Monday, May 13, 2024
5/13/2024
PROJECT DESCRIPTION Vascular and lymphatic systems have emerged as attractive therapeutic targets in a variety of diseases. Stimulating angiogenesis accelerates wound healing and tissue regeneration after myocardial infarction whereas inhibition of angiogenesis suppresses tumor growth1 and progression of intraocular neovascular diseases. Likewise, stimulating lymphangiogenesis aids in the treatment of secondary lymphedema, prevents atherosclerosis and could promote cancer immunotherapy. Endothelial cells (ECs) are key components of arterial, venous, and lymphatic vasculatures. Studies in mice identified the transcription factor NR2F2, also known as COUP-TFII, as the key regulator of EC fate. However, major gaps exist in our knowledge of the cellular and molecular mechanisms by which NR2F2 regulates EC specification. Which EC subsets, developmental transitions and molecular networks are targeted by NR2F2 is unknown. NR2F2 and its homolog NR2F1 are members of the nuclear hormone receptor (NHR) family of transcription factors. NHR activities are controlled by small molecules derived from endogenous metabolism or diet. Recently, we identified 1-deoxysphingosines as natural ligands for NR2F1/2. Although 1-deoxysphingosines have been detected in tissues, no physiological roles have yet been proposed for these metabolites - they are considered toxic byproducts of sphingolipid biosynthesis resulting from mutations in subunits of the SPT complex. Our study is the first to suggest that these metabolites have a physiological function as regulators of NR2F1/2-mediated transcription. The mechanistic understanding of how NR2F1/2:1-deoxysphingosine axis regulates EC development would yield knowledge needed to modulate blood/lymphatic vessel development in research and clinical settings. In this proposal, we will (1) define the cellular and molecular networks regulated by NR2F1/2 and its ligand, 1-deoxysphingosine, during arterial venous, and lymphatic specification of hESCs, (2) delineate molecular pathways that modulate 1- deoxysphingosine synthesis and uptake and identify major physiological sources of this metabolites in vivo, and (3) define the structure of ligand-bound NR2F2 LBD and validate ligand-receptor interactions. The work proposed is significant because it will identify molecular pathways that modulate NR2F2 transcriptional activity thus contributing to an understanding how NR2F2-mediated transcriptional networks regulate development and physiology of vascular and lymphatic systems. This knowledge will be instrumental for developing ligand analogs that can act as chemical modulators of NR2F2 activity under normal and disease conditions. Our approach is innovative because we will develop new concepts and methodologies that could be adapted to understand the molecular bases of NHR-mediated transcription and to search for ligands of other orphan NHRs.
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