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Immune Cell and Epithelial Cell Interactions in Autosomal Dominant Polycystic Kidney Disease

常染色体显性多囊肾病中免疫细胞和上皮细胞的相互作用

基本信息

批准号：
10749617
负责人：
Victoria Rai
金额：
$ 4.77万
依托单位：
YALE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2023
资助国家：
美国
起止时间：
2023-09-01 至 2026-08-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10749617
关键词：
Affect Age Antigen-Antibody Complex Architecture Autosomal Dominant Polycystic Kidney Biological Markers C-terminal CD8-Positive T-Lymphocytes Career Choice Cell Communication Cells Chemotactic Factors Chronic Disease Classification Clonality Communication Cyst Data Development Dialysis procedure Discipline Disease Disease Progression Disease model Doxycycline Educational Status End stage renal failure Epithelial Cells Equipment and supply inventories Fibrosis Flow Cytometry Gene Expression Profile Genes Genetic Genetic Suppression Growth Immune Immune Targeting Immune signaling Immunofluorescence Immunologic Immunologics Immunology Impaired Renal Function Infiltration Intervention Investigation Kidney Kidney Diseases Kidney Failure Lead Liquid substance Literature Location Lymphoid Cell Macrophage Mediating Mendelian disorder Mentorship Metabolic Methodology Modeling Monitor Morphology Mus Mutation Myeloid Cells Nature Outcome PKD1 gene PKD2 gene PKD2 protein Pathogenesis Pathologic Persons Phenotype Physiology Population Prevention Process Proliferating Property Proteins Public Health Renal function Role Signal Transduction Site T-Lymphocyte Subsets Tail Techniques Time Tissues Transgenic Organisms Transplantation Tumor Immunity Work cell type comparison control experience immune cell infiltrate in vivo insight migration mouse model novel polycystic kidney disease 1 protein prevent receptor recruit renal epithelium response single cell sequencing treatment strategy tumor metabolism

项目摘要

PROJECT SUMMARY Autosomal dominant polycystic kidney disease (ADPKD) is the most common, potentially lethal, monogenic disease. Affecting 1:400 to 1:1000 people, mutations in PKD1 and PKD2 genes encoding polycystin-1 (PC1) and polycystin-2, respectively, lead to development of fluid-filled cysts that progressively expand from renal epithelial cells. This expansion damages surrounding kidney tissue, causing fibrosis, and leads to worsening kidney function that ultimately requires dialysis or transplant. Half of the ADPKD population will experience renal failure by the age of 50, and there are few treatment options to prevent such pathogenesis. These preventative solutions are lacking due to limited understanding into the process of cystogenesis, meaning why cysts form and what makes them worsen over time. Immune cells may contribute to this process. Prior literature has suggested a role for macrophages in cyst initiation and expansion, and CD8+ T cells have recently emerged as exerting a potential anti-cystogenic role. Using a novel transgenic suppression model of ADPKD in which a portion of the C-terminal tail of PC1 is expressed, I will compare the immune cell populations present in a non-suppressed disease model and the suppression model with non-cystic controls. I hypothesize that the differential immune cell landscapes between disease models will reveal pro-cystogenic and anti-cystogenic factors that regulate renal epithelial cells in ADPKD pathogenesis. With the expertise in ADPKD from the Caplan Lab and in immunological investigation from the Craft Lab, I will investigate the role of immune cells in ADPKD pathogenesis in murine models using in vivo interventional strategies, and analyze these models by flow cytometry, immunofluorescence, and single-cell sequencing approaches. I seek to define immune cell signaling in ADPKD and to elucidate the implications of this signaling for ADPKD pathogenesis, expecting to identify immune- mediated factors implicated in cystogenesis. In addition to elucidating cellular signaling that modifies the cystic and fibrotic manifestations of ADPKD, this proposal simultaneously aims to identify immune cell properties that could serve as disease biomarkers and provide insight into treatment and monitoring strategies.

项目总结常染色体显性遗传性多囊肾病(ADPKD)是最常见的、具有潜在致死性的单基因肾病疾病。影响1：400到1：1000的人，编码多囊蛋白-1(PC1)的PKD1和PKD2基因突变和多囊蛋白-2分别导致从肾脏逐渐扩大的充满液体的囊泡的发展。上皮细胞。这种扩张破坏了周围的肾组织，导致纤维化，并导致病情恶化。最终需要透析或移植的肾功能。半数ADPKD患者将经历肾功能衰竭在50岁之前失败，而且几乎没有什么治疗选择来防止这种发病机制。这些都是预防性的由于对囊变过程的了解有限，缺乏解决方案，这意味着为什么囊肿形成和是什么让它们随着时间的推移而恶化。免疫细胞可能参与了这一过程。先前的文献表明巨噬细胞在囊腔起始和扩张中的作用，CD8+T细胞最近在发挥作用时出现潜在的抗囊性作用。使用一种新的ADPKD转基因抑制模型，在该模型中 PC1的C末端尾巴是表达的，我会比较免疫细胞群中目前存在的非抑制疾病模型和非囊性对照的抑制模型。我假设差异免疫疾病模型之间的细胞图谱将揭示调节促囊变和抗囊变的因子肾上皮细胞在ADPKD发病机制中的作用凭借卡普兰实验室和来自工艺实验室的免疫学调查，我将研究免疫细胞在ADPKD发病机制中的作用在使用体内干预策略的小鼠模型中，并通过流式细胞仪分析这些模型，免疫荧光和单细胞测序方法。我试图在ADPKD中定义免疫细胞信号并阐明该信号在ADPKD发病机制中的意义，以期确定免疫- 参与囊变的介导性因素。除了阐明细胞信号改变囊状细胞外和ADPKD的纤维化表现，这项建议同时旨在识别免疫细胞特性可以作为疾病的生物标志物，并为治疗和监测战略提供洞察。