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Multicellular organisms critically rely on systems such as red blood cell production (erythropoiesis) to sense oxygen availability and ensure a continuous systemic supply. Yet, the precise underlying molecular mechanisms and their regulatory dynamics are not well understood.In this project, I will use the lens of human evolution to decipher gene regulatory networks that govern cellular systems functions responsible for Tibetan adaptation to high-altitude hypoxia. This low oxygen environment poses extreme challenges to human physiology, yet Tibetans have genetically adapted and show increased fitness compared to non-adapted neighbours. Investigating this natural experiment can shed light onto fundamental mechanisms regulating biological processes that control oxygen homeostasis. To this end, I will develop a novel interdisciplinary approach using human kidney organoids to model erythropoiesis regulation in genetically adapted backgrounds and apply state of the art genome engineering and single cell high resolution technologies as readouts. This innovative interdisciplinary approach will elucidate the genetic and regulatory mechanisms that are fundamental in hypoxia physiology. New insights may shed light on ̽»¨¾«Ñ¡ly relevant hypoxia and the next generation of regenerative medicinal approaches to better human health.

Understanding the evolution and function of genetic variants affecting human fitness opens new avenues to investigate and explain global health disparities. The non-coding genome is arising as a promising target

however, it remains largely experimentally untested which and how genetic changes shape human molecular circuits, physiology, and disease. As an incoming independent group leader at MBB at ̽»¨¾«Ñ¡, my lab aims to bring human evolutionary genomics to life in 3D-tissue organoids and use high-throughput single cell transcriptomic and epigenetic readouts. In this SSMF-project, we will use the well-studied genetic and physiological adaptation of Tibetans to living in high altitude hypoxia and the protective changes in red blood cell production (erythropoiesis) critical to oxygen homeostasis. Building on my recent discovery of the kidney erythropoietin producing Norn cells that are central to erythropoiesis regulation, the specific aims of the lab are: 1) Profile human kidney in homeostasis, hypoxia, and disease to discover the key regulators of human Norn cells. 2) Build erythropoietin producing human kidney organoid model system. 3) Dissect the molecular mechanism of Tibetan fitness using human kidney organoids of adapted and non-adapted ancestry. Together, this approach will decipher the intricate interplay between the genome, epigenome, and physiology, and may shed new light on ̽»¨¾«Ñ¡ hypoxia and advance regenerative approaches to better human health.