Clonal hematopoiesis, mild cognitive impairment and kidney function decline

项目总结 慢性肾脏疾病(CKD)是一种主要与年龄相关的疾病，与加速 认知功能下降。尽管流行病学证据表明轻度认知障碍(MCI)和 痴呆伴肾功能下降，我们对其所涉及的因素仍有不完全的认识 发病机制表明，还有其他与年龄相关的不明原因风险因素推动了 MCI的发展和进展、痴呆症和肾功能下降。最近的数据表明，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的生长优势，允许渐进的克隆性扩张 它被定义为克隆性造血(CH)，其特征是慢性全身性恶化 发炎。然而，CH与包括心血管疾病在内的几种病理情况有关， 它与认知和肾脏终点的关系还没有被探索过。此外，潜在的 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 慢性心肌梗塞、痴呆和肾脏疾病进展之间的关系。鉴于CH和衰老之间的相互作用 骨髓(BM)脂肪微环境的相关变化，这项应用的一个关键次要目标是 确定骨髓脂肪在先天性心脏病发生发展中的作用。我们还将检查血液代谢物的特征 与临床上有意义的认知和CKD终点的风险较高以及BM脂肪含量较高有关。 我们的初步数据显示慢性肾脏病患者发生明显的慢性肾功能衰竭。此外，我们还展示了 骨髓脂肪细胞产生局部炎症信号，包括促进CH的IL-6升高。 这些发现为我们的假设提供了强有力的前提，即CH与MCI、痴呆症和CKD有关， BM脂肪在CH的发生发展中起着重要作用。我们将利用独一无二的资源 收缩压干预试验(SPRINT)，包括关于认知评估的纵向数据 CH.的功能和CKD、生物显微镜和DNA使能评估。在6,000个Sprint的子集中 50岁或以上的受试者在基线时肾功能正常，我们将使用以下方法确定基线时的CH 我们的靶向测序小组和分析流水线用于体细胞突变的调用和评估 确定那些认知和肾功能受损风险最高的人。我们提出了三个目标；目标1： 评估CH和代谢组学与MCI和痴呆事件的前瞻性关联 在基线肾功能正常的短跑参赛者中。目标2：评估未来 Sprint人群中CH和代谢组学与肾脏疾病进展事件的关系 基线时肾功能正常的受试者。目标3：确定骨髓脂肪和克隆之间的联系 慢性肾脏病的造血功能。了解与CH相关的疾病相关危险因素及相关因素 这些机制可能会发现减轻MCI、痴呆症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.