Glomerulosclerosis in Human FSGS and Animal Models

描述（由申请方提供）：局灶性节段性肾小球硬化症（FSGS）是一种异质性和破坏性疾病，是肾衰竭的主要原因之一。拟议研究的长期目标是更深入地了解这种疾病，确定可能导致更有效治疗的新治疗靶点，并定义基于基因表达特征的亚型，这些亚型是治疗的有用指南。为此，我们提出以下具体目标。具体目标1。定义肾小球及其细胞成分，足细胞，系膜细胞和内皮细胞的正常基因表达模式。结果将揭示这些非常有趣的细胞中活跃的分子途径。我们建议使用激光捕获显微切割（LCM），以及转基因小鼠与细胞特异性报告基因表达和荧光激活细胞分选，分离肾小球及其三种细胞类型的组件。然后将使用微阵列来分析精确的基因表达模式。具体目标2。我们还建议使用四个肾小球硬化症的小鼠模型来定义改变的基因表达状态和功能途径，导致四个不同的启动侮辱，一个化学和三个遗传。这将创建肾小球硬化进展的详细分子图像，并测试共同的最终途径假说，该假说指出，无论最初的原因如何，在所导致的肾小球硬化中存在重要的共同方面。具体目标3。明确人FSGS肾小球功能改变的途径。通过使用LCM和微阵列，将有可能确定在患病肾小球中发生的基因表达的变化。通过检查来自50名患者的许多肾小球，将有可能开始理解所观察到的肾小球硬化症的潜在分子原因，基于基因表达特征对这种异质性疾病进行分型，比较基因表达模式作为疾病进展的函数，并将基因表达标记与治疗反应相关联。对于大多数FSGS患者，目前没有有效的治疗方法，最终结果是肾衰竭。我们建议使用尖端技术的组合来研究正常肾小球以及患病肾小球，在人类和明确定义的小鼠模型中，以更好地了解这种疾病，并帮助发现改进的治疗方法。公共卫生相关性：对于大多数FSGS患者，目前没有有效的治疗方法，最终结果是肾衰竭。我们建议使用尖端技术的组合来研究正常肾小球以及患病肾小球，在人类和明确定义的小鼠模型中，以更好地了解这种疾病，并帮助发现改进的治疗方法。

DESCRIPTION (provided by applicant): Focal Segmental Glomerulosclerosis (FSGS) is a heterogeneous and devastating disease that is one of the major causes of renal failure. The long-term goals of the proposed research are to provide a deeper understanding of this disease, to identify novel therapeutic targets that might lead to more effective treatments, and to define gene expression signature based subtypes that are useful guides for therapy. Towards these ends we propose the following specific aims. Specific Aim 1. Define the normal gene expression patterns of the glomerulus, and its cellular constituents, the podocyte, the mesangial cell and the endothelial cell. The results will reveal the molecular pathways active in each of these very interesting cells. We propose to use laser capture microdissection (LCM), as well as transgenic mice with cell specific reporter expression and fluorescent activated cell sorting, to isolate glomeruli and its three cell type components. Microarrays will then be used to profile precise gene expression patterns. Specific Aim 2. We also propose to use four mouse models of glomerulosclerosis to define the altered gene expression states and functional pathways resulting from four distinct initiating insults, one chemical and three genetic. This will create a detailed molecular picture of the progression of glomerulosclerosis and test the common final pathway hypothesis, which states that regardless of initial cause there are important shared aspects in the resulting glomerulosclerosis. Specific Aim 3. To define the altered functional pathways of the Human FSGS glomerulus. By using LCM and microarrays it will be possible to define the changes in gene expression that occur in the diseased glomerulus. By examining many glomeruli, from fifty patients, it will be possible to begin to understand the underlying molecular causes of the observed glomerulosclerosis, to subtype this heterogeneous disease based on gene expression signatures, to compare gene expression patterns as a function of disease progression, and to correlate gene expression markers with therapeutic response. For most FSGS patients there is currently no effective therapy, and kidney failure is the end result. We propose to use a combination of cutting edge technologies to study the normal glomerulus as well as the diseased glomerulus, in both humans and well- defined mouse models, to better understand this disease and to help discover improved methods of treatment. PUBLIC HEALTH RELEVANCE: For most FSGS patients there is currently no effective therapy, and kidney failure is the end result. We propose to use a combination of cutting edge technologies to study the normal glomerulus as well as the diseased glomerulus, in both humans and well- defined mouse models, to better understand this disease and to help discover improved methods of treatment.