Heme Oxygenase-1 Gene Expression by TGF-beta

描述（由申请人提供） 本研究计划的主要目标是为申请人提供 在细胞和分子生物学方面进行新的密集培训，以扩大她的研究 工具，目的是成为一名独立的调查员。实现这一 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，在哈利尼克博士的赞助下。和 Anupam Agarwal，M.D. 这项提案的长期目标是确定细胞保护作用， 血红素氧合酶-1基因表达在乳腺癌中的作用及其分子机制 肾脏对转化生长因子-β 1（TGF-β 1）的反应。 TGF-β 1在肾小球和肾小管中的表达增加导致 细胞增殖和细胞外基质沉积增加， 进行性肾纤维化，最终导致终末期肾病。 然而，TGF-β 1通过免疫调节作用稳定和减轻组织损伤。 细胞保护蛋白的激活。一种这样的细胞保护蛋白是血红素 氧合酶-1，具有抗氧化、抗炎和抗凋亡作用 特性.血红素氧合酶-1的诱导作为一种适应性和有益的 对肾损伤的反应。本提案的目标一和二将评估 TGF-β 1介导的血红素加氧酶-1诱导对细胞的细胞效应 增殖、细胞外基质沉积和细胞凋亡 或存在Smad蛋白，参与TGF-β 1信号传导的分子。旨在 III和IV将确定参与控制的转录机制， TGF-β 1介导的血红素加氧酶-1诱导。进一步理解本 血红素氧合酶-1基因的细胞保护作用及其分子机制 对TGF-β 1的反应性表达将在设计 肾损伤发病机制的干预策略。 拟议的研究将是培训申请人的基础， 最先进细胞和分子生物学技术如重组DNA， 转染，北方和免疫印迹分析，启动子缺失分析， 电泳迁移率变动分析和核运行分析，这将 大大提高了申请人？的研究职业发展， 独立研究员。

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.