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)是一种发病率和死亡率都很高的疾病，影响着数百万人 而且没有任何改善的迹象。因为没有临床批准的疗法可以 阻止或逆转CKD进展为终末期肾脏疾病，需要研究来阐明新的 分子和细胞靶标。这个项目的科学前提是炎症和纤维化是 慢性肾脏病进展过程中的关键因素。虽然最近的研究强调了免疫的重要性 在CKD系统中，驻留记忆T细胞(TRMS)的具体作用尚不清楚。我们有 建立并验证了马兜铃酸(AA)诱导的模拟临床CKD的CKD小鼠模型。 连续5天注射AA会导致肾功能持续下降，表现为 6周后肾小球滤过率和血清肌酐升高。肾脏的流式细胞术显示 第一次AA注射后两周内以淋巴细胞为主，CD4和CD8T细胞是 最丰富的。这些T细胞持续至少6周，与肾脏功能的持续下降相吻合。 此外，这些小鼠肾脏中的大量T细胞表现出促炎和纤维化 细胞因子，以及CD103，TRMS的标志性上皮细胞黏附分子。TRMS被描述为 在其他慢性疾病中导致不必要炎症的因素以及它们的存在已被描述性地注意到 在人的肾脏里。因此，我们的中心假设是TRMS通过一种 促进肾脏损伤和纤维化，同时抑制修复的炎症反应。这项提议的目的是 将1)确定TRMS的激活状态和细胞因子谱以及它们对肾脏的贡献 2)确定CD103‘S对T细胞-上皮细胞黏附的必要性及其调节。 T细胞在受损肾脏的定位，以及其对TRM促炎状态的必要性。要实现 这些目标，我们将利用基因敲除模型，过继免疫细胞转移，流式细胞术， 免疫荧光显微镜，以及体外和体内的药物干预。成功 拟议研究的实施将阐明CKD涉及的基本机制，并可能提供 慢性肾脏病治疗新靶点的临床证据。这与NIDDK的使命是一致的，因为 提案的重点是阐明进行性肾脏疾病的治疗方法。世界银行的实验室 赞助商及其在肾病和免疫学方面的专业知识将为以下人员提供理想的培训环境 开展拟开展的研究，推动私教事业的发展。所接受的培训将提高知识水平， 批判性思维、技术和专业技能将是PI过渡到独立的必备技能 他在心脏肾脏疾病领域的学术研究和利基的建立。