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Complement C3 is Essential for Development of Kidney Cysts in ADPKD Mice

补体 C3 对于 ADPKD 小鼠肾囊肿的发育至关重要

基本信息

批准号：
8512389
负责人：
Tianqing Kong
金额：
$ 7.9万
依托单位：
BRIGHAM AND WOMEN'S HOSPITAL
依托单位国家：
美国
项目类别：
财政年份：
2013
资助国家：
美国
起止时间：
2013-04-01 至 2015-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8512389
关键词：
Affect Age Antibodies Autosomal Dominant Polycystic Kidney Biology C3 gene Cell Line Cells Chronic Chronic Kidney Failure Cleaved cell Clinical Complement Complement 3 Cyst Cystic kidney Development Dialysis procedure Disease End stage renal failure Enzyme-Linked Immunosorbent Assay Gene Deletion Genes Genetic Polymorphism Genotype Growth Factor Hereditary Disease Histology Human Immunology In Situ Hybridization Infiltration Inflammation Inflammation Mediators Inflammatory Inherited Interleukin-6 Kidney Knock-out Knockout Mice Laboratories Life Liquid substance Literature Live Birth Maine Mass Spectrum Analysis Mediator of activation protein Mus Mutation Outcome Study PKD2 gene Patients Play Prevalence Primary Cell Cultures Process Production Proteins Publishing Quality of life Reaction Renal Replacement Therapy Renal function Reporting Research Research Project Grants Role Severities Staging Structure Symptoms Testing Therapeutic Time Tissues Tumor Necrosis Factor-alpha Western Blotting Work animal facility base cell type cytokine expectation human TNF protein improved in vivo kidney epithelial cell mouse model novel novel strategies novel therapeutics public health relevance research study

项目摘要

DESCRIPTION (provided by applicant): This proposal is to determine whether complement C3 is required for development and progressive expansion of kidney cysts induced by Pkd1 inactivation in mice. As the most common inherited disease, autosomal dominant polycystic kidney disease (ADPKD) affects approximately 1 in 400 to 1000 live births. Approximately 85% of ADPKD results from mutation of PKD1, and the remaining 15% are from mutation of PKD2 gene. It is the progressive expansion and enlargement of numerous cysts that destroys normal kidney structure, impairs kidney function and causes clinical symptoms. There are also other factors that control onset and severity of ADPKD, especially aggressive progression of kidney cysts. Enlargement of kidney cysts is a slowly inflammatory process. Cytokines, growth factors and other inflammatory mediators are involved, but the exact mechanism and key mediators remain unclear. We found that complement C3 was elevated and activated in mouse and human AKPKD kidneys and cystic fluid. The local concentration and activation of complement C3 may be involved in development and expansion of kidney cysts. Based on the literature, complement C3 is one of the most highly induced genes in kidney tissue from a PKD mouse model. It is also present and highly expressed in cystic fluid and kidney tissue in human ADPKD. Thus, in order to further determine the essential role of complement C3 in development and aggressive expansion of kidney cysts in vivo, we will generate a double knockout mice (Mx1Cre+Pkd1flox/flox C3-/-) in which the C3 gene is deleted, and Pkd1 can also be conditionally knocked-out by crossing conditional ADPKD mice (Mx1Cre+Pkd1flox/flox) with C3 knockout mice (C3-/-). We will carry out several experiments to investigate how complement C3 promotes the aggressive cystic development, which includes the cell type producing local increased C3, the role of activated and cleaved fragments of C3 leading to focal inflammation and cystic expansion, the mechanism of C3 activation in cystic kidney (Aim 1). In mouse models, we expect that deletion of the complement C3 gene blocks or delays development and progression of kidney cysts induced by Pkd1 inactivation (Aim 2). Approximately one-half of ADPKD patients progress to chronic renal failure by age 60. Current treatment for this disease is dialysis or renal replacement therapy. Our proposed study would reveal a novel therapeutic strategy for this most common life-threatening genetic disease.

描述（由申请方提供）：本提案旨在确定小鼠中Pkd 1失活诱导的肾囊肿发生和进行性扩张是否需要补体C3。作为最常见的遗传性疾病，常染色体显性遗传性多囊肾病（ADPKD）影响约1/400至1000活产。约85%的ADPKD由PKD 1基因突变引起，其余15%由PKD 2基因突变引起。它是许多囊肿的进行性扩张和增大，破坏正常的肾脏结构，损害肾功能并引起临床症状。还有其他因素控制ADPKD的发病和严重程度，特别是肾囊肿的侵袭性进展。肾囊肿的治疗方法有哪些？细胞因子、生长因子和其他炎症介质参与其中，但确切机制和关键介质仍不清楚。我们发现补体C3在小鼠和人AKPKD肾脏和囊液中升高并活化。局部补体C3的浓度和活化可能参与了肾囊肿的发生和扩展。根据文献，补体C3是PKD小鼠模型肾组织中诱导程度最高的基因之一。它也存在于人ADPKD的囊液和肾组织中并高度表达。因此，为了进一步确定补体C3在体内肾囊肿发展和侵袭性扩张中的重要作用，我们将产生C3基因缺失的双敲除小鼠（Mx 1Cre + Pkd 1flox/flox C3-/-），并且通过将条件性ADPKD小鼠（Mx 1Cre + Pkd 1flox/flox）与C3敲除小鼠（C3-/-）杂交，也可以条件性敲除Pkd 1。我们将进行几个实验来研究补体C3如何促进侵袭性囊性发展，其中包括产生局部增加的C3的细胞类型，C3的活化和切割片段导致局灶性炎症和囊性扩张的作用，C3在囊性肾中的活化机制（目的1）。在小鼠模型中，我们预期补体C3基因的缺失可阻断或延迟由Pkd 1失活诱导的肾囊肿的发展和进展（目的2）。大约一半的ADPKD患者在60岁时进展为慢性肾衰竭。目前对这种疾病的治疗是透析或肾脏替代疗法。我们提出的研究将揭示这种最常见的危及生命的遗传疾病的新治疗策略。