PROTECTIVE POISON AT HIGH ALTITUDE: THERAPEUTIC EFFECTS OF ELEVATED ENDOGENOUS CO FROM ADAPTIVE HMOX2 VARIANTS

The key focus of this project is to determine the link between genotype and phenotype in the context of Tibetan adaptation to high altitude and to elucidate the currently unresolved mechanism of action through which Tibetans are conferred protection from pulmonary arterial hypertension. The project’s long-term goal is to further the understanding and use of carbon monoxide releasing molecules (CORMs) in treating pulmonary arterial hypertension. Pulmonary arterial hypertension is a global health concern that is characterized by pulmonary arterial wall thickening, vasoconstriction, and thrombus. Recent investigations of populations residing at high altitude revealed that many Tibetans residing at 4,200 m of altitude are protected from maladaptations to hypoxia relative to other populations resident at comparable high altitudes. Specifically, many Tibetans exhibit lower hemoglobin concentrations and pulmonary arterial pressures as well as elevated levels of nitric oxide. The Simonson lab previously conducted a genome wide selection scan of 31 Tibetan individuals, revealing a strong signal of natural selection in a region of the genome encompassing the gene coding for the constitutively active heme oxygenase isoform 2, HMOX2. In a study of individuals of Tibetan descent, they also determined that Tibetans have higher levels of carboxyhemoglobin than individuals of Han Chinese descent living at similar intermediate altitude. Recent studies demonstrate the therapeutic potential of carbon monoxide and CORMs through regulation of inflammatory and vasoactive responses. Together, these findings and preliminary data point to the hypothesis that adaptive changes in Tibetans are associated with a heme oxygenase-mediated increase in carbon monoxide, which confers protection from pulmonary hypertensive indications arising from chronic hypoxic stress. The design of this project’s research strategy is divided into two parts: (1) bioinformatics and functional analysis of Tibetan genetic variation at HMOX2, (2) biochemical and transcriptomic investigation of CORMs. The project’s focus and goals are aligned with NHLBI’s mission. It aims to investigate newly discovered cardiopulmonary traits in Tibetan populations that are key to their adaptation to high altitude and may provide insight into treating pulmonary arterial hypertension. The project seeks to understand, on the genetic and the cellular level, the mechanism by which carbon monoxide might affect the onset and progression of pulmonary arterial hypertension. Importantly, this project sheds light on differences in health in a unique population and identifies factors at the individual level which will contribute to our knowledge of human response to hypoxia. Project Number: 5F31HL174120-02 | Fiscal Year: 2026 | NIH Institute/Center: National Heart Lung and Blood Institute (NHLBI) | Principal Investigator: Mitchell Kong | Institution: UNIVERSITY OF CALIFORNIA, SAN DIEGO, LA JOLLA, CA | Award Amount: $42,596 | Activity Code: F31 | Study Section: Special Emphasis Panel[ZRG1-F08-L(20)L] View on NIH RePORTER: https://reporter.nih.gov/project-details/5F31HL17412002