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Impact of Clonal Hematopoiesis on the Progression of Kidney Disease

克隆造血对肾脏疾病进展的影响

基本信息

批准号：
10611485
负责人：
RAYMOND C. HARRIS
金额：
$ 71.75万
依托单位：
VANDERBILT UNIVERSITY MEDICAL CENTER
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：
2022-04-20 至 2026-03-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10611485
关键词：
APOL1 gene Acceleration Acute Acute Renal Failure with Renal Papillary Necrosis Adoptive Transfer Adult Affect Age Animal Model Aortic Valve Stenosis Atherosclerosis Biological Cardiovascular Diseases Cells Cessation of life Chronic Chronic Disease Chronic Kidney Failure DNMT3a DNMT3a mutation Data Dependence Diabetic Nephropathy Dialysis procedure Disease Disease Pathway Disease Progression Elderly Epidemiology Epithelial Cells Experimental Animal Model Fibroblasts Fibrosis Future Genes Genetic Hematologic Neoplasms Hematopoiesis Hematopoietic Stem Cell Transplantation Hematopoietic System Hematopoietic stem cells Individual Infiltration Inflammasome Inflammation Inflammatory Infiltrate Injury to Kidney Interleukin-1 Intervention Investigation JAK2 gene Kidney Kidney Diseases Lesion Leukocytes Link Macrophage Malignant - descriptor Malignant Neoplasms Modeling Molecular Biology Mus Mutation Myocardial Infarction Pathologic Processes Persons Population Prevalence Renal Hypertension Renal function Risk Risk Factors Role Somatic Mutation Stroke TP53 gene Testing Tissues Trans-Omics for Precision Medicine Transplantation Tubular formation UMOD gene Work age related atherogenesis cohort coronary fibrosis experience functional decline genetic risk factor high risk human old age (65+)interstitial monocyte mouse model multidisciplinary novel premature programs resilience systemic inflammatory response

项目摘要

Clonal hematopoiesis of indeterminate potential (CHIP) is a newly recognized disorder characterized by the ontogenesis of a genetically distinct, proliferative clonal leukocyte population. The prevalence of CHIP increases with older age and is associated not only with risk of hematologic cancers, but with fibrosis, systemic inflammation, and atherosclerotic cardiovascular diseases. Recapitulation of CHIP in mice by transplantation of clonal leukocytes results in accelerated atherosclerosis, cardiac fibrosis and direct tissue infiltration of clonal macrophages and stimulation of interstitial fibrosis. Age is a dominant risk factor for chronic kidney disease (CKD), which is associated with accelerated cardiovascular disease, premature death, and progression to dialysis dependence. The biological mechanisms conferring this age-associated risk are incompletely understood. The final common pathologic process in progressive CKD is tubulointerstitial fibrosis, which is characterized by the accumulation of inflammatory infiltrates and fibroblasts within the kidney interstitium and permanent loss of tubular epithelial cells. Tubulointerstitial fibrosis also represents the central underlying lesion in the progression of acute kidney injury (AKI) to chronic disease. Based on mechanistic links between CHIP and atherogenesis, kidney interstitial inflammation, and fibrosis, we hypothesize that CHIP is a novel biological risk factor for CKD progression. To test this hypothesis, we propose to determine the associations of CHIP with kidney disease progression in established cohorts of CKD and AKI. In parallel, we propose to delineate potential causal mechanisms using recognized animal models of chronic and acute kidney disease. The identification of clonal leukocytes as a novel mechanism of CKD progression would represent a new disease pathway that could motivate future targeted interventions.

不确定潜能克隆性造血（CHIP）是一种新认识的疾病，其特征是遗传上不同的增殖性克隆白细胞群体的个体发生。CHIP的患病率增加不仅与血液系统癌症的风险有关，而且与纤维化、全身性炎症和动脉粥样硬化性心血管疾病。通过在小鼠中移植CHIP来重现CHIP 克隆性白细胞导致加速的动脉粥样硬化、心脏纤维化和克隆性白细胞的直接组织浸润。巨噬细胞和间质纤维化的刺激。年龄是慢性肾脏病（CKD）的主要风险因素，与慢性肾脏病（CKD）的加速相关。心血管疾病、过早死亡和进展为透析依赖。的生物学机制与年龄相关的风险还不完全清楚。最后一个共同的病理过程，进行性CKD是肾小管间质纤维化，其特征在于炎性细胞因子的积聚。肾间质内的浸润和成纤维细胞以及肾小管上皮细胞的永久性丧失。肾小管间质纤维化也是急性肾损伤进展的中心基础病变 (AKI)到慢性病。基于CHIP与动脉粥样硬化形成、肾间质炎症和纤维化之间的机制联系，我们假设CHIP是CKD进展一种新的生物学危险因素。为了验证这一假设，我们建议在已建立的CKD和阿基队列中确定CHIP与肾脏疾病进展的相关性。与此同时，我们建议使用公认的慢性炎症动物模型来描述潜在的因果机制。和急性肾病。克隆性白细胞作为CKD进展的新机制的鉴定将代表一种新的疾病这是一个可以激励未来有针对性的干预措施的途径。

项目成果

期刊论文数量（2）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Infection risk associated with clonal hematopoiesis of indeterminate potential is partly mediated by hematologic cancer transformation in the UK Biobank.

在英国生物库中，与不确定潜力的克隆造血相关的感染风险部分是由血液癌转化介导的。

DOI：
10.1038/s41375-023-02023-7
发表时间：
2023
期刊：
Leukemia
影响因子：
11.4
作者：
Vlasschaert,Caitlyn;Akwo,Elvis;Robinson-Cohen,Cassianne;Cook,ElinaK;Lanktree,MatthewB;Rauh,MichaelJ;Bick,AlexanderG
通讯作者：
Bick,AlexanderG