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

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

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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.

不确定电势（CHIP）的克隆造血作用是一种新认识的疾病，其特征是遗传上不同，增殖性克隆白细胞种群的个体发生。芯片的患病率增加年龄较大，不仅与血液学癌症的风险有关，而且与纤维化，全身性有关炎症和动脉粥样硬化心血管疾病。通过移植的小鼠概括芯片克隆白细胞导致加速性动脉粥样硬化，心脏纤维化和克隆的直接组织浸润巨噬细胞和间质纤维化的刺激。年龄是慢性肾脏疾病（CKD）的主要危险因素，与加速有关心血管疾病，过早死亡以及透析依赖性的进展。生物学机制赋予这种与年龄相关的风险尚不完全理解。最终的常见病理过程进行性CKD是微管间隙纤维化，其特征是炎症的积累肾脏间质和肾小管上皮细胞的永久损失内的浸润和成纤维细胞。微管间质纤维化也代表了急性肾脏损伤进展的中心基础病变（AKI）慢性病。基于芯片与动脉粥样硬化，肾脏间隙炎症和纤维化之间的机械联系，我们假设芯片是CKD进展的新型生物学风险因素。为了检验这一假设，我们提出了确定芯片与肾脏疾病进展的关联，在既定的CKD和AKI中。同时，我们建议使用公认的慢性动物模型来描述潜在的因果机制和急性肾脏疾病。克隆白细胞鉴定为CKD进展的新机制将代表一种新疾病可以激发未来目标干预措施的途径。