Mechanisms of monocytosis and accelerated atherosclerosis in patients with CKD

CKD患者单核细胞增多和加速动脉粥样硬化的机制

• 批准号: 8581168
• 负责人: Anjali Ganda
• 金额: $ 18.13万
• 依托单位: COLUMBIA UNIVERSITY HEALTH SCIENCES
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-07-15 至 2018-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8581168
• 关键词: ATP-Binding Cassette Transporters; Arterial Fatty Streak; Atherosclerosis; Automobile Driving; Autophagocytosis; Basic Science; Biological Assay; Biology; Blood Cells; Blood Circulation; Bone Marrow; Cardiovascular Diseases; Cardiovascular system; Cause of Death; Cell Count; Cell surface; Cessation of life; Cholesterol; Chronic Kidney Failure; Clinical; Clinical Research; Clinical Trials; Cross-Sectional Studies; Data; Defect; Dialysis patients; Discipline; Documentation; End stage renal failure; Event; Flow Cytometry; Functional disorder; Funding; Future; Goals; Granulocyte-Macrophage Colony-Stimulating Factor; Harvest; Health; Hematopoietic; Heterogeneity; High Density Lipoproteins; Human; In Vitro; Individual; Institution; Institutional Review Boards; Interleukin-3; Isoleucine; Kidney; Knock-out; Laboratories; Lead; Learning; Link; Lipids; Liquid Chromatography; Lysosomes; Manuscripts; Measurement; Measures; Mediating; Medicine; Mentored Patient-Oriented Research Career Development Award; Mentors; Messenger RNA; Methodology; Methods; Monocytosis; Mus; Myelogenous; Myeloid Progenitor Cells; Nutrient; Oral; Pathway interactions; Patients; Phenylalanine; Play; Population; Process; Publications; Research; Research Personnel; Research Project Grants; Risk; Risk Factors; Solutions; Stem cells; Testing; Therapeutic; Training; Training Activity; Training Programs; Tyrosine; atherogenesis; base; cardiovascular risk factor; career; career development; clinical application; clinical phenotype; cohort; design; diet and cancer; human data; improved; in vivo; innovation; macrophage; metabolomics; monocyte; novel; professor; prospective; public health relevance; receptor; research study; stem; tandem mass spectrometry

DESCRIPTION (provided by applicant): Patients with chronic kidney disease (CKD) suffer from excessive rates of cardiovascular disease and death. There is a need for multi-disciplinary research that can bring together scientific discoveries and methodologies from different disciplines to find solutions to this problem. This K23 proposal details a comprehensive 5-year training program for my career development. My principal goal is to develop an independent career in mechanistically-based clinical research studies focused on accelerated atherosclerosis in patients with CKD. Ultimately, I would like to link my findings at the bench with bedside therapeutics that will reduce atherosclerosis and improve the lives of patients with CKD. My primary Mentor Dr. Alan Tall, Tilden-Weger- Bieler Professor of Medicine (with tenure) at Columbia, has pioneered research in mechanisms of atherogenesis and will lead a multi-disciplinary team of mentors. Two ATP-binding cassette transporters, ABCA1 and ABCG1, play key roles in promoting HDL-mediated cholesterol efflux. Murine studies in Dr. Tall's laboratory have shown that their knockout leads to proliferation of hematopoietic stem and multipotential progenitor cells, myeloid progenitor cells, and increased blood monocytes in association with accelerated atherosclerosis. Given the strong clinical association between monocytosis and atherosclerosis, this important basic science finding motivates further study in humans. In preliminary studies for this proposal, we present the first human data suggesting a link between defective cholesterol efflux pathways and monocytosis. The overarching goal of this proposal is to investigate mechanisms of monocytosis in CKD. My short-term goals are to: 1. Receive focused training in two key scientific learning modules: Monocyte/Macrophage Biology & Atherosclerosis and Clinical Phenotyping of Patients via Metabolomics 2. Enhance my understanding of the translational implications of my bench-related findings. I will learn how to link my basic findings at the bench to clinical applications that can improve the health of patient with CKD. 3. Refine my ability to articulate research ideas and findings through publications and oral presentations. 4. Develop independent research projects, and formulate an R01 application in years 3-4 of the K23 award period. I aim to become an independent investigator with R01 funding by the end of the K23 period. My long-term goals are to: 1. Build a productive, independent career in mechanistically-based clinical research studies focused on alleviating the burden of accelerated atherosclerosis in patients with CKD. My career will have both a laboratory and an active clinical trials component. 2. Expand my network of colleagues and collaborators, both at my own institution and elsewhere. 3. Train and mentor future researchers as they develop into independent investigators.

描述（由申请人提供）：患有慢性肾脏疾病（CKD）的患者心血管疾病和死亡率过多。需要多学科研究，可以将不同学科的科学发现和方法融合在一起，以找到解决这个问题的解决方案。该K23提案详细介绍了我的职业发展的全面5年培训计划。我的主要目的是在基于机械的临床研究中发展独立的职业，该研究的重点是加速CKD患者的动脉粥样硬化。最终，我想将我在长凳上的发现与床旁治疗剂联系起来，这些疗法将减少动脉粥样硬化并改善CKD患者的生活。我的主要导师艾伦·塔（Alan Tall）博士是哥伦比亚的蒂尔登·威格（Tilden-Weger-Bieler）医学教授（任职），他开创了动脉粥样硬化机制的研究，并将领导多学科的导师团队。两个ATP结合盒转运蛋白ABCA1和ABCG1在促进HDL介导的胆固醇外排起关键作用。塔博士实验室中的鼠研究表明，它们的敲除导致造血茎和多稳态祖细胞，髓样祖细胞的增殖，以及与加速动脉粥样硬化有关的血液单核细胞的增加。鉴于单核细胞增多症与动脉粥样硬化之间存在牢固的临床关联，这一重要的基础科学发现激发了对人类的进一步研究。在该提案的初步研究中，我们介绍了第一个人类数据，提示有缺陷的胆固醇外排途径与单核细胞增多症之间存在联系。该提案的总体目标是研究CKD中单核细胞增多症的机制。我的短期目标是：1。在两个关键的科学学习模块中接受重点培训：单核细胞/巨噬细胞生物学和动脉粥样硬化以及通过代谢组学对患者的临床表型2进行2。增强我对与替补席上相关发现的翻译意义的理解。我将学习如何将我的基本发现与可以改善CKD患者健康的临床应用联系起来。 3。完善我通过出版物和口头演示来表达研究思想和发现的能力。 4。开发独立的研究项目，并在K23奖励期的3 - 4年内制定R01应用程序。我的目标是在K23时期结束时成为R01资金的独立调查员。我的长期目标是：1。在基于机械的临床研究中建立富有成效的独立职业，重点是减轻CKD患者加速动脉粥样硬化的负担。我的职业生涯将具有实验室和活跃的临床试验组成部分。 2。在我自己的机构和其他地方扩展我的同事和合作者网络。 3.培训和导师未来的研究人员发展成为独立研究人员。