Resident Memory T cells in Chronic Kidney Disease

慢性肾脏病中的常驻记忆 T 细胞

• 批准号: 10676628
• 负责人: Kyle H Moore
• 金额: $ 7.18万
• 依托单位: UNIVERSITY OF ALABAMA AT BIRMINGHAM
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-05-01 至 2024-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10676628
• 关键词: Ablation; Acute Renal Failure with Renal Papillary Necrosis; Adhesions; Adoptive Transfer; Affect; American; Animal Model; Apoptotic; Aristolochic Acids; Binding; Bioinformatics; CD8-Positive T-Lymphocytes; CD8B1 gene; Cardiorenal syndrome; Cell Adhesion Molecules; Cell Communication; Cells; Cessation of life; Chronic; Chronic Disease; Chronic Kidney Failure; Clinical; Coculture Techniques; Compensation; Creatinine; Critical Thinking; Cytolysis; Data; Development; Disease; E-Cadherin; End stage renal failure; Environment; Epithelial Cells; Epithelium; Fibrosis; Flow Cytometry; Foundations; Future; Genes; Genetic; Glomerular Filtration Rate; Glomerular capsule structure; Goals; Health; Histology; Human; Immune; Immune system; Immunofluorescence Immunologic; Immunofluorescence Microscopy; Immunologics; Immunology; In Vitro; Induction of Apoptosis; Infection; Inflammation; Inflammation Mediators; Inflammatory; Inflammatory Response; Injections; Injury; Injury to Kidney; Intervention; Kidney; Kidney Diseases; Knock-in Mouse; Knock-out; Knowledge; Laboratories; Lead; Leukocytes; LoxP-flanked allele; Lung; Lymphocyte; Lymphocytic Infiltrate; Measurement; Measures; Mediating; Mediator; Mission; Modeling; Molecular Target; Morbidity - disease rate; Mus; National Institute of Diabetes and Digestive and Kidney Diseases; Nephrology; Nephrons; Pathologic Processes; Patient risk; Patients; Pharmacologic Substance; Physiology; Population; Renal function; Research; Risk; Serum; Skin; Small Interfering RNA; Stroke; Structure; Surface; T cell infiltration; T cell regulation; T-Lymphocyte; T-Lymphocyte Subsets; Techniques; Testing; Therapeutic; Tissues; Training; Tubular formation; cardiovascular disorder risk; career; cell injury; cellular targeting; chronic inflammatory disease; cytokine; cytotoxicity; differential expression; experimental study; functional loss; improved; in vivo; inflammatory milieu; injured; insight; kidney fibrosis; knock-down; mortality; mouse model; novel; pharmacologic; pre-clinical; receptor; recruit; repaired; single-cell RNA sequencing; skills; tissue resident memory T cell

Project Summary Chronic kidney disease (CKD) is a disorder with significant morbidity and mortality which affects millions of Americans and shows no sign of improvement. Because there are no clinically approved therapeutics that can halt or reverse the progression of CKD to end stage kidney disease, research is needed to elucidate novel molecular and cellular targets. This project is based on the scientific premise that inflammation and fibrosis are key components in the progression of CKD. While recent research has highlighted the importance of the immune system in CKD, the specific contributions of resident memory T cells (TRMs) remain unknown. We have established and validated an aristolochic acid (AA)-induced mouse model of CKD which mimics clinical CKD. Five consecutive days of AA injections lead to a sustained decline in kidney function, indicated by reduced glomerular filtration rate and increased serum creatinine six weeks later. Flow cytometry of kidneys reveals a predominantly lymphocytic infiltrate within two weeks of the first AA injection, CD4 and CD8 T cells being the most abundant. These T cells persist for at least 6 weeks, coinciding with the persistent decline in kidney function. Moreover, a large population of T cells in the kidneys of these mice express pro-inflammatory and fibrotic cytokines, as well as CD103, a hallmark epithelial adhesion molecule of TRMs. TRMs have been described as contributors to unwanted inflammation in other chronic diseases and their presence has been descriptively noted in human kidneys. Thus, our central hypothesis is that TRMs mediate the progression of CKD through an inflammatory response that promotes kidney injury and fibrosis while inhibiting repair. The aims of this proposal will 1) determine the activation status and cytokine profiles of TRMs as well as their contributions to kidney inflammation and fibrosis; and 2) determine CD103’s necessity for T cell-epithelial adhesion and its regulation of T cell localization to injured kidneys, as well as its necessity for the TRM pro-inflammatory state. To achieve these goals, we will utilize genetic knockout models, adoptive immune cell transfer, flow cytometry, immunofluorescence microscopy, and pharmaceutical interventions both in vitro and in vivo. Successful execution of the proposed studies will illuminate basic mechanisms involved in CKD and could provide pre- clinical evidence for novel targets in the treatment of CKD. This is in line with the mission of the NIDDK, as this proposal focuses on the elucidation of treatments for progressive kidney disease. The laboratories of the sponsors along with their expertise in nephrology and immunology will provide an ideal training environment to carry out the proposed studies and advance the PI’s career. The training received will advance the knowledge, critical thinking, technical, and professional skills that will be required for the PI’s transition into independent academic research and establishment of his niche in the field of cardiorenal disease.

项目摘要 慢性肾脏疾病（CKD）是一种疾病，具有明显的发病率和死亡率，影响数百万 美国人和没有改善的迹象。因为没有临床批准的疗法可以 停止或扭转了CKD到末期肾脏疾病的进展，需要进行研究以阐明新型 分子和细胞靶标。该项目基于科学前提，即注射和纤维化是 CKD进展中的关键组成部分。虽然最近的研究强调了免疫的重要性 在CKD中，居民记忆T细胞（TRM）的特定贡献仍然未知。我们有 建立并验证了Aristolacic Acid（AA）诱导的CKD小鼠模型，该模型模仿了临床​​CKD。 连续五天的AA注射会导致肾功能持续下降，这表明 六周后，肾小球滤过率和血清肌酐升高。孩子的流式细胞仪揭示了 在第一次AA注射后的两周内，主要是淋巴细胞浸润，CD4和CD8 T细胞是 最丰富。这些T细胞持续至少6周，与肾功能的持续下降相吻合。 此外，这些小鼠的孩子中的大量T细胞表达促炎和纤维化 细胞因子以及CD103是TRM的标志性上皮粘合剂。 TRM已被描述为 描述了其他慢性疾病及其存在的不良炎症的原因 在人类肾脏中。那就是我们的中心假设是TRM介导CKD的进展 促进肾脏损伤和纤维化的炎症反应，同时抑制修复。该提议的目的 会1）确定TRM的激活状态和细胞因子谱以及它们对肾脏的贡献 炎症和纤维化； 2）确定CD103对于T细胞上皮粘附及其调节所必需的CD103 T细胞定位于受伤的肾脏及其对TRM促炎状态的必要条件。实现 这些目标，我们将利用遗传基因敲除模型，自适应免疫细胞转移，流式细胞仪， 免疫荧光显微镜以及体外和体内的药物干预措施。成功的 拟议的研究的执行将阐明CKD中涉及的基本机制，并可以提供前 CKD治疗中新目标的临床证据。这符合NIDDK的任务， 提案的重点是阐明进行性肾脏疾病的治疗方法。实验室 赞助商及其肾脏科和免疫学专业知识将为理想的培训环境提供 进行拟议的研究并推进PI的职业。接受的培训将提高知识， PI向独立过渡将需要的批判性思维，技术和专业技能 在心脏疾病领域的学术研究和建立他的利基市场。