Glomerulosclerosis in Human FSGS and Animal Models

描述（由申请人提供）：局灶节段性肾小球硬化（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提供对这种疾病的更深入的了解，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，这是有用的治疗指南。为此，我们提出以下具体目标。具体目标确定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解剖（LCM），以及具有细胞特异性报告基因表达和荧光激活细胞分选的转基因小鼠，分离肾小球及其三种细胞类型成分。然后，微阵列将被用于分析精确的基因表达模式。具体目标2。我们还建议使用四种肾小球硬化小鼠模型来定义四种不同的初始损伤（一种化学损伤和三种遗传损伤）导致的基因表达状态和功能途径的改变。这将创建肾小球硬化进展的详细分子图谱，并验证共同最终途径假说，即无论初始原因如何，最终肾小球硬化都有重要的共同方面。具体目标3。定义人类FSGS肾小球功能通路的改变。通过使用LCM和微阵列，可以确定病变肾小球中基因表达的变化。通过检查来自50名患者的许多肾小球，将有可能开始了解观察到的肾小球硬化的潜在分子原因，根据基因表达特征对这种异质性疾病进行亚型，比较基因表达模式作为疾病进展的功能，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，最终结果是肾功能衰竭。我们建议结合尖端技术来研究正常肾小球和病变肾小球，在人类和定义良好的小鼠模型中，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。我们建议结合尖端技术来研究正常肾小球和病变肾小球，在人类和定义良好的小鼠模型中，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.