Iron homeostasis and monocyte differentiation in patients with chronic kidney disease

慢性肾病患者的铁稳态和单核细胞分化

• 批准号: 10648527
• 负责人: Oleh Akchurin
• 金额: $ 12.71万
• 依托单位: WEILL MEDICAL COLL OF CORNELL UNIV
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-04-01 至 2025-03-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10648527
• 关键词: Acceleration; Address; Adult; Affect; American; Anemia; Animal Model; Antioxidants; Award; Behavior; CX3CL1 gene; Cells; Characteristics; Chemotactic Factors; Chemotaxis; Child; Chronic; Chronic Kidney Failure; Clinical; Collecting Cell; Color; Data; Dialysis procedure; Disease Progression; End stage renal failure; Etiology; Evaluation; Excretory function; Exhibits; Fibrosis; Flow Cytometry; Functional disorder; Funding; Genes; Goals; Homeostasis; Human; Individual; Inflammatory; Injury to Kidney; Invaded; Iron; Kidney; Kidney Diseases; Kidney Failure; Kidney Transplantation; Knowledge; Life Cycle Stages; Macrophage; Molecular; Mus; Myelogenous; Myeloid Cells; Pathogenicity; Pathologic; Patients; Peripheral; Peripheral Blood Mononuclear Cell; Persons; Phenotype; Play; Population; Proteins; Renal function; Research Personnel; Role; Serum; Techniques; Testing; Therapeutic; Time; Tissues; Urine; Work; biobank; chemokine; chemokine receptor; experience; experimental study; human data; improved outcome; iron deficiency; iron metabolism; kidney fibrosis; migration; monocyte; novel; peripheral blood; preclinical study; receptor; repository; response; systemic inflammatory response; therapeutic target; transcriptomics

PROJECT SUMMARY Chronic kidney disease (CKD) affects 10% of the population worldwide. More than 37 million people are estimated to have CKD in the US, and 2 in every 1000 Americans need dialysis or a kidney transplant to survive. CKD has numerous systemic complications including anemia and dysfunctional systemic iron homeostasis. Kidney fibrosis is the final mechanism common for all progressive kidney disorders. Unfortunately, very few therapies are available to slow the progression of kidney fibrosis in patients with CKD. Kidney macrophages are one of the key cells implicated in the pathophysiology of kidney fibrosis. The majority of kidney macrophages originate from circulating monocytes. In his K08-funded project Dr. Akchurin elucidated the pathologic role of depletion of labile iron pool in kidney macrophages in propagation of kidney fibrosis. This R03 proposal will enhance his capabilities of deciphering the role of iron in pathologic behavior of myeloid cells in CKD by now, in addition to kidney macrophages focusing on their precursors, circulating monocytes. Based on the preliminary data, the central hypothesis of this proposal is that in patients with CKD, circulating monocytes, similar to kidney macrophages, exhibit pathologically depleted intracellular labile iron pool LIP, which alters their phenotype by inducing CX3CR1 and other receptors facilitating chemotaxis and tissue invasion. Repletion of this intracellular monocyte labile iron pool through correction of systemic iron imbalance will be associated with reduction of this pro-inflammatory differentiation. This hypothesis will be tested in two specific aims: (1) determine the intracellular iron status of classical, intermediate, and non-classical circulating monocytes in patients with CKD and (2) elucidate the role of systemic and intracellular iron status in the differentiation of monocytes in patients with CKD. To test this hypothesis, the applicant will use the existing repository of peripheral blood mononuclear cells collected from children with CKD with and without functional or absolute iron deficiency and from healthy control children. He will evaluate these cells using single cell transcriptomic and multicolor flow cytometry approaches with the focus on delineating the phenotypic features responsible for subsequent tissue invasion, such as expression relevant chemokine receptors, including CX3CR1. Furthermore, he will perform ex vivo evaluation of human monocytes collected from CKD patients to directly assess their relevant functional characteristics in the presence and absence of iron stimulation. Monocyte functional characteristics will be analyzed I the context of clinical parameters, levels of circulating and urine-excreted chemokines, and systemic parameters of iron homeostasis. Results techniques an kidney from t he outlined experiments will provide preliminary data, as well as experience in for the functional ex-vivo testing of uman monocytes, to support the K08 awardee's application for R01 proposal to evaluate the impact of iron metabolism and iron therapy on myeloid cells in the context of fibrosis and CKD progression. h

项目总结