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）是总体公共卫生问题之一 患病率为约15％，几乎没有治愈疗法。可能允许的最有前途的疾病组 迫切需要的CKD药物靶标的是具有已知基础分子缺陷的药物靶标。之中 它们，最普遍，最常见的导致终末期肾脏疾病（ESRD）是常染色体显性 多囊肾脏疾病（ADPKD；美国60万名患者； ESRD的第四个主要原因）。因为 诊断直到40岁才被排除在外，许多ADPKD患者是退伍军人。而触发的机制 或促进ADPKD的发病机理尚未完全理解，我们和其他人指出 特定的肾脏免疫细胞是小鼠肾囊性疾病的关键结果调节剂。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，最近定义为 控制特定T细胞亚的活性 血统。这些T细胞反过来分泌促进MPS招募/分化的因素。作为我们的额外 初步数据表明，可以通过特定内部内部触发或增强这种积极的反馈回路 促进特定T细胞亚线的活性的微生物群。该反馈循环的破坏级别 MPS或淋巴细胞谱系的小鼠模型中的肾囊肿发生。因此，这条路 代表一个有吸引力的治疗靶标。但是，必须首先解决知识中的几个关键差距， 例如，为了建立微生物群之间的因果关系，囊性肾脏中的T细胞反应异常 这个概念与人ADPKD患者的相关性。拟议研究的目的是解决这些问题 小鼠模型中的介入研究局限性，并通过在ADPKD患者中验证这一概念。一起 我们的初步研究支持了一个模型，其中不同的进化保存的细胞间信号传导 网络调节肾脏内T细胞功能多样性，反过来控制上皮分化 增强ADPKD进展的异常。我们将测试该模型与ADPKD患者的相关性 三个相互关联的目的：i）检验以下假设：降低微生物群对Th17细胞的影响 减弱小鼠的肾脏囊肿发生； ii）检验以下假设：特定于特定的Th17活性 细菌种类加剧小鼠的肾脏囊肿发生； iii）检验血浆或尿标志物的假设 异常Th17活性与肾囊肿生长速率相关并预测ADPKD的肾功能丧失 患者。实现该项目的目标将使我们能够运用大量遗传和细胞 从小鼠研究中与人类患者的功能对应物获得的信息，为人类患者提供了一种手段 对ADPKD严重程度的更准确评估，并开放新的途径以改善ADPKD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