Frontiers in Genomics: Juan Rene Alvarez Dominguez
Chrono-energetics: Linking Circadian Metabolism to Islet Replacement Therapeutics

Resumen
Rhythms in energy availability, driven by earth’s 24-hour rotation, are the oldest, most consistent external input for life on earth. All life forms (from bacteria to all of our cells) have thus evolved autonomous “circadian” clocks that align physiology—from nutrient transport and uptake to breakdown and storage—to daily feeding-fasting. Chronic misalignment between endogenous and external rhythms triggers multi-system dysfunction, including metabolic, cardiovascular, and neural syndromes. Common to such diverse disorders is the loss of specialized cell phenotypes, suggesting that timing cellular tasks to daily energy cycles is vital for mature functioning.

Our tissues mature along with daily environment fluctuations, yet organoids today are grown in constant environments. Most efforts to foster organoid maturation have focused on the nature, not the timing, of maturational cues, despite the built-in rhythmicity of cellular processes. Thus, to better understand and harness maturation, we must shift from “static” to “rhythmic” paradigms.

Recently, I discovered that daily feeding rhythms can foster maturation of SC-islets (human stem cell-derived islets), which functioned in vivo within days of transplant. This provided the first proof-of-principle that rhythms can be harnessed to engineer mature organoids for regenerative medicine. I now seek to follow up on this research to dissect the underlying molecular mechanisms, to robustly generate mature organoids, and to further their use as research models and diabetes replacement therapy.

My lab focuses on understanding how rhythms regulate cell maturation, to enable creating fully functional organoids for tissue replacement therapies. Specifically, we aim to:
1) Link chrono-energetic mechanisms to SC-islet cell maturation trajectories, integrating novel tissue engineering and single-cell approaches that leverage my cross-disciplinary expertise in cell fate control and gene regulation.
2) Harness these mechanisms for disease-modeling, screening, and therapeutic applications via functional laboratory experiments and animal transplantation studies.

These studies will reveal the principles by which circadian rhythms shape islet maturation, which will help us understand, and eventually prevent, its loss during diabetes and chrono-disruption. Unlocking these principles may also illuminate general means to harness control over maturity of any human tissue.

Juan Rene Alvarez Dominguez. Assistant Professor of Cell and Developmental Biology. Perelman School of Medicine. University of Pennsylvania.

https://www.med.upenn.edu/apps/faculty/index.php/g275/p9558766

https://cdb.med.upenn.edu/people/juan-alvarez-ph-d/

Frontiers in Genomics