Investigating CD4 T regulatory cells during rapid cystogenesis

研究快速囊肿发生过程中的 CD4 T 调节细胞

基本信息

批准号：
10398117
负责人：
Kurt A Zimmerman
金额：
$ 15.17万
依托单位：
UNIVERSITY OF OKLAHOMA HLTH SCIENCES CTR
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-05-01 至 2024-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10398117
关键词：
Adoptive Transfer Adult Affect Antibodies B-Lymphocytes CD4 Positive T Lymphocytes CD8-Positive T-Lymphocytes Carrier Proteins Cell Count Cell physiology Cells Cilia Clinic Cyst Cystic Kidney Diseases Cystic kidney Data Development Disease End stage renal failure Environmental Risk Factor Epithelial Epithelial Cell Proliferation FOXP3 gene Flow Cytometry Foxes Functional disorder Future Genetic Goals Growth Healthcare Healthcare Industry Human Immune Inflammatory Injury Injury to Kidney Interleukin-10 Intervention Kidney Knowledge Link Meckel-Gruber syndrome Mediating Modeling Mus Mutation PKD2 protein Patients Persons Pharmaceutical Preparations Pharmacology Population Process Proteins Rag1 Mouse Regulatory T-Lymphocyte Renal function Reperfusion Injury Reporter Reporting Severities Testing Time Wild Type Mouse care burden cell motility cytokine disease-causing mutation experience imaging approach injured interleukin-10 receptor intravital imaging mouse model mutant new therapeutic target novel polycystic kidney disease 1 protein recruit repaired targeted treatment transcription factor

项目摘要

Project Abstract Cystic kidney diseases affect 1:500 people and account for 5-10% of all patients with end stage renal disease representing a significant health care burden. This spectrum of disorders is caused by mutations in proteins required for cilia formation (Intraflagellar transport protein 88, Ift88) or function (Polycystin 1, Pkd1; Polycsytin 2, Pkd2). In addition, patients with these disorders experience periods of slow focal cyst formation and rapid, severe cyst progression. Data from mouse models indicate that loss of cilia related proteins (Ift88, Pkd1, Pkd2) results in slow focal cyst formation suggesting that additional environmental factors are required for rapid cystogenesis often observed in human patients. This hypothesis is supported by data from multiple labs, including our own, indicating that renal injury promotes rapid cystogenesis in mice with cilia dysfunction. Importantly, renal injury promotes the accumulation of immune cells in wild type mice. Data from our lab and others indicate that immune cell accumulation is further enhanced and prolonged in mice with cilia dysfunction suggesting that persistent immune cell accumulation may be the cause of rapid cyst formation following injury in mice with cilia dysfunction. However, the type of immune cell that promotes cystic disease following injury is poorly understood and represents a gap in knowledge. The preliminary data outlined in this application show that genetic deletion of all adaptive immune cells (CD4 T cells, CD8 T cells, and B cells) or pharmacological depletion of just CD4 T cells reduces cyst severity following injury in mice with cilia dysfunction suggesting that CD4 T cells may be the critical link between renal injury and rapid cystogenesis. To identify the subtype of CD4 T cell important in this process, we performed flow cytometry analysis of control and cilia mutant kidneys at various time points following injury. Our preliminary data indicate that mice with cilia dysfunction have increased and persistent accumulation of CD4+ Foxp3+ T regulatory cells (Tregs). These data led to the overall hypothesis that increased and persistent accumulation of Tregs following injury causes prolonged and abnormal epithelial proliferation and rapid cyst expansion in mice with cilia dysfunction. The goal of this application is to identify the mechanistic link between rapid cystogenesis and T regulatory cells. Our hypotheses will be tested with the following specific aims: 1. To test the hypothesis that cilia dysfunction causes persistent and/or enhanced accumulation of Tregs in regions adjacent to expanding cysts following renal injury. 2. To test the hypothesis that Tregs promote injury induced cyst expansion in conditional Ift88 mice through secretion of IL-10, a cytokine that is predominantly produced by Tregs and has previously been reported to drive cystic epithelial cell proliferation. Data collected from this proposal will be used to develop novel immune cell modulating drugs that affect Treg number and function (ability to produce IL-10) in patients with rapidly progressive cystic kidney disease.

项目摘要囊性肾病影响 1:500 人，占所有终末期肾病患者的 5-10% 代表着重大的医疗保健负担。这一系列疾病是由蛋白质突变引起的纤毛形成（鞭毛内转运蛋白 88、Ift88）或功能（多囊蛋白 1、Pkd1；多囊蛋白 2、 PKD2）。此外，患有这些疾病的患者会经历缓慢的局灶性囊肿形成和快速、严重的形成时期。囊肿进展。小鼠模型的数据表明纤毛相关蛋白（Ift88、Pkd1、Pkd2）的丢失导致缓慢的局灶性囊肿形成表明快速囊肿发生需要额外的环境因素经常在人类患者中观察到。这一假设得到了多个实验室（包括我们自己的实验室）的数据的支持，表明肾损伤促进纤毛功能障碍小鼠的快速囊肿发生。重要的是肾损伤促进野生型小鼠免疫细胞的积累。我们实验室和其他实验室的数据表明，免疫在具有纤毛功能障碍的小鼠中，细胞积累进一步增强并延长，这表明持续存在免疫细胞积累可能是纤毛功能障碍的小鼠受伤后快速形成囊肿的原因。然而，人们对损伤后促进囊性病变的免疫细胞类型知之甚少，并且代表着知识上的差距。本申请中概述的初步数据表明，所有基因删除适应性免疫细胞（CD4 T 细胞、CD8 T 细胞和 B 细胞）或仅 CD4 T 细胞的药物消耗降低纤毛功能障碍小鼠损伤后囊肿的严重程度，表明 CD4 T 细胞可能是关键肾损伤和快速囊肿发生之间的联系。为了确定在此过程中重要的 CD4 T 细胞亚型，我们在损伤后的不同时间点对对照肾和纤毛突变肾进行了流式细胞术分析。我们的初步数据表明，纤毛功能障碍的小鼠中，纤毛的积累增加并持续积累。 CD4+ Foxp3+ T 调节细胞 (Treg)。这些数据导致了总体假设的增加和损伤后 Tregs 的持续积累导致上皮细胞长期异常增殖以及纤毛功能障碍小鼠的囊肿快速扩张。该应用程序的目标是识别快速囊肿发生和 T 调节细胞之间的机制联系。我们的假设将通过以下具体目标： 1. 检验纤毛功能障碍导致持续和/或增强的假设肾损伤后，Treg 细胞在邻近扩张囊肿的区域积聚。 2. 检验假设 Tregs 通过分泌细胞因子 IL-10 促进条件性 Ift88 小鼠损伤诱导的囊肿扩张主要由 Tregs 产生，之前已被报道可驱动囊性上皮细胞增殖。从该提案中收集的数据将用于开发新型免疫细胞调节药物影响快速进展性囊性肾患者的 Treg 数量和功能（产生 IL-10 的能力）疾病。