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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：
10419907
负责人：
RAYMOND C. HARRIS
金额：
$ 74.05万
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/10419907
关键词：
APOL1 gene 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 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 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 base cohort coronary fibrosis experience functional decline genetic risk factor high risk interstitial macrophage monocyte mouse model multidisciplinary novel premature programs 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.

不确定潜能克隆造血 (CHIP) 是一种新近认识的疾病，其特征是遗传上独特的增殖性克隆白细胞群体的个体发生。 CHIP 患病率增加随着年龄的增长，不仅与血液癌症的风险相关，而且与纤维化、全身性癌症的风险相关。炎症和动脉粥样硬化性心血管疾病。通过移植在小鼠体内重现 CHIP 克隆性白细胞导致动脉粥样硬化加速、心脏纤维化和克隆性白细胞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) 的主要危险因素，与加速肾病相关心血管疾病、过早死亡和发展为透析依赖。生物学机制这种与年龄相关的风险尚不完全清楚。最终共同的病理过程进行性 CKD 是肾小管间质纤维化，其特征是炎症细胞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损失。肾小管间质纤维化也是急性肾损伤进展中的核心潜在病变 (AKI) 到慢性疾病。基于 CHIP 与动脉粥样硬化、肾间质炎症和纤维化之间的机制联系，我们假设 CHIP 是 CKD 进展的一种新的生物危险因素。为了检验这个假设，我们提出确定 CHIP 与已建立的 CKD 和 AKI 队列中肾脏疾病进展的关联。与此同时，我们建议使用公认的慢性病动物模型来描绘潜在的因果机制。和急性肾脏疾病。克隆白细胞作为 CKD 进展的新机制的鉴定将代表一种新疾病可以激发未来有针对性的干预措施的途径。