Retinoic acid (RA), the biologically active form of Vitamin A, is essential for a variety of biological processes. RA binds to nuclear receptors, retinoic acid receptor (RAR) and retinoid receptor X (RXR), to regulate target gene expression by triggering recruitment of coregulators that act, primarily, through chromatin remodeling and modification on the regulatory regions of target genes. Nuclear Receptor Interacting Protein 1 (NRIP1, originally known as RIP140) is a ligand-dependent co-repressor, i.e. it represses hormonal induction of target gene expression in a hormone-dependent manner. The long-term goal of this project is to understand the mechanisms underlying homeostatic control of vitamin A signaling. The proposal focuses on chromatin remodeling events orchestrated by RIP140 and coactivators that form complexes with hormone receptors, such as RIP140-RAR/RXR complex and coactivator-RAR/RXR complexes, as well as the biological significance of several newly identified post-translational modifications in the modulation of receptor/coregulator activities. Two questions will be addressed: 1) how does RIP140 function in hormone-induced chromatin remodeling? 2) How does protein modification regulate the biological activity of RIP140? Wild type and genetically modified cells, including RIP140-knockout (RIP-/-) and TRAP220-knockout (TRAP-/-) cells, as well siRNA mediated gene knockdown in P19 cells will be used as the principal experimental systems. Chromatin segments containing hormone response elements (HREs) will be the targets of examination to address mechanistic details in a physiologically relevant context. These studies will provide mechanistic insights into crosstalk of hormones (vitamin A and thyroid hormones) via coordinated formation of specific transcription factor complexes. These studies will also uncover potentially novel signals and cellular factors that are critical to cell differentiation program where vitamin A and other endocrine factors play vital roles. Knowledge gained from these studies could also be applied to understand clinical diseases that are affected by, or involve, hormonal and nutritional factors, such as metabolic diseases, the studies will also delineate the role of nutrients, such as vitamin A, in the maintenance of human health.

Public Health Relevance

Retinoic acid (RA), the biologically active form of Vitamin A, is essential for a variety of biological processes. RA functions by regulating target gene expression through chromatin remodeling that involves Nuclear Receptor Interacting Protein 1 (NRIP1, originally known as RIP140). The long-term goal of this project is to understand the mechanisms underlying homeostatic control of vitamin A signaling. The current proposal focuses on the functional role of NRIP1 from a mechanistic stand point. Knowledge gained from these studies could also be applied to understand clinical diseases that are affected by, or involve, hormonal and nutritional factors, such as metabolic diseases. The studies will also delineate the role of nutrients, such as vitamin A, in the maintenance of human health.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
5R01DK060521-10
Application #
8242858
Study Section
Integrative Nutrition and Metabolic Processes Study Section (INMP)
Program Officer
Maruvada, Padma
Project Start
2002-03-15
Project End
2013-06-30
Budget Start
2012-04-01
Budget End
2013-06-30
Support Year
10
Fiscal Year
2012
Total Cost
$308,990
Indirect Cost
$100,719
Name
University of Minnesota Twin Cities
Department
Pharmacology
Type
Schools of Medicine
DUNS #
555917996
City
Minneapolis
State
MN
Country
United States
Zip Code
55455
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
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
Hwang, Cheol Kyu; Wagley, Yadav; Law, Ping-Yee et al. (2015) Analysis of epigenetic mechanisms regulating opioid receptor gene transcription. Methods Mol Biol 1230:39-51
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
Liu, Pu-Ste; Lin, Yi-Wei; Burton, Frank H et al. (2015) Injecting engineered anti-inflammatory macrophages therapeutically induces white adipose tissue browning and improves diet-induced insulin resistance. Adipocyte 4:123-8
Liu, Pu-Ste; Lin, Yi-Wei; Burton, Frank H et al. (2015) M1-M2 balancing act in white adipose tissue browning - a new role for RIP140. Adipocyte 4:146-8
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
Wei, Li-Na; Dmintrovsky, Ethan (2015) Retinoids are back. FASEB J 29:1131-5
Liu, Pu-Ste; Lin, Yi-Wei; Lee, Bomi et al. (2014) Reducing RIP140 expression in macrophage alters ATM infiltration, facilitates white adipose tissue browning, and prevents high-fat diet-induced insulin resistance. Diabetes 63:4021-31

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