Vitamin d receptor/smad genomic circuit gates fibrotic response
AssigneesThe Salk Institute for Biological Studies, The University of Sydney
InventorsNing Ding, Michael Downes, Christopher Liddle, Ronald M. Evans
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Abstract
The present disclosure provides compositions that include a nanoparticle and a compound that increases the biological activity of the vitamin D receptor (VDR) (e.g., a VDR agonist), and methods of using such compounds to increase retention or storage of vitamin A, vitamin D, and/or lipids by a cell, such as an epithelial or stellate cell. Such methods can be used to treat or prevent fibrosis.
Claims23
A composition, comprising:
- a nanoparticle comprising on its surface one or more of albumin, retinol binding protein, mannose-6-phosphate modified albumin, a fatty acid ester, a retinyl ester, or a linear-dendritic hybrid polymer;
- and
- a compound that increases the biological activity of a vitamin D receptor (VDR) which is in or attached to the nanoparticle.
A method of screening for an agent that can treat fibrosis, comprising:
- contacting a stellate cell with one or more test agents;
- contacting the stellate cell with an amount of TGF-β1 sufficient to increase vitamin D receptor (VDR) expression by at least 2-fold in the stellate cell relative to expression in an absence of the TGF-β1;
- detecting production of a VDR agonist by the stellate cell, production of CYP24A1 by the stellate cell, production, post-translational modification, or expression of SMAD3 by the stellate cell, or combinations thereof;
- and
- selecting test agents that increase production of the VDR agonist by the stellate cell by at least 5-fold relative to the absence of the one or more test agents, increase production of CYP24A1 by the stellate cell by at least 5-fold relative to the absence of the one or more test agents, reduce production, post-translational modification, or expression of SMAD3 by the stellate cell by at least 5-fold relative to the absence of the one or more test agents, or combinations thereof, wherein the selected test agents are agents that can treat fibrosis.
A method of increasing expression of VDR by a stellate cell, comprising:
- contacting the stellate cell with an amount of a VDR agonist and an amount of TGF-β1 sufficient to enhance binding of VDR agonist to the VDR by at least 10-fold.
Dependencies are inferred from the claim text.