Monocyte Mitochondrial Dysfunction and Kidney Stone Disease

单核细胞线粒体功能障碍和肾结石病

• 批准号: 9352842
• 负责人: Tanecia R Mitchell
• 金额: $ 15.35万
• 依托单位: UNIVERSITY OF ALABAMA AT BIRMINGHAM
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-09-15 至 2021-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9352842
• 关键词: Age; Area; Biometry; Blood Platelets; Calcium Oxalate; Cell Line; Cells; Chromatography; Clinical Research; Confocal Microscopy; Crystal Formation; Crystallization; Data; Diet; Disease; Event; Exposure to; Filtration; Flow Cytometry; Functional disorder; Funding; Gender; Genetic; Goals; Human; Immune; Immunology; Inflammasome; Inflammation; Inflammatory; Inflammatory Response; Interleukin-1 beta; Interleukin-6; Ions; Kidney; Kidney Calculi; Lead; Link; Mass Spectrum Analysis; Measures; Mediating; Mentors; Mitochondria; Molecular Biology Techniques; Monocyte Chemoattractant Protein-1; Nephrons; Oxalates; Oxidation-Reduction; Oxidative Stress; Pathogenesis; Pathway interactions; Patients; Plasma; Play; Population; Process; Production; Property; Recruitment Activity; Renal Tissue; Reporting; Research; Research Personnel; Role; Signal Transduction; Techniques; Testing; Tissues; Training; Translational Research; United States; United States National Institutes of Health; Urine; Work; biological adaptation to stress; chemokine; cohort; cytokine; experience; high throughput screening; inflammatory marker; insight; kidney cell; lifestyle factors; macrophage; mitochondrial dysfunction; monocyte; nephrogenesis; outcome forecast; response; skills; success; urinary

Project Summary/Abstract Approximately 9% of the United States population will develop a kidney stone in their lifetime. Lifestyle factors, genetics, and diet all contribute to the development of kidney stones. The most common type of kidney stone is comprised of calcium oxalate (CaOx) crystals. Research on kidney stones is hampered by limited access to kidney cells and tissue from patients. Very few studies have focused on circulating immune cells which may play a role in disease processes. Monocytes/macrophages are essential for crystal clearance and are recruited to the renal interstitium. We recently determined that monocytes but not lymphocytes or platelets have lower mitochondrial function in patients with CaOx kidney stones compared to healthy subjects. The objective of the current proposal is to evaluate for changes in mitochondrial function, oxidative stress, and inflammatory responses in circulating monocytes and plasma from a large cohort of patients with CaOx kidney stones and healthy subjects. This may identify specific responses associated with this disease. The central hypothesis of the current proposal is circulating monocytes in patients with CaOx kidney stones develop mitochondrial dysfunction due to cellular events mediated by CaOx stones and/or exposure to CaOx crystals in the nephron. This hypothesis will be tested by pursuing three specific aims: 1) Determine whether mitochondrial dysfunction, oxidative stress, and inflammation are associated with circulating monocyte subtypes in patients with CaOx kidney stones; 2) Elucidate whether cytokines or CaOx crystals induce NLRP3 inflammasome pathways and mitochondrial dysfunction in primary monocytes and a human derived monocyte cell line; and 3) Determine whether a dietary oxalate load that produces urinary CaOx crystals in healthy subjects causes similar monocyte responses to those observed in patients. The proposed studies may provide new insights regarding the role of monocyte function and inflammation in CaOx kidney stone disease. This research plan will allow the applicant to gain additional experience in kidney stone disease and clinical research plus training in mass spectrometry, renal pathophysiology, immunology, and biostatistics through practical experience, course work, and guidance from an experienced mentoring team. It will also advance and facilitate the success of the applicant to transition into becoming an independent and productive NIH-funded investigator focused on monocytes and kidney stone disease.

项目概要/摘要 大约 9% 的美国人一生中会患上肾结石。生活方式 因素、遗传和饮食都会导致肾结石的形成。最常见的肾脏类型 石头由草酸钙 (CaOx) 晶体组成。肾结石的研究受到有限的阻碍 获取患者的肾细胞和组织。很少有研究关注循环免疫细胞 这可能在疾病过程中发挥作用。单核细胞/巨噬细胞对于晶体清除和 被募集至肾间质。我们最近确定单核细胞而不是淋巴细胞或血小板 与健康受试者相比，CaOx 肾结石患者的线粒体功能较低。这 当前提案的目标是评估线粒体功能、氧化应激和线粒体功能的变化 来自大量 CaOx 肾患者的循环单核细胞和血浆中的炎症反应 结石和健康受试者。这可以识别与这种疾病相关的特定反应。中央 目前提议的假设是 CaOx 肾结石患者的循环单核细胞发育 由于 CaOx 结石和/或暴露于 CaOx 晶体介导的细胞事件导致线粒体功能障碍 肾单位。该假设将通过追求三个具体目标来检验：1）确定是否 线粒体功能障碍、氧化应激和炎症与循环单核细胞有关 CaOx 肾结石患者的亚型； 2) 阐明细胞因子或CaOx晶体是否诱导NLRP3 原代单核细胞和人源单核细胞的炎症小体途径和线粒体功能障碍 细胞系； 3) 确定健康人体内的膳食草酸负荷是否会产生尿 CaOx 晶体 受试者引起与患者中观察到的相似的单核细胞反应。拟议的研究可能会提供 关于单核细胞功能和炎症在 CaOx 肾结石疾病中的作用的新见解。这 研究计划将使申请人获得肾结石疾病和临床的额外经验 质谱、肾脏病理生理学、免疫学和生物统计学方面的研究和培训 实践经验、课程作业以及经验丰富的指导团队的指导。也将推进并 促进申请人成功过渡成为独立且富有成效的 NIH 资助的人 研究人员专注于单核细胞和肾结石疾病。