Mechanisms of gene expression control during the cellular response to hypoxia

项目摘要。 氧稳态对于细胞存活、正常发育和组织功能至关重要。低水平的氧 缺氧（hypoxia）激活称为缺氧诱导因子（hypoxia-inducible factors，HIFs）的转录因子。HIF是关键 调节对缺氧的适应性反应，调节参与代谢重编程的基因， 血管生成、多能性和分化、上皮-间充质转化（EMT）和凋亡。 因此，HIF活性在许多病理过程中是至关重要的，包括癌症进展、肥胖、 心脏病和中风这里提出的工作重点是HIF 1A，其直接目标是显著提高 推进我们对缺氧细胞反应的机械知识，以及阐明 用于由HIF 1A驱动的人类病理学的新治疗策略。详细剖析了 HIF 1A及其辅因子直接和间接调节基因表达的机制，以及 确定细胞对缺氧适应所需的关键基因对于充分研究缺氧的生物学特性至关重要。 了解不同的细胞类型和组织如何对这种压力作出反应，并设想这些反应如何 在疾病过程中被操纵。 使用基因组学，分子生物学和功能方法的组合，该研究提案旨在： ·定义缺氧激活HIF 1A后驱动细胞类型特异性基因表达的机制。 ·阐明HIF 1A转录共激活因子的作用机制。 ·识别和表征细胞在缺氧中存活所需的基因。

PROJECT SUMMARY. Oxygen homeostasis is critical for cell survival, normal development, and tissue function. Low levels of oxygen (hypoxia) activate the transcription factors known as hypoxia-inducible factors (HIFs). HIFs are the key regulators of the adaptive response to hypoxia, regulating genes involved in metabolic reprograming, angiogenesis, pluripotency and differentiation, epithelial-to-mesenchymal transition (EMT), and apoptosis. Accordingly, HIF activity is critical during many pathological processes, including cancer progression, obesity, heart disease, and stroke. The work proposed here focuses on HIF1A with the immediate goal of significantly advancing our mechanistic knowledge of the cellular response to hypoxia, and the ultimate goal of illuminating novel therapeutic strategies for human pathologies driven by HIF1A. A detailed dissection of the molecular mechanisms by which HIF1A and its cofactors regulate gene expression, both directly and indirectly, as well as the identification of the key genes required for the cellular adaptation to hypoxia will be critical to fully understand how different cell types and tissues react to this stress, and to envision how these responses can be manipulated during the course of disease. Using a combination of genomic, molecular biology, and functional approaches, this research proposal aims to: · Define mechanisms driving cell type-specific gene expression upon activation of HIF1A by hypoxia. · Elucidate the mechanisms of action of HIF1A transcriptional coactivators. · Identify and characterize genes required for cell survival in hypoxia.