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

• 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
• 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

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.

项目摘要 常染色体显性遗传性多囊肾病（ADPKD）是最常见的、潜在致死的、单基因的 疾病影响1：400至1：1000人，编码多囊蛋白-1（PC 1）的PKD 1和PKD 2基因突变 和多囊蛋白-2分别导致充满液体的囊肿的发展， 上皮细胞这种扩张损害周围的肾组织，引起纤维化，并导致恶化 最终需要透析或移植的肾功能。半数ADPKD人群将发生肾性 在50岁之前失败，并且几乎没有治疗选择来预防这种发病机制。这些预防 由于对囊肿发生过程的了解有限，缺乏解决方案，这意味着为什么囊肿形成， 是什么让它们随着时间的推移而恶化。免疫细胞可能有助于这一过程。先前的文献表明， 巨噬细胞在囊肿形成和扩张中的作用，最近出现了CD 8 + T细胞， 潜在的抗囊肿作用。使用一种新的ADPKD转基因抑制模型，其中一部分 表达PC 1的C-末端尾，我将比较存在于非抑制的免疫细胞群。 疾病模型和具有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景观将揭示促囊性和抗囊性因子， 肾上皮细胞在ADPKD发病机制中的作用凭借Caplan实验室在ADPKD方面的专业知识， 在Craft Lab的免疫学研究中，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鼠模型中，并通过流式细胞术分析这些模型， 免疫荧光和单细胞测序方法。我试图定义ADPKD中的免疫细胞信号传导 并阐明该信号通路在ADPKD发病机制中的意义，以期鉴定免疫- 介导的因素参与囊肿形成。除了阐明细胞信号，修改囊性 和ADPKD的纤维化表现，该提议同时旨在鉴定免疫细胞特性， 可以作为疾病的生物标志物，并提供治疗和监测策略的见解。