Wednesday, April 23, 2025
4/23/2025
Targeting Hypoxia-Inducible Factors (HIFs) for Heart and Lung Disease - PROJECT SUMMARY The current application for R35 funding is focused on targeting hypoxia-inducible factors (HIFs) for heart and lung disease. HIFs were discovered as transcription factors that are stabilized during hypoxia and promote adaptive responses. However, during inflammation or ischemia and reperfusion, changes in metabolic supply and demand result in inflammatory hypoxia and similarly promote the stabilization of HIFs. Studies from our laboratory and other investigators indicate that HIFs can dampen excessive tissue inflammation during inflammatory hypoxia, particularly during myocardial ischemia and reperfusion injury or during acute respiratory distress syndrome (ARDS). The stabilization of HIFs is controlled by prolyl hydroxylase domain enzymes (PHDs). Different isoforms of HIFs and PHDs exist, and ongoing efforts are focused on deciphering isoform-selective and tissue-specific roles for HIFs and PHDs during inflammatory conditions. Moreover, identifying specific transcriptional target genes and strategies for therapeutic targeting of HIFs are areas of intense research. Therefore, our NHLBI-funded research has been focused on studying hypoxia-signaling during inflammatory conditions, including myocardial injury and ARDS. To make progress on this front, we are requesting R35 funding in support of our “Hypoxia-Inflammation Program” at UTHealth Houston. For this program, we have incorporated three complementary projects. All three projects are extensions of ongoing research funded by 3 individual NHLBI R01 grants with Dr. Eltzschig as PI or contact PI (R01HL154720, R01HL169519, and R01HL165748). Project 1 focuses on the upstream regulation of HIFs by PHDs during ARDS. Our findings identify a novel feed-forward signaling loop under the control of alveolar-epithelial PHD1. Project 2 explores the functional roles of HIF-driven microRNAs during ARDS. We identified alveolar miR-147 as a novel HIF-target gene that dampens alveolar inflammation. Project 3 identifies a novel function of HIFs in mediating circadian variations of myocardial injury. We observed that the core circadian rhythm molecule BMAL1 forms a transcriptionally active heterodimer with HIF2A that modulates circadian-dependent cardiac injury. Substantiating this finding, we determined the cryo-EM structure of the BMAL1/HIF2F/DNA complex, revealing a previously unknown capacity for structural rearrangement within BMAL1. All three project themes are closely aligned and, as a whole, will provide a comprehensive understanding of molecular pathways that dampen inflammatory hypoxia, promote cellular resistance to ischemia, and define highly translational therapeutic targets controlled by HIFs. The projects are further linked by their shared use of technological resources, our hypoxia-signaling mouse core, and the human hypoxia-signaling biobank. The 7-year funding period of the R35 mechanism will allow the development of the critical clinical and basic science infrastructure. The result is a Program in which the whole is greater than the sum of its parts.
HHS’ Tracking Accountability in Government Grants System (TAGGS) website provides access to detailed descriptions of grants, loans, aggregated direct payments and other types of financial assistance awarded by the HHS Operating Divisions (OPDIVs) and the Office of the Secretary Staff Divisions (STAFFDIVs).