Intra-renal T-cell heterogeneity in ADPKD patients

ADPKD 患者肾内 T 细胞异质性

• 批准号: 10292929
• 负责人: Michal Mrug
• 金额: --
• 依托单位: BIRMINGHAM VA MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-10-01 至 2023-09-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10292929
• 关键词: Address; Adverse event; Age; Ampicillin; Animal Model; Antibiotic Therapy; Applications Grants; Archives; Attenuated; Autoimmune; Autosomal Dominant Polycystic Kidney; CSF1 gene; Cells; Characteristics; Cholera Toxin; Chronic Kidney Failure; Cilia; Citrobacter rodentium; Clinical; Clinical Treatment; Combined Antibiotics; Complement; Complex; Cystic Kidney Diseases; Cystic kidney; Data; Data Reporting; Defect; Diagnosis; Disease; Disease Marker; Disease Outcome; Disease Pathway; Disease Progression; Disease model; Drug Targeting; End stage renal failure; Environment; Epithelial; Evaluation; Feedback; Future; Genetic; Genetic Heterogeneity; Germ-Free; Gnotobiotic; Goals; Growth; Heterogeneity; Human; Immune; Infection; Infiltration; Inflammatory; Interleukin-17; Intervention; Intervention Studies; Intracolonic; Kidney; Kidney Diseases; Knowledge; Link; Lymphocyte; Lymphocyte Depletion; Maintenance; Metronidazole; Modeling; Molecular; Mononuclear; Mus; Natural Immunity; Neomycin; Nephritis; Outcome; Pathogenesis; Pathway interactions; Patient Recruitments; Patients; Phagocytes; Pharmaceutical Preparations; Plasma; Play; Prevalence; Progress Reports; Public Health; Renal function; Research; Role; Sampling; Serum; Severities; Severity of illness; Signal Transduction; Site; Staging; T cell response; T-Lymphocyte; Testing; Therapeutic; Tissues; Urine; Validation; Vancomycin; Veterans; Work; activity marker; adaptive immune response; adaptive immunity; appropriate dose; base; burden of illness; cell type; clinical heterogeneity; clinically relevant; cohort; curative treatments; gut microbiota; improved; indexing; interleukin-23; intervention effect; loss of function; macrophage; microbiota; mouse model; new therapeutic target; predictive modeling; recruit; research clinical testing; response; therapeutic target; tool; urinary; virtual

PROJECT SUMMARY/ABSTRACT Chronic kidney diseases (CKD) are among the most significant public health problems with an aggregate prevalence of ~15% and virtually no curative therapies. The most promising group of disorders that may allow identification of urgently needed CKD drug targets are those with a known underlying molecular defect. Among them, the most prevalent and most commonly leading to end-stage renal disease (ESRD) is autosomal dominant polycystic kidney disease (ADPKD; 600,000 patients in the US; the fourth leading cause of ESRD). Because the diagnosis cannot be excluded until age 40, many ADPKD patients are veterans. While mechanisms that trigger or promote the pathogenesis of ADPKD are not yet completely understood, we and others have pointed to specific renal immune cells as key outcome regulators of renal cystic disorders in mice. Our preliminary data show that these renal immune cells include T-cells, a common renal immune cell type, and recently defined sub- populations of renal mononuclear phagocytes/macrophages (MP) that control the activity of specific T-cell sub- lineages. These T-cells, in turn, secrete factors that promote recruitment/differentiation of MPs. As our additional preliminary data suggest, this positive feedback loop can be triggered or enhanced by specific intra-cystic microbiota that promote the activity of specific T-cell sub-lineages. Disruption of this feedback loop at the level of MPs or lymphocytic lineage attenuates renal cystogenesis in mouse models. Therefore, this pathway represents an attractive therapeutic target. However, several critical gaps in knowledge must be addressed first, e.g., to establish a causal relationship between microbiota, abnormal T-cell responses in cystic kidneys and relevance of this concept to human ADPKD patients. The objective of the proposed studies is to address these limitations by interventional studies in a mouse model and by validating this concept in ADPKD patients. Together our preliminary studies support a model in which distinct evolutionarily-conserved inter-cellular signaling networks regulate intra-renal T-cell functional diversification that, in turn, controls epithelial differentiation abnormalities that enhance ADPKD progression. We will test the relevance of this model to ADPKD patients in three inter-related aims: i) Test the hypothesis that reduction of microbiota-stimulating effects on Th17 cells attenuates renal cystogenesis in mice; ii) Test the hypothesis that enhancement of Th17 activity by specific bacterial species exacerbates renal cystogenesis in mice; iii) Test the hypothesis that plasma or urinary markers of abnormal Th17 activity correlate with rate of renal cyst growth and predict renal function loss in ADPKD patients. Accomplishing the goals of this project will allow us to apply the wealth of genetic and cellular information obtained from the functional counterparts in mouse studies to human patients, provide a means for a more accurate assessment of ADPKD severity, and open new avenues to improve ADPKD outcomes.

项目总结/摘要 慢性肾脏疾病（CKD）是最重要的公共卫生问题之一， 患病率约为15%，几乎没有治愈性治疗。最有希望的一组疾病， 确定急需的CKD药物靶点是具有已知潜在分子缺陷的那些。之间 其中，最普遍和最常导致终末期肾病（ESRD）的是常染色体显性遗传 多囊肾病（ADPKD;美国有600，000例患者; ESRD的第四大病因）。因为 虽然ADPKD的诊断直到40岁才能排除，但许多ADPKD患者都是退伍军人。而触发的机制 或促进ADPKD的发病机制尚未完全了解，我们和其他人指出， 特异性肾脏免疫细胞作为小鼠肾脏囊性疾病的关键结局调节因子。我们的初步数据 显示这些肾免疫细胞包括T细胞，一种常见的肾免疫细胞类型，以及最近定义的亚群， 控制特异性T细胞亚群活性的肾单核吞噬细胞/巨噬细胞（MP）群体， 血统反过来，这些T细胞分泌促进MP募集/分化的因子。作为我们额外的 初步数据表明，这种正反馈循环可以被特定的囊内 这些微生物群促进特定T细胞亚系的活性。在这个层面上破坏这个反馈循环 MPs或淋巴细胞系的表达减弱了小鼠模型中的肾囊肿形成。因此，这条路 代表了一个有吸引力的治疗靶点。然而，必须首先解决知识方面的几个关键差距， 例如，在一个实施例中，建立微生物群、囊性肾中异常T细胞反应和 这一概念与人类ADPKD患者的相关性。拟议研究的目的是解决这些问题， 通过在小鼠模型中的干预性研究和在ADPKD患者中验证这一概念，我们发现了一个局限性。一起 我们的初步研究支持了一个模型，在这个模型中， 网络调节肾内T细胞功能多样化，进而控制上皮分化 这些异常会促进ADPKD的进展。我们将测试该模型与ADPKD患者的相关性， 三个相互关联的目的：i）检验减少微生物群刺激对Th 17细胞的作用的假设 ii）检验特异性免疫抑制剂增强Th 17活性的假设， 细菌物种加剧小鼠中的肾囊肿形成; iii）检验血浆或尿标志物 Th 17活性异常与ADPKD患者肾囊肿生长速度及肾功能损害相关 患者完成这个项目的目标将使我们能够应用基因和细胞的财富， 从小鼠研究中的功能对应物到人类患者获得的信息提供了一种手段， 更准确地评估ADPKD的严重程度，并为改善ADPKD结局开辟新途径。