Intra-renal T-cell heterogeneity in ADPKD patients

ADPKD 患者肾内 T 细胞异质性

• 批准号: 10516046
• 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/10516046
• 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; Epithelium; Evaluation; Exclusion; Feedback; Future; Genetic; Genetic Heterogeneity; Germ-Free; Gnotobiotic; Goals; Growth; Heterogeneity; Human; IL17 gene; Immune; Infection; Infiltration; Inflammatory; Intervention; Intervention Studies; Intracolonic; Kidney; Kidney Diseases; Knowledge; Link; Lymphocyte; Lymphocyte Depletion; Macrophage; 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; burden of illness; cell type; clinical heterogeneity; clinically relevant; cohort; curative treatments; gut microbiota; improved; indexing; interleukin-23; intervention effect; loss of function; microbiota; mouse model; new therapeutic target; predictive modeling; recruit; 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.

项目摘要/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%，几乎没有根治疗法。最有希望的一组障碍可能会让 鉴定迫切需要的CKD药物靶点是那些具有已知潜在分子缺陷的药物。其中 其中，最常见和最常导致终末期肾病的是常染色体显性遗传 多囊肾病(ADPKD；美国有60万患者；ESRD的第四大病因)。因为 诊断要到40岁才能排除，许多ADPKD患者都是退伍军人。而触发的机制 或促进ADPKD的发病机制尚不完全清楚，我们和其他人已经指出 特定的肾脏免疫细胞作为小鼠肾囊性疾病的关键结果调节器。我们的初步数据 表明这些肾脏免疫细胞包括T细胞，一种常见的肾脏免疫细胞类型，以及最近定义的亚细胞 控制特定T细胞亚群活性的肾脏单核巨噬细胞(MP)群 血统。这些T细胞反过来又分泌促进MPS招募/分化的因子。作为我们的附加服务 初步数据表明，这种正反馈环路可以由特定的囊腔内触发或增强 促进特定T细胞亚系活性的微生物区系。在这个层面上扰乱这个反馈循环 在小鼠模型中，MPS或淋巴细胞谱系的作用减弱了肾脏的囊变。因此，这条路径 代表了一个有吸引力的治疗靶点。然而，必须首先解决知识中的几个关键差距， 例如，为了建立微生物区系、囊性肾脏中异常T细胞反应和 这一概念与人类ADPKD患者的相关性。拟议研究的目标是解决这些问题 在小鼠模型中的介入研究和在ADPKD患者中验证这一概念的局限性。同舟共济 我们的初步研究支持一个模型，在该模型中，不同的进化保守的细胞间信号 网络调节肾内T细胞功能多样化，进而控制上皮细胞分化 促进ADPKD进展的异常。我们将测试该模型与ADPKD患者的相关性 三个相互关联的目标：i)检验微生物区系刺激对Th17细胞的影响减少的假设 减轻小鼠肾脏囊变；ii)验证Th17活性通过特异性增强的假说 细菌种类加剧小鼠肾脏囊变；iii)检验血浆或尿液标志物 ADPKD患者Th17活性异常与肾囊肿生长速度及肾功能丧失的相关性 病人。完成这个项目的目标将使我们能够应用遗传和细胞的财富 从小鼠研究中获得的功能对应信息对人类患者来说，提供了一种手段 更准确地评估ADPKD的严重性，并开辟新的途径来改善ADPKD的结果。

项目成果

Genetic Testing for Chronic Kidney Diseases: Clinical Utility and Barriers Perceived by Nephrologists.

• DOI: 10.1016/j.xkme.2021.08.006
• 发表时间: 2021-11
• 期刊: Kidney medicine
• 影响因子: 3.9
• 作者: Mrug M;Bloom MS;Seto C;Malhotra M;Tabriziani H;Gauthier P;Sidlow V;McKanna T;Billings PR
• 通讯作者: Billings PR