Cordyceps Sinensis Evaluation in IgA Nephropathy Model

冬虫夏草在 IgA 肾病模型中的评价

• 批准号: 6820657
• 负责人: ABDALLA RIFAI
• 金额: $ 18.58万
• 依托单位: RHODE ISLAND HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-09-15 至 2006-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6820657
• 关键词: Basidiomycetes; IgA nephropathy; alternative medicine; biological signal transduction; cyclosporines; cytokine; enzyme activity; gene expression; genetically modified animals; glomerulonephritis; growth factor; high performance liquid chromatography; laboratory mouse; luciferin monooxygenase; mass spectrometry; medicinal plants; nuclear factor kappa beta; plant extracts; prednisolone; renal failure

DESCRIPTION (provided by applicant): IgA nephropathy is the most common form of glomerulonephritis worldwide. Renal deposits of IgA immune complexes (IgA-IC) cause injury with remarkable similarities in the pathophysiologic features of human and experimental IgA nephropathy. This suggests that common genomic expression profiles account for the similar phenotypic changes of IgA nephropathy. Despite extensive studies, there is paucity of information about an effective therapeutic modality for IgA nephropathy. The mushroom Cordyceps sinensis extracts (CSE), a traditional Chinese medicine has been reported as a potential therapy for IgA nephropathy. Our long-term goal is to elucidate the molecular mechanisms underlying the pathogenesis of IgA nephropathy as a necessary pre-requisite to the development of rational therapeutic modalities. Based on clinical and experimental observations, the specific hypothesis is that IgA-IC activate Nuclear Factor-KappaB (NF-KappaB) signalinq pathway to generate a cascade of pro-inflammatory cytokines and growth factors consummating in glomerular sclerosis, interstitial fibrosis, and renal failure. A corollary of this postulate that Cordyceps (alternative medicine) inhibition of the NF-KappaB signalinq pathway will ameliorate IgA nephropathy. The specific aims are to: 1. Determine the influence of Cordyceps sinensis extract on NF-KappaB signaling pathway activation and ability to halt progression of renal injury in IgA nephropathy. This will be achieved by correlating the level of NF-KappaB activation in transgenic luciferase reporter model with (i) IgA-IC deposition in immune and renal tissues, (ii) induction and progression of renal injury and (iii) comparing CSE effects with known anti-inflammatory and immunosuppressive NF-KappaB modulators (Prednisolone and Cyclosporine-A). 2. Identify pivotal genes in IgA nephropathy transcriptome profiles modulated by NF-KappaB signaling and in response to CSE, Prednisolone or Cyclosporine-A. This will be achieved by (i) comprehensive transcriptome analysis, (ii) correlation of tissue luciferase activity level (NF-KappaB activation) with transcripts intensity, and (iii) expression validation of identified informative genes. These studies will generate novel insights into molecular mechanisms underlying pathogenesis of IgA nephropathy and predict outcomes from safe traditional alternative medicine for prevention of renal failure.

描述（由申请人提供）：伊加肾病是全球最常见的肾小球肾炎。伊加免疫复合物（IgA-IC）的肾沉积物引起的损伤在人类和实验性伊加肾病的病理生理特征中具有显着的相似性。这表明共同的基因组表达谱解释了伊加肾病相似的表型变化。尽管有广泛的研究，但关于伊加肾病的有效治疗方式的信息很少。冬虫夏草提取物是一种传统中药，已被报道为伊加肾病的潜在治疗药物。我们的长期目标是阐明伊加肾病发病机制的分子基础，作为一个必要的先决条件，合理的治疗方式的发展。基于临床和实验观察，具体的假设是IgA-IC激活核因子-κ B（NF-κ B）信号通路以产生促炎细胞因子和生长因子的级联，从而在肾小球硬化、间质纤维化和肾衰竭中完成。这一假设的推论是，虫草（替代药物）抑制NF-κ B信号通路将改善伊加肾病。具体目标是： 1.确定冬虫夏草提取物对NF-κ B信号通路活化的影响和阻止伊加肾病肾损伤进展的能力。这将通过将转基因荧光素酶报告基因模型中的NF-κ B活化水平与（i）免疫和肾组织中的IgA-IC沉积、（ii）肾损伤的诱导和进展以及（iii）将CSE作用与已知的抗炎和免疫抑制NF-κ B调节剂（泼尼松龙和环孢菌素-A）进行比较来实现。 2.识别受NF-KappaB信号传导调节并响应CSE、泼尼松龙或环孢菌素A的伊加肾病转录组谱中的关键基因。这将通过（i）全面的转录组分析，（ii）组织荧光素酶活性水平（NF-κ B活化）与转录物强度的相关性，以及（iii）鉴定的信息基因的表达验证来实现。 这些研究将对伊加肾病发病机制的分子机制产生新的见解，并预测安全的传统替代药物预防肾衰竭的结果。