Modifiers of Cyst Progression in Polycystic Kidney Disease

多囊肾囊肿进展的调节因素

基本信息

批准号：
8542164
负责人：
Phillip Darwin Bell
金额：
--
依托单位：
RALPH H JOHNSON VA MEDICAL CENTER
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 2017-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8542164
关键词：
Acceleration Acute Renal Failure with Renal Papillary Necrosis Adult Affect Age-Years Alleles Animals Apoptosis Area Autosomal Dominant Polycystic Kidney Blood Glucose Blood Pressure Cardiovascular system Cell Culture Techniques Cell Death Cell Line Cell Proliferation Cell Signaling Process Cells Cilia Complex Cyst Cystic Kidney Diseases Cystic kidney Development Diabetes Mellitus Diabetic Nephropathy Disease Disease Progression Drug Design Duct (organ) structure Electron Microscopy Embryonic Development Epithelial Cells Ethnic Origin Excretory function Female General Population Genes Genomics Glucose Goals Growth Factor Healthcare Hereditary Disease Human Hyperglycemia Hypertension Hypertrophy Immunofluorescence Immunologic Incidence Kidney Kidney Failure Kidney Glomerulus Knock-out Lead MAP Kinase Gene Measures Modeling Molecular Target Morphology Mus Mutate Mutation Nature Nephrectomy Organ Oxidative Stress Pathway interactions Patients Permeability Physiological Play Polycystic Kidney Diseases Population Procedures Proprotein Convertase 1 Proteins Proteinuria RNA Regulation Renal Mass Renal function Renal tubule structure Reporting Research Resistance Role Signal Pathway Signal Transduction Streptozocin Stroke Symptoms Time Transplantation Uncertainty United States Veterans Western Blotting Work computerized data processing cytokine diabetic effective therapy epithelial to mesenchymal transition experience human FRAP1 protein indexing kidney cell light microscopy male mature animal mouse model non-diabetic novel strategies patient population polycystic kidney disease 1 protein prevent public health relevance response tissue/cell culture urinary

项目摘要

DESCRIPTION (provided by applicant): Polycystic kidney disease (PKD) is a "ciliopathic" disease since the loss of cilia or mutations in proteins involved in the function of cilia lead to renal cystic development. During embryonic development, deletion of cilia or mutations in cystoproteins such as polycystin 1 and 2 lead to PKD. However, in the adult animal, using conditional floxed alleles, to knockout cilia or delete cystoproteins, development of significant cystic disease only occurs after a number of months. The reason for this delay is not clear but it has provided a model to study factors or conditions that modify the initiation and progression of cystogenesis. This has led to the concept of a "third hit" in which an environmental influences, physiological adaptive responses, or associated pathophysiological conditions initiates and accelerates cystogenesis. Previous work has shown that acute kidney injury can accelerate cystogenesis. Recently we have shown that reduced renal mass also accelerates the formation of cysts. Finally, it has been reported in humans that kidney size, which is an index of cystic burden, is doubled in diabetic versus non-diabetic autosomal dominant PKD patients. Thus, hypertrophic signaling and hyperglycemia may be two extremely important regulators of disease progression in PKD. Hypothesis: That the presence of reduced renal mass or elevated blood glucose levels result in the initiation and acceleration of cystogenesis in mouse models of PKD. In addition, lack of cilia or mutations in cystoproteins may affect the renal adaptive response to hypertrophy and hyperglycemia Specific objectives: (1) investigate reduced renal mass (nephrectomy), hyperglycemia (diabetes), or both as third hits that accelerate cystogenesis; (2) determine if cilia or cystoproteins modulates renal hypertrophy and affects disease progression thereby leading to accelerated diabetic nephropathy; and (3) unravel the complex signaling processes that result in cystogenesis. Determine how these pathways are altered in the presence of hyperglycemia and hypertrophic signaling. Relevance: In ADPKD, cyst progression is highly variable and understanding what triggers initiation and what regulates cyst progression has become a major focus in PKD research. The studies outlined in this application will provide new and important information on what regulates the onset and progression of cystogenesis. Procedures to be used: Adult mice with and without PKD will be studied in presence or absence of nephrectomy to reduce renal mass or after induction of diabetes with streptozotocin or in the presence of both conditions. Light and electron microscopy will be used to study cystic development and assess pathological changes in kidney and other organs and in cell culture models. Physiological studies will be performed to assess GFR, blood pressure, and proteinuria, Western blot, immunofluorescence, genomic analysis will be used to evaluate the complex signaling pathways that are activated in these models. Significance of potential new findings: Only recently has hypertrophic signaling and hyperglycemia been identified as playing critical roles in the initiation and rate of cyst progression in PKD. In addition the role of cilia in controlling structural and functional hypertrophy and in the renal response to diabetes has not been studied. This work may lead to new approaches to arrest or slow the progression of cystic disease. Potential impact on Veterans health care: Autosomal Dominant Polycystic kidney disease affects both males and females of all ethnicities with symptoms beginning between 30 and 40 years of age. It is a devastating disease that usually results in renal failure with treatment options limited to dialysi and transplantation. There are also cardiovascular effects including hypertension and stroke. For reasons that are not clear, the incidence of PKD reported in the VA population is nearly double of that found in the general non- VA population. Thus there is a compelling reason to focus on this disease and its effective treatment or cure, which would greatly benefit the VA patient population.

描述（由申请人提供）：多囊肾病 (PKD) 是一种“纤毛病”疾病，因为纤毛缺失或参与纤毛功能的蛋白质突变导致肾囊性发育。在胚胎发育过程中，纤毛缺失或囊蛋白（如多囊蛋白 1 和 2）突变会导致 PKD。然而，在成年动物中，使用条件floxed等位基因敲除纤毛或删除囊蛋白，仅在数月后才会发生明显的囊性疾病。这种延迟的原因尚不清楚，但它提供了一个模型来研究改变囊肿发生的起始和进展的因素或条件。由此产生了“第三个”的概念。环境影响、生理适应性反应或相关的病理生理条件启动并加速囊肿发生。之前的研究表明，急性肾损伤可以加速囊肿发生。最近我们发现，肾质量减少也会加速囊肿形成。最后，据报道，在人类中，糖尿病患者的肾脏大小（囊性负担的指标）是非糖尿病常染色体显性多囊肾患者的两倍，因此，肥大信号传导和高血糖可能是两个极其重要的因素。假设：肾脏质量减少或血糖水平升高会导致 PKD 小鼠模型中囊肿发生的启动和加速。此外，纤毛缺乏或囊蛋白突变可能会影响肾脏。对肥大和高血糖的适应性反应具体目标：（1）研究肾质量减少（肾切除术）、高血糖（糖尿病）或两者作为加速囊肿发生的第三个打击； (2)确定纤毛或囊蛋白是否调节肾脏肥大并影响疾病进展，从而导致加速糖尿病肾病； (3) 揭示导致囊肿发生的复杂信号传导过程。确定在高血糖和肥大信号传导存在的情况下这些途径如何改变。相关性：在 ADPKD 中，囊肿进展变化很大，了解触发囊肿进展的因素和调节囊肿进展的因素已成为 PKD 研究的主要焦点。本申请中概述的研究将为调节囊肿发生和进展的因素提供新的重要信息。使用的程序：有或没有 PKD 的成年小鼠将在存在或不存在肾切除术以减少肾质量的情况下或在用链脲佐菌素诱导糖尿病后或在两种情况存在的情况下进行研究。光学和电子显微镜将用于研究囊性发育并评估肾脏和其他器官以及细胞培养模型的病理变化。将进行生理学研究来评估 GFR、血压和蛋白尿，蛋白质印迹、免疫荧光、基因组分析将用于评估在这些模型中激活的复杂信号通路。潜在新发现的意义：直到最近，肥大信号传导和高血糖才被确定在 PKD 囊肿进展的起始和速率中发挥关键作用。此外，尚未研究纤毛在控制结构和功能肥大以及肾脏对糖尿病的反应中的作用。这项工作可能会带来阻止或减缓囊性疾病进展的新方法。对退伍军人医疗保健的潜在影响：常染色体显性多囊肾病影响所有种族的男性和女性，症状开始于 30 至 40 岁之间。这是一种毁灭性的疾病，通常会导致肾衰竭，治疗选择仅限于透析和移植。还有心血管影响，包括高血压和中风。由于尚不清楚的原因，退伍军人群体中报告的 PKD 发病率几乎是一般非退伍军人群体中发现的两倍。因此，我们有充分的理由关注这种疾病及其有效的治疗或治愈方法，这将极大地造福退伍军人事务部患者群体。