Clonal hematopoiesis, mild cognitive impairment and kidney function decline

项目摘要 慢性肾脏病（CKD）是一种主要与年龄相关的疾病， 认知功能下降尽管有流行病学证据表明轻度认知障碍（MCI）和 虽然老年痴呆症伴肾功能下降，但我们对其相关因素仍有不完全的了解， 发病机制表明，还有其他未确定的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， 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生长优势，允许进行性克隆扩增 其被定义为克隆性造血（CH），其特征在于慢性全身性 炎症然而，CH与包括心血管疾病在内的几种病理状况有关， 其与认知和肾脏终点的关联尚未探索。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。考虑到CH和衰老之间的相互作用 骨髓（BM）脂肪微环境的相关变化，本申请的关键次要目标是 确定BM脂肪在CH演变中的作用。我们还将检查血液代谢物特征 与具有临床意义的认知和CKD终点的风险较高以及BM脂肪含量较高相关。 我们的初步数据表明，慢性肾脏病患者中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信号，包括促进CH的增加的白细胞介素-6。 这些发现为我们的假设提供了一个强有力的前提，即CH与MCI、痴呆和CKD相关， 并且BM脂肪在CH发展中起重要作用。我们将充分利用 收缩压干预试验（SPRINT），包括认知功能评估的纵向数据 功能和CKD，生物标本和DNA，使CH的评估。在一个子集的6,000 SPRINT 基线时肾功能正常的50岁或以上受试者，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 识别认知和肾功能受损风险最高的人群。我们提出三个目标：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 在基线时肾功能正常的SPRINT参与者中。目的2：评估前瞻性 CH和代谢组学与SPRINT中肾脏疾病进展事件之间的相关性 基线时肾功能正常的受试者。目的3：确定BM脂肪和克隆性脂肪之间的联系 CKD中的造血。了解与CH相关的疾病相关危险因素和相关的 这些机制可能会发现减少MCI，痴呆和肾脏疾病进展负担的新方法。

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.