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.

项目摘要 这个指导的研究科学家发展奖（K01）的应用程序描述了职业发展和 研究计划旨在将我定位为凋亡细胞吞噬作用的独立研究者 （肾上腺细胞增多）在肾脏损伤中。主要研究重点是建立一种改善急性肾脏的方法 受伤（AKI），这是一个与高发病率和死亡率相关的重大临床问题，易感性 患有慢性肾脏疾病甚至死亡的人。我们目前的知识表明肿瘤性是 在AKI期间触发，并且在此过程中的缺陷导致病理加剧。但是，有一个 关于促进肿瘤病是否会导致AKI的分辨率更快的明显缺乏知识 另外，尚未探讨哪种细胞类型。为此，我们建立了一种新颖的方式 通过修饰一种吞噬受体更活跃并具有 将其应用于生成唯一的鼠标模型系统。我相信这种方法将提供原则的证明 增强胚细胞增多症作为增强慢性进行性快速分辨率和预防的方法 纤维化。我的初步数据表明该吞噬受体的表达增强了原发性的肿瘤性 巨噬细胞和人类近端管状上皮细胞系。在当前建议中，我们将阐明：1） 通过使用双侧缺血再灌注（IRI）模型，增强胚细胞增多症对AKI的影响，2）识别细胞 类型的类型，其中增强凋亡细胞去除会影响肾脏损伤。从中获得的知识 项目将开辟一项新的研究，以找到一种靶向吞噬细胞以促进肾脏损伤的吞噬作用的方法 疗法。 通过此研究计划，我们将1）使用我们独特创建的超噬细胞转基因小鼠模型 第一次在该领域，2）熟练使用啮齿动物肾脏损伤模型，3） 了解肾脏生理学的最终目标是建立和资助独立实验室 专注于治疗和治疗急性肾脏疾病。职业发展计划包括培训 在弗吉尼亚大学（UVA）和Didactic的Mark D. Okusa博士的指导下，肾脏伤害模型 通过NIH P50 O'Brien（UAB）进行课程工作，使我对 肾脏疾病模型和生理学。为了获得这个奖项，我将由Kodi S. Ravichandran博士指导 公认的凋亡细胞吞噬作用专家。在计划，故障排除和 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。成功完成该培训计划后，独立的NIH资助了R01申请 将在K01奖的后期提交。