The long-term goal of this project is to understandhow vitamin A signaling is modulated by orphannuclear receptors belonged to the TR2 and TR4 family. Previous studiesfocused on the repressive mechanisms of TR2 that include i) directly recruitingco-repressors like histone deacetylases (HDACs), receptor interacting protein 140 (RIP140) and SMRT (an active mechanism), and ii) competing with RA receptors (RARs) and retinoid X receptor (RXR) for DNA binding (a passive mechanism).By extending from these conclusions and based upon recent studies, this renewal proposal focuses on novel ligand-independent signaling pathways that can modify the property and activity of TR2 and TR4 for the regulation of RAR|32, cyclin D1 and apoE genes. Three hypotheses will be tested: i) the biological activity of TR2 and TR4 can be modulated by protein modification (biochemical factors) and their interaction with coregulators (kinetic factors), ii) the physiologically relevant receptor activity is manifested through their interaction with, or recruitment of, specific coregulators onto the regulatory region of the target gene (dynamic factors), and iii)the ligand- independently activated receptor complex can contribute to chromatin remodeling of target gene to activate transcription.
Aim I will address the first and second hypotheses by examining the mechanisms of ligand- independent modulation of receptor activity elicited through protein modifications (using a proteomic approach) that affect: i) the biochemical nature of receptors, ii) the general property of receptors, iii) receptor- coregulator interaction kinetics and iv) dynamics of TR2 and TR4 coregularory complex on target genes.
Aim II will address the third hypothesis in physiologically relevant cell cultures by manipulatingTR2 and TR4, and determiningthe effects of their modification on target genes. The biological effects to be examined include the formation of coregulatory complexes and alteration in chromatin conformation (remodeling) or histone modification on the target gene promoters (RAR|32, cyclin Dl and apoE) and theirbiological activities in P19 cell cycle progression as well as transcription efficiency of target genes. Results from both in vitro (aim 1) and in vivo (aim 2) systems will be integrated to construct a comprehensive overview of the mechanisms underlyingthe modulation of vitamin A signalingpathways by these orphan receptors, specifically with respect to signals generated from protein modifications of receptors.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
5R01DK054733-10
Application #
7769888
Study Section
Special Emphasis Panel (ZRG1-EMNR-D (02))
Program Officer
Margolis, Ronald N
Project Start
1999-08-01
Project End
2012-04-30
Budget Start
2010-03-01
Budget End
2012-04-30
Support Year
10
Fiscal Year
2010
Total Cost
$246,469
Indirect Cost
Name
University of Minnesota Twin Cities
Department
Pharmacology
Type
Schools of Medicine
DUNS #
555917996
City
Minneapolis
State
MN
Country
United States
Zip Code
55455
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Heisel, Timothy; Montassier, Emmanuel; Johnson, Abigail et al. (2017) High-Fat Diet Changes Fungal Microbiomes and Interkingdom Relationships in the Murine Gut. mSphere 2:
Lee, Bomi; Wu, Cheng-Ying; Lin, Yi-Wei et al. (2016) Synergistic activation of Arg1 gene by retinoic acid and IL-4 involves chromatin remodeling for transcription initiation and elongation coupling. Nucleic Acids Res 44:7568-79
Wu, Cheng-Ying; Persaud, Shawna D; Wei, Li-Na (2016) Retinoic Acid Induces Ubiquitination-Resistant RIP140/LSD1 Complex to Fine-Tune Pax6 Gene in Neuronal Differentiation. Stem Cells 34:114-23
Lin, Yi-Wei; Lee, Bomi; Liu, Pu-Ste et al. (2016) Receptor-Interacting Protein 140 Orchestrates the Dynamics of Macrophage M1/M2 Polarization. J Innate Immun 8:97-107
Persaud, Shawna D; Park, Sung Wook; Ishigami-Yuasa, Mari et al. (2016) All trans-retinoic acid analogs promote cancer cell apoptosis through non-genomic Crabp1 mediating ERK1/2 phosphorylation. Sci Rep 6:22396
Feng, Xudong; Lin, Yu-Lung; Wei, Li-Na (2015) Behavioral stress reduces RIP140 expression in astrocyte and increases brain lipid accumulation. Brain Behav Immun 46:270-9
Lin, Yi-Wei; Liu, Pu-Ste; Adhikari, Neeta et al. (2015) RIP140 contributes to foam cell formation and atherosclerosis by regulating cholesterol homeostasis in macrophages. J Mol Cell Cardiol 79:287-94
Adhikari, Neeta; Shekar, Kadambari Chandra; Staggs, Rodney et al. (2015) Guidelines for the isolation and characterization of murine vascular smooth muscle cells. A report from the International Society of Cardiovascular Translational Research. J Cardiovasc Transl Res 8:158-63
Wei, Li-Na; Dmintrovsky, Ethan (2015) Retinoids are back. FASEB J 29:1131-5

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