Heme Oxygenase-1 Gene Expression by TGF-beta

描述(由申请人提供) 该研究计划的主要目标是为申请者提供 在细胞和分子生物学方面进行了新的强化培训，以扩大她的研究 工具，目的是成为一名独立的调查员。要做到这一点 目标申请人将在丰富的科学环境中进行培训 佛罗里达大学，由哈里·尼克博士和 共同赞助Anupam Agarwal，M.D. 这项提案的长期目标是确定细胞保护性 血红素加氧酶-1基因表达的作用及分子机制 肾脏对转化生长因子-β1的反应。 转化生长因子-β1在肾小球和肾小管间质中的表达增加 增加细胞增殖和细胞外基质的沉积，结果 导致进行性肾脏纤维化，最终导致终末期肾脏疾病。 然而，转化生长因子-β1通过以下途径稳定和减轻组织损伤 激活细胞保护蛋白。一种这样的细胞保护蛋白是亚铁血红素 具有抗氧化、抗炎、抗细胞凋亡作用的加氧酶-1 属性。血红素加氧酶-1的诱导是一种适应性的和有益的 对肾脏损伤的反应。本提案的目标I和目标II将评估 转化生长因子-β1介导的血红素加氧酶-1诱导对细胞的影响 细胞外基质的增殖、沉积和缺失时的细胞凋亡 或存在Smad蛋白，参与转化生长因子-β1信号转导的分子。目标 III和IV将确定参与控制的转录机制 转化生长因子-β1介导的血红素加氧酶-1的诱导。对新世纪的认识 血红素加氧酶-1基因的细胞保护作用及其分子机制 响应于转化生长因子-β1的表达在设计中将是重要的 肾损伤发病机制中的干预策略。 建议的研究将作为对申请者进行培训的基础 最先进的细胞和分子生物学技术，如重组DNA， 转染，Northern和免疫印迹分析，启动子缺失分析， 电泳迁移率改变分析和核运行分析，这将 大大提升申请人？S研究事业发展迈向安邦 独立研究人员。

DESCRIPTION (provided by applicant) The major objective of this research program is to provide the applicant with new and intensive training in cell and molecular biology to expand her research tools with the purpose of becoming an independent investigator. To achieve this goal the applicant will train in the rich scientific environment of the University of Florida, under the sponsorship of Harry Nick, Ph. D. and co-sponsorship of Anupam Agarwal, M.D. The long-term goals of this proposal are to determine the cytoprotective actions and molecular mechanisms of heme oxygenase-1 gene expression in response to transforming growth factor-beta1 (TGF-beta1) in the kidney. Increased expression of TGF-beta1 in glomeruli and tubulointerstitium leads to increased cell proliferation and deposition of extracellular matrix, resulting in progressive kidney fibrosis and, ultimately, end stage renal disease. TGF-beta1, however, stabilizes and attenuates tissue injury through the activation of cytoprotective proteins. One such cytoprotective protein is heme oxygenase-1, which has antioxidant, anti-inflammatory and anti-apoptotic properties. Induction of heme oxygenase-1 occurs as an adaptive and beneficial response to renal injury. Aims I and II of this proposal will evaluate the cellular effects of TGF-beta1-mediated heme oxygenase-1 induction on cell proliferation, deposition of extracellularmatrix, and apoptosis in the absence or presence of Smad proteins, molecules involved in TGF-beta1 signalling. Aims III and IV will identify the transcriptional mechanisms involved in controlling TGF-beta1-mediated heme oxygenase-1 induction. Further understanding of the cytoprotective actions and molecular mechanisms of heme oxygenase-1 gene expression in response to TGF-beta1 will be important in designing interventional strategies in the pathogenesis of renal injury. The proposed studies will be the basis for training the applicant in state-of-the-art cell and molecular biology techniques such as recombinant DNA, transfection, northern and immunoblot analyses, promoter-deletion analysis, electrophoretic mobility shift assays and nuclear run on assays, which will greatly enhance the applicant?s research career development towards an independent researcher.