓（BM）脂肪微环境的相关变化，该应用的一个关键的次要目标是 确定 BM 脂肪在 CH 进化中的作用。我们还将检查血液代谢特征 与具有临床意义的认知和 CKD 终点的较高风险以及较高的 BM 脂肪含量相关。 我们的初步数据表明 CKD 患者中 CH 的发生率很高。此外，我们还展示了 BM 脂肪细胞产生局部炎症特征，包括促进 CH 的白细胞介素 6 增加。 这些发现为我们的假设提供了强有力的前提，即 CH 与 MCI、痴呆和 CKD 相关， BM 脂肪在 CH 发育中起着重要作用。我们将利用独特的资源 收缩压干预试验 (SPRINT)，包括认知评估的纵向数据 功能和 CKD、生物样本和 DNA 来评估 CH。在 6,000 个 SPRINT 的子集中 基线时肾功能正常的 50 岁或以上参与者，我们将使用以下方法确定基线时的 CH 我们的靶向测序面板和分析管道用于体细胞突变调用并评估 CH 是否 识别认知和肾功能损害风险最高的人群。我们提出3个目标；目标 1： 评估 CH 和代谢组学与 MCI 和痴呆事件之间的前瞻性关联 基线时肾功能正常的 SPRINT 参与者。目标 2：评估预期 CH 和代谢组学与 SPRINT 中肾脏疾病进展事件之间的关联 基线时肾功能正常的参与者。目标 3：确定骨髓脂肪和克隆之间的联系 CKD 中的造血作用。了解与 CH 相关的疾病相关危险因素以及相关疾病 机制可能会揭示减轻 MCI、痴呆和肾脏疾病进展负担的新方法。