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: 10359797
• 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/10359797
• 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; Mentored Research Scientist Development Award; Mentors; Modeling; Monitor; Morbidity - disease rate; Mus; Nature; Necrosis; Nephrology; Organ; Pathology; Patients; Phagocytes; Phagocytosis; Pharmacology; 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; base; cadherin 5; career development; cell regeneration; cell type; cytokine; design; effective therapy; in vivo; in vivo regeneration; inflammatory milieu; innovation; macrophage; monocyte; mortality; mouse model; neutrophil; novel; 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 这个指导研究科学家发展奖（K01）应用程序描述了职业发展， 研究计划，旨在定位我作为一个独立的研究人员在吞噬凋亡细胞 （红细胞增多症）在肾损伤。目前的研究重点是建立一种改善急性肾功能的方法 急性肾损伤（阿基）是一个与高发病率和死亡率相关的重要临床问题， 慢性肾脏疾病甚至死亡。我们目前的知识表明，红细胞增多症 在阿基期间触发，并且该过程中的缺陷导致病理恶化。但有一个 显著缺乏关于促进红细胞增多是否导致阿基更快消退的知识， 此外，还没有探索应该靶向哪种细胞类型。为此，我们建立了一种新颖的方法， 为了通过修饰吞噬受体之一使其更有活性来促进凋亡细胞清除， 应用这个来生成一个独特的小鼠模型系统。我相信这种方法将提供原则性的证明 增强红细胞增多症作为一种方法，以提高快速解决和预防慢性进行性 纤维化我的初步数据表明，这种吞噬受体的表达增强了原发性肝癌的吞噬作用。 巨噬细胞和人近端肾小管上皮细胞系。在目前的建议中，我们将阐明：1） 通过使用双侧缺血再灌注（IRI）模型，增强红细胞对阿基的影响，2）鉴定细胞 其中增强凋亡细胞去除影响肾损伤的类型。从中获得的知识 该项目将开辟一项新的研究，寻找一种靶向吞噬细胞的方法，以促进肾损伤的吞噬作用 治疗 通过这项研究计划，我们将1）使用我们独特的高吞噬转基因小鼠模型， 第一次在该领域，2）精通啮齿动物肾损伤模型，3）开发一种 了解肾脏生理学，最终目标是建立和资助一个独立的实验室 专注于急性肾脏疾病的治愈和治疗。职业发展计划包括以下培训： 在Mark D. Okusa在弗吉尼亚大学（UVA）和教学 通过NIH P50奥布莱恩（UAB）的课程工作，使我具备先进和全面的知识， 肾脏疾病模型和生理学。为了这个奖项，我将接受Kodi S博士的指导。Ravichandran，a 公认的凋亡细胞吞噬专家。在规划、故障排除和 将由Peter Lobo博士、Rahul Sharma博士和维克托H博士提供解读结果。恩格尔哈德 免疫学在成功完成此培训计划后，一个独立的NIH资助的R01应用程序 将在K01裁决的后半部分提交。