The overall objective of our research is to establish the developmental and physiological functions of the orphan nuclear receptor, nor-1. Nor-1 is a member of the nuclear receptor superfamily and acts as a constitutively active transcription factor without an apparent requirement for ligand binding. The gene was originally identified through its involvement in a chromosomal rearrangement associated with extraskeletal myxoid chondrosarcoma (EMC), a tumor that originates in cartilage forming mesenchyme. However, virtually no information is available on the functions of this nuclear receptor in vivo. In order to gain insights into the developmental and physiological role of nor-1, we have begun to examine the spatiotemporal expression of this developmental and physiological role of nor-1, we have begun to examine the spatiotemporal expression of this factor during murine development and to establish the consequences of genetic ablation of nor-1 in mice. Our preliminary data indicates that nor-1 expression in the embryo is closely associated with the critical periods of inner ear morphogenesis and embryonic chondrogenesis and synovial joint formation in the appendicular skeleton. Consistent with its expression in the developing inner ear, ablation of nor-1 in mice results in an abnormal circling behavior phenotype that is consistent with a primary defect in the vestibular apparatus of the inner ear. The goal of this project is to define the specific role of nor-1 in inner ear and bone development and it identify the molecular development signaling pathways in which nor-1 resides. Specifically, we will 1) establish the relationship between nor-1 expression and molecular signals of vestibular and cochlear development and the consequences of nor-1 ablation on these pathways, 2) establish the role of nor1-1 in chondrocyte differentiation and synovial joint formation and function by comparison of its expression with molecular markers of differentiation and analysis of the phenotypic consequences of nor-1 ablation and 3) determine whether transgenic over- expression of nor-1 alone is sufficient to alter the program of chondrocyte differentiation and induce a phenotype similar to EMC.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Program Projects (P01)
Project #
5P01DK057743-03
Application #
6589549
Study Section
Special Emphasis Panel (ZDK1)
Project Start
2002-06-01
Project End
2003-05-31
Budget Start
Budget End
Support Year
3
Fiscal Year
2002
Total Cost
$177,233
Indirect Cost
Name
Baylor College of Medicine
Department
Type
DUNS #
074615394
City
Houston
State
TX
Country
United States
Zip Code
77030
Demayo, Janet L; Wang, Jie; Liang, Dongcai et al. (2012) Genetically Engineered Mice by Pronuclear DNA microinjection. Curr Protoc Mouse Biol 2:245-262
Huang, Jiansheng; Iqbal, Jahangir; Saha, Pradip K et al. (2007) Molecular characterization of the role of orphan receptor small heterodimer partner in development of fatty liver. Hepatology 46:147-57
Wang, Li; Huang, Jiansheng; Saha, Pradip et al. (2006) Orphan receptor small heterodimer partner is an important mediator of glucose homeostasis. Mol Endocrinol 20:2671-81
Wang, Li; Liu, Jun; Saha, Pradip et al. (2005) The orphan nuclear receptor SHP regulates PGC-1alpha expression and energy production in brown adipocytes. Cell Metab 2:227-38
Gu, Peili; Goodwin, Bryan; Chung, Arthur C-K et al. (2005) Orphan nuclear receptor LRH-1 is required to maintain Oct4 expression at the epiblast stage of embryonic development. Mol Cell Biol 25:3492-505
Lee, Christopher T; Li, Luoping; Takamoto, Norio et al. (2004) The nuclear orphan receptor COUP-TFII is required for limb and skeletal muscle development. Mol Cell Biol 24:10835-43
Zhou, Ge; Hashimoto, Yoshihiro; Kwak, Inseok et al. (2003) Role of the steroid receptor coactivator SRC-3 in cell growth. Mol Cell Biol 23:7742-55
Wang, Li; Han, Yunqing; Kim, Chang-Soo et al. (2003) Resistance of SHP-null mice to bile acid-induced liver damage. J Biol Chem 278:44475-81
Wang, Li; Lee, Yoon-Kwang; Bundman, Donnie et al. (2002) Redundant pathways for negative feedback regulation of bile acid production. Dev Cell 2:721-31
Lee, Yoon-Kwang; Moore, David D (2002) Dual mechanisms for repression of the monomeric orphan receptor liver receptor homologous protein-1 by the orphan small heterodimer partner. J Biol Chem 277:2463-7

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