Removal of apoptotic cells during acute kidney injury

急性肾损伤期间凋亡细胞的去除

• 批准号: 10576894
• 负责人: Sho Morioka
• 金额: $ 15.23万
• 依托单位: UNIVERSITY OF VIRGINIA
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-03-20 至 2025-02-28
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10576894
• 关键词: Acute; Acute Renal Failure with Renal Papillary Necrosis; Address; Adverse effects; Affect; Animal Model; Anti-Inflammatory Agents; Apoptosis; Apoptotic; Area; Award; Bilateral; Biological Assay; Biological Models; Blood Urea Nitrogen; Bone Marrow; Bromodeoxyuridine; Cell Line; Cell Proliferation; Cells; Cessation of life; Chimera organism; Chronic; Chronic Kidney Failure; Clinical; Creatinine; Data; Defect; Dendritic Cells; Development Plans; Disease; Disease model; Eating; Endothelial Cells; Epithelial Cells; Excision; Fibrosis; Foundations; Functional disorder; Funding; Glomerular Filtration Rate; Goals; Hematopoietic; Human; Human body; Immunology; In Vitro; Incidence; Individual; Induction of Apoptosis; Inflammation; Inflammatory; Injections; Injury; Injury to Kidney; Ischemia; Kidney; Kidney Diseases; Knowledge; Laboratories; Lead; Link; Macrophage; Mentored Research Scientist Development Award; Mentors; Modeling; Monitor; Morbidity - disease rate; Mus; Nature; Necrosis; Nephrology; Organ; Pathology; Patients; Phagocytes; Phagocytosis; Physiology; Plasma; Population; Positioning Attribute; Pre-Clinical Model; Prevention; Process; Reperfusion Injury; Reperfusion Therapy; Research; Research Personnel; Resolution; Risk; Rodent; S100A8 gene; Sampling; Source; System; Testing; Therapeutic; Time; Training; Training Programs; Transgenic Mice; Tubular formation; United States National Institutes of Health; Universities; Virginia; Work; cadherin 5; career development; cell regeneration; cell type; cytokine; design; effective therapy; in vivo; in vivo regeneration; inflammatory milieu; innovation; monocyte; mortality; mouse model; neutrophil; novel; pharmacologic; preclinical study; receptor; research and development; skills; tissue injury; wound

Project Summary This Mentored Research Scientist Development Award (K01) application describes a career development and research plan designed to position me as an independent investigator in phagocytosis of apoptotic cell (efferocytosis) in kidney injuries. The main research focus is establishing a way to ameliorate acute kidney injury (AKI), a significant clinical problem associated with high morbidity and mortality, which predisposes individuals to chronic renal disease or even death. Our current knowledge suggests that efferocytosis is triggered during AKI and that defects in this process lead to exacerbation of the pathology. However, there is a significant lack of knowledge as to whether boosting efferocytosis results in faster resolution of AKI, and in addition, which cell type(s) should be targeted has not been explored. To this end, we established a novel way to facilitate apoptotic cell clearance by modifying one of the phagocytic receptors to be more active and have applied this to generate a unique mouse model system. I believe this approach will provide proof of principle that enhancing efferocytosis as an approach to enhance rapid resolution and prevention of chronic progressive fibrosis. My preliminary data suggest expression of this phagocytic receptor enhances efferocytosis in primary macrophages and human proximal tubular epithelial cell line. In the current proposal, we will elucidate: 1) the effect of boosting efferocytosis on AKI by using bilateral ischemia reperfusion (IRI) model, 2) identify the cell type(s) in which enhancing apoptotic cell removal affects kidney injuries. The knowledge gained from this project will open up a new research to find a way to target phagocyte to promote efferocytosis for kidney injury therapies. Through this research plan we will 1) use our uniquely created hyper-phagocytic transgenic mouse model for the first time in the field, 2) become proficient with rodent kidney injury models, and 3) develop an understanding of renal physiology with the ultimate goal of establishing and funding an independent laboratory focused on cures and treatments for acute kidney diseases. The career development plan includes training in kidney injury models under the guidance of Dr. Mark D. Okusa at the University of Virginia (UVA) and didactic course work through NIH P50 O'Brien (UAB) to equip me with advanced and comprehensive knowledge of kidney disease models and physiology. For this award, I will be mentored by Dr. Kodi S. Ravichandran, a recognized expert in phagocytosis of apoptotic cells. Additional assistance in planning, troubleshooting, and interpreting results will be provided by Dr. Peter Lobo, Dr. Rahul Sharma and Dr. Victor H. Engelhard for immunology. After successful completion of this training program, an independent NIH funded R01 application will be submitted in the latter part of the K01 award.

项目概要 该指导研究科学家发展奖（K01）申请描述了职业发展和 研究计划旨在使我成为凋亡细胞吞噬作用的独立研究者 （胞吞作用）肾损伤。主要研究重点是建立一种改善急性肾病的方法 损伤（AKI），一个与高发病率和死亡率相关的重要临床问题， 个人患慢性肾病甚至死亡。我们目前的知识表明胞吞作用是 AKI 期间触发，该过程中的缺陷会导致病理恶化。然而，有一个 关于增强胞吞作用是否会导致 AKI 更快消退以及 此外，尚未探索应针对哪种细胞类型。为此，我们建立了一种新颖的方法 通过修饰吞噬细胞受体之一使其更加活跃并具有促进凋亡细胞清除的作用 应用它来生成独特的小鼠模型系统。我相信这种方法将提供原理证明 增强胞吞作用是增强快速解决和预防慢性进行性进展性疾病的一种方法 纤维化。我的初步数据表明这种吞噬受体的表达增强了原代细胞的胞吞作用 巨噬细胞和人近端肾小管上皮细胞系。在当前的提案中，我们将阐明：1） 使用双侧缺血再灌注 (IRI) 模型增强胞吞作用对 AKI 的影响，2) 识别细胞 增强凋亡细胞清除会影响肾损伤的类型。由此获得的知识 该项目将开启一项新研究，寻找一种靶向吞噬细胞促进胞吞作用治疗肾损伤的方法 疗法。 通过这个研究计划，我们将 1) 使用我们独特创建的超吞噬转基因小鼠模型 首次进入该领域，2）精通啮齿动物肾损伤模型，3）开发 了解肾脏生理学，最终目标是建立和资助独立实验室 专注于急性肾脏疾病的治疗和治疗。职业发展计划包括培训 弗吉尼亚大学 (UVA) Mark D. Okusa 博士指导下的肾损伤模型和教学 通过 NIH P50 O'Brien (UAB) 进行的课程工作使我掌握了先进而全面的知识 肾脏疾病模型和生理学。为了获得这个奖项，我将得到 Kodi S. Ravichandran 博士的指导，他是一位 公认的凋亡细胞吞噬专家。规划、故障排除和解决方案方面的其他帮助 解释结果将由 Peter Lobo 博士、Rahul Sharma 博士和 Victor H. Engelhard 博士提供 免疫学。成功完成此培训计划后，独立的 NIH 资助了 R01 申请 将在K01奖项的后期提交。