Mechanisms of gene expression control during the cellular response to hypoxia

项目总结。 氧稳态对细胞存活、正常发育和组织功能至关重要。含氧量低 (低氧)激活称为低氧诱导因子(HIF)的转录因子。高强度聚焦是关键 对低氧的适应性反应的调节器，调节涉及代谢重新编程的基因， 血管生成、多能性和分化、上皮向间充质转化(EMT)和细胞凋亡。 因此，HIF活性在许多病理过程中都是至关重要的，包括癌症进展、肥胖、 心脏病和中风。这里提出的工作重点是HIF1a，近期目标是显著 提高我们对细胞对低氧的反应的机械知识，以及阐明 由HIF1a驱动的人类病理的新治疗策略。对分子的详细剖析 HIF1a及其辅因子直接和间接调节基因表达的机制 确定细胞对低氧的适应所需的关键基因将是充分 了解不同类型的细胞和组织对这种压力的反应，并设想这些反应如何 在疾病过程中被操控。 利用基因组、分子生物学和功能方法的组合，这项研究提案旨在： ·确定缺氧激活HIF1a时驱动细胞类型特定基因表达的机制。 ·阐明HIF1a转录共激活因子的作用机制。 ·识别和描述细胞在低氧条件下生存所需的基因。

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.