Unexpected Oxygen Sensing: Real-Time Imaging of HIF Pathway Dynamics at Single-Cell Resolution

While Novak et al. (2019) and Campello et al. (2025) demonstrate time- and context-dependent HIF responses, existing studies rarely capture the real-time, single-cell dynamics of HIF activation and downstream effects. This project would engineer fluorescent HIF-1α reporters and combine them with advanced single-cell live imaging and optogenetic oxygen control. The goal is to track the spatiotemporal dynamics of HIF stabilization, nuclear translocation, and target gene induction (e.g., VEGF, EPO) in living cells exposed to dynamic oxygen fluctuations. This could reveal unexpected heterogeneity, pulsing, or even refractory states in HIF signaling, challenging the notion of a uniform hypoxia response. Such insights could inform more precise therapeutic interventions that exploit temporal vulnerabilities in diseases where hypoxia is central.

References:

1. Induction of the HIF pathway: Differential regulation by chemical hypoxia and oxygen glucose deprivation. A. E. Novak, Susan M. Jones, J. P. Elliott (2019). bioRxiv.
2. Transcriptional Heterogeneity and Differential Response of Rod Photoreceptor Pathway Uncovered by Single‐Cell RNA Sequencing of the Aging Mouse Retina. Laura Campello, Matthew J Brooks, Benjamin R. Fadl, Hyo Sub Choi, Soumitra Pal, Anand Swaroop (2025). Aging Cell.