Abstract

The goal of our proposed research is to explore the effects of targeted disruption of the nuclear orphan receptors TR2 and TR4, as well as consequences of disruption of the two genes in combination, in order to determine the physiological roles of these receptors. We hypothesize that both TR2 and TR4 play significant roles in the regulation of developmental, physiological, and behavioral systems. To determine the specific roles of TR2 and TR4 in vivo, we will employ mouse models exhibiting ablation of either orphan receptor, as well as animals exhibiting simultaneous ablation of both receptors.
Specific aim 1 : Characterization of TR4 knockout/Beta-gal knockin (TR4 -/-) mice.
Specific aim 2 : Characterization of TR2 knockoutJBeta-gal knockin (TR2 -/-) mice. We hypothesize this receptor is more important in early stages of development, and that TR2 -/- mice may die pre- or postnatally. Mortality will be investigated by morphological and histological analyses, and animals surviving to adulthood will be assessed for growth rate and fertility.
Specific aim 3 : Characterization of TR2/TR4 double knockout mice. Analysis of the double knockout animals will follow the approach described in Specific Aim 2, and the phenotypes will be analyzed in comparison to TR2 knockout, TR4 knockout, and wildtype mice.
Specific Aim 4 : Analysis of the effects of TR4 and/or TR2 ablation on target gene regulation. TR4, TR2, and TR2/TR4 knockout animals will be tools to study the known target genes of these orphan receptors in an in vivo system, and to confirm the physiological significance of the identified regulatory pathways, and provide sources of material for the screening of novel TR2/TR4 target genes. 4a: Determination of effect of TR4 and/or TR2 target gene ablation on known target gene expression. Compare endogenous gene expression, and protein levels of TR4 and TR2 downstream targets in knockout animals versus wildtype controls. 4b: Identifiy novel genes regulated uniquely or differentially by TR4 and/or TR2 through the use of gene microarray technology, we hope to dissect the differences in target gene regulation mediated by TR4 and TR2 and, in this way, further understand the roles of these enigmatic orphan receptors in mammalian development and physiology. In summary, this proposal provides us the first opportunity to study the potential in vivo physiological roles of the TR2 and TR4 orphan nuclear receptors.

  Funding Agency

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
5R01DK063212-04
Application #
7010706
Study Section
Reproductive Endocrinology Study Section (REN)
Program Officer
Margolis, Ronald N
Project Start
2003-02-01
Project End
2007-01-31
Budget Start
2006-02-01
Budget End
2007-01-31
Support Year
4
Fiscal Year
2006
Total Cost
$361,428
Indirect Cost

  Institution

Name
University of Rochester
Department
Pathology
Type
Schools of Dentistry
DUNS #
041294109
City
Rochester
State
NY
Country
United States
Zip Code
14627

  Publications

Yan, Shian-Jang; Lee, Yi-Fen; Ting, Huei-Ju et al. (2012) Deficiency in TR4 nuclear receptor abrogates Gadd45a expression and increases cytotoxicity induced by ionizing radiation. Cell Mol Biol Lett 17:309-22
Collins, Loretta L; Lee, Yi-Fen; Ting, Huei-Ju et al. (2011) The roles of testicular nuclear receptor 4 (TR4) in male fertility-priapism and sexual behavior defects in TR4 knockout mice. Reprod Biol Endocrinol 9:138
Lee, Yi-Fen; Liu, Su; Liu, Ning-Chun et al. (2011) Premature aging with impaired oxidative stress defense in mice lacking TR4. Am J Physiol Endocrinol Metab 301:E91-8
Chen, Yei-Tsung; Collins, Loretta L; Chang, Shu-Shi et al. (2008) The roles of testicular orphan nuclear receptor 4 (TR4) in cerebellar development. Cerebellum 7:9-17
Chen, Yei-Tsung; Collins, Loretta L; Uno, Hideo et al. (2007) Abnormal cerebellar cytoarchitecture and impaired inhibitory signaling in adult mice lacking TR4 orphan nuclear receptor. Brain Res 1168:72-82
Kim, Eungseok; Ma, Wen-Lung; Lin, Din-Lii et al. (2007) TR4 orphan nuclear receptor functions as an apoptosis modulator via regulation of Bcl-2 gene expression. Biochem Biophys Res Commun 361:323-8
Zhang, Yanqing; Chen, Yei-Tsung; Xie, Shaozhen et al. (2007) Loss of testicular orphan receptor 4 impairs normal myelination in mouse forebrain. Mol Endocrinol 21:908-20
Chen, Yei-Tsung; Collins, Loretta L; Uno, Hideo et al. (2005) Deficits in motor coordination with aberrant cerebellar development in mice lacking testicular orphan nuclear receptor 4. Mol Cell Biol 25:2722-32
Mu, Xiaomin; Lee, Yi-Fen; Liu, Ning-Chun et al. (2004) Targeted inactivation of testicular nuclear orphan receptor 4 delays and disrupts late meiotic prophase and subsequent meiotic divisions of spermatogenesis. Mol Cell Biol 24:5887-99
Collins, Loretta L; Lee, Yi-Fen; Heinlein, Cynthia A et al. (2004) Growth retardation and abnormal maternal behavior in mice lacking testicular orphan nuclear receptor 4. Proc Natl Acad Sci U S A 101:15058-63

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