Molecular timekeepers: converging pathways in circadian control

The National Institute of General Medical Sciences awarded The Trustees of The University of Pennsylvania $487,287 on March 10, 2026, under the Biomedical Research and Research Training program (CFDA 93.859) to support investigation of circadian rhythm mechanisms beyond traditional genetic control.

The research explores how cells and organisms maintain daily temporal organization through integration of genetic and non-genetic mechanisms, with focus on metabolic and redox processes that sustain circadian rhythms independently of gene expression. The funded work includes development of novel tools to track rhythms in real time, investigation of how metabolic cycles sustain timekeeping in cells lacking genetic rhythms, and identification of regulatory factors that maintain rhythmicity when core clock genes are absent. The research employs real-time imaging of single cells, genetic manipulation of engineered mouse models expressing fluorescent redox sensors, and comprehensive molecular profiling. The laboratory has demonstrated that circadian rhythms persist in contexts previously considered impossible, including nuclei-free red blood cells and mice missing essential clock genes, challenging conventional understanding of biological timekeeping.

The work is performed in Philadelphia, Pennsylvania, with a period of performance ending January 31, 2031. The assistance type is a Project Grant.

Abstract

Circadian rhythms-daily cycles in physiology and behavior-were long thought to rely exclusively on genetic feedback loops. However, our laboratory has uncovered surprising evidence that these biological rhythms persist in contexts previously considered impossible, including red blood cells that lack nuclei and mice missing essential clock genes. These findings challenge conventional understanding of biological timekeeping and suggest the existence of fundamental timing mechanisms beyond traditional genetic control. Over the past five years, our work has established that metabolic and redox processes can sustain circadian rhythms independently of gene expression, developed novel tools to track these rhythms in real-time, and identified new regulatory factors that maintain rhythmicity even when core clock genes are absent. Building on these discoveries, our research program explores how cells and organisms maintain temporal organization through the integration of genetic and non-genetic mechanisms. We have engineered unique mouse models expressing fluorescent sensors that allow unprecedented visualization of cellular redox states alongside traditional clock gene activity. Using these tools, we investigate how metabolic cycles sustain timekeeping in cells lacking genetic rhythms, how newly discovered regulators coordinate different types of cellular rhythms, and how organisms maintain robust daily timing through redundant mechanisms. This work employs cutting-edge approaches including real-time imaging of single cells, genetic manipulation of model systems, and comprehensive molecular profiling. Our findings are reshaping understanding of biological timekeeping and have direct implications for human health. Disrupted circadian rhythms-whether from shift work, jet lag, or genetic variants-contribute to numerous diseases including metabolic disorders, cardiovascular disease, and cancer. By uncovering new mechanisms that cells use to maintain temporal organization, this research program aims to identify novel therapeutic strategies for treating circadian-related disorders. Our work thus addresses fundamental questions in biology while advancing the NIH's mission to reduce illness and improve human health.