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Molecular and Cellular Biology

Houston, Texas

Image 1: Ovulated mouse cumulus cell oocyte complex immunostained for matrix proteins hyaluronan and versican. By JoAnne Richards, Ph.D.; Image 2: By Yi LI, Ph.D.; Image 3: Mouse oocyte at meiosis I immunostained  for tubulin (red) phosphop38MAPK (green) and DNA (blue). By JoAnne Richards,  Ph.D.;  Image 4: Expanded cumulus cell ooctye ocmplex  immunostained for hyaluronan (red), TSG6 (green) and DAN (blue). By JoAnne  Richards, Ph.D.;  Image 5: Epithelial cells taken from a mouse  mammary gland were cultured in a dish and transduced with a retrovirus  expressing two genes. The green staining shows green fluorescent protein and the red  staining shows progesterone receptor expression. The nucleus of each cell is  stained blue. Photomicrograph taken at 200X magnification.  By Sandra L. Grimm,  Ph.D.; Image 6: Ovarian vasculature (red) is excluded from the granulosa cells (blue) within growing follicles (round structures); Image 7:  Ovulated mouse cumulus cell oocyte  complex immunostained for matrix proteins hyaluronan and versican. By JoAnne Richards, Ph.D.
Department of Molecular and Cellular Biology
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Sophia Y. Tsai, Ph.D.

Professor
Department of Molecular and Cellular Biology

Education

Ph.D.: University of California, Davis
Postdoctoral training: Cornell University, Ithaca
M.D. Anderson Cancer Center, Houston

Research Interest

COUP-TFII and Vein Identity, Angiogenesis, Diabetes and Obesity and Kidney Disease
My research interests focus on understanding the physiological role of an orphan nuclear receptor, COUP-TFII. Our studies could be divided into three areas:

1. Tumor growth and metastasis: Using mouse model, we showed previously that COUP-TFII suppresses notch-signaling pathway to confer vein identity. Since lymphatic vessels derive from veins, the formation of lymphatic vessels is impaired in the absence of COUP-TFII. Recently, we showed that COUP-TFII regulates angiogenesis and tumor progression within the tumor microenvironment. Conditional ablation of COUP-TFII in adult mice resulted in defective angiogenesis and compromised tumor growth in xenograft and in spontaneous mouse tumor models. COUP-TFII regulates multiple genes in various growth signaling pathways to promote tumor growth and tumor metastasis. Since COUP-TFII expression is elevated in prostate cancer patient samples, we are studying the cell autonomous function of COUP-TFII in tumor cells. Using cell culture and animal model, we demonstrated that COUP-TFII plays a cell autonomous function to promote tumor growth in prostate tumorigenesis.

2. Cardiovascular development: Congenital heart defects are common genetic defects of infants. A hypomorphic mutant of COUP-TFII exhibits defects in formation of atrial-ventricular septum and coronary vessels, defects commonly seen in CHD patients. Ablation of COUP-TFII in atrial cardiomyocytes, converts atrial cardiomyocytes to adopt ventricular fate, while ectopic-expression of COUP-TFII in ventricular cardiomyocytes changes ventricular identity to atrial identity.

3. Energy metabolism and diseases: It is also shown that the expression of COUP-TFII is elevated in heart patients with familial heart disease and in a pressure overloaded mouse model. Heart failure is a major medical problem in US. To address the potential role of COUP-TFII in energy metabolism in the heart, we generated a mouse model overexpressing COUP-TFII in the heart. We showed that elevated COUP-TFII expression results in the suppression of the expression of key enzymes essential for fatty acid trafficking and oxidation, suggesting a defect in usage of lipid as fuel. The expression of many enzymes involved in fatty acid metabolism is regulated by the PGC/ERR axis, suggesting COUP-TFII might control the PGC/ERR axis to regulate fuel usage and mitochondrial function, leading to dysregulation of energy metabolism.

The major questions remaining to be addressed are: How is COUP-TFII being regulated in different tissues? What are the direct downstream targets of COUP-TFII? What are the molecular pathways impacted by COUP-TFII to confer all these defects? Understanding the function of COUP-TFII may provide new novel targets for future treatment of cardiovascular and metabolic diseases and cancer.

Current projects:
1.The role of COUP-TFII in prostate cancer
2.The role of COUP-TFII in energy metabolism in heart and muscle
3. The role of COUP-TFII in cardiovascular development and diseases

Ying-Yang of Vessel Formation. Model illustration

Contact Information

Baylor College of Medicine
One Baylor Plaza, DeBakey M707
Houston, TX 77030

Phone: 713-798-6251
E-mail: stsai@bcm.edu

Selected Publications

  1. Xie X, Qin J, Lin S-H, Tsai SY and Tsai M-J. (2011). COUP-TFII modulates mesenchymal cell lineage commitment and differentiation. Proc. Natl. Acad. Sci. USA, 108: 14843-14848. PMID: 21873211
  2. Qin J, Chen X, Yu-Lee L, Tsai M-J and Tsai SY. (2010). Nuclear receptor COUP-TFII controls pancreatic islet tumor angiogenesis by regulating VEGF/VEGFR-2 signaling. Cancer Res. 70: 8812-8821. PMID: 20978203; PMCID: PMC: 2970665
  3. Lin FJ, Chen X, Qin J, Hong YK, Tsai MJ, Tsai SY. (2010). Direct transcriptional regulation of neuropilin-2 by COUP-TFII modulates multiple steps in murine lymphatic vessel development. J. Clin Investigation. 120:1694-1707 PMCID: PMC2860940
  4. Qin J, Chen X, Xie X, Tsai MJ, Tsai SY. (2010). COUP-TFII regulates tumor growth and metastasis by modulating tumor angiogenesis. Proc Natl Acad Sci 107:2431-6 PMCID: PMC2840495
  5. Tang K, Park J-I, Jamrich M, Tsai SY and Tsai M-J. (2010). COUP-TFs regulate eye development by controlling factors essential for optic vesicle morphogenesis. Development 137: 725-734 PMCID: PMC2827684
  6. Li L, Xie X, Qin J, Jeha G, Saha PK, Yan J, Haueter CM, Chan L, Tsai SY and Tsai M-J.(2009). The Nuclear orphan receptor COUP-TFII plays an essential role in adipogenesis, glucose homeostasis and energy metabolism. Cell Metabolism 9: 77-87 PMCID: PMC2630393.
  7. Kurihara K, Lee D-K, Petit FG, Jeong J, Lee K, Lydon JP, DeMayo FJ, Tsai M-J and Tsai SY. (2007). COUP-TFII mediates progesterone regulation of uterine implantation by controlling ER activity. PLoS Genetics 3: e102, 1053-1064 PMCID: PMC1892047.
  8. Petit FG, Jamin SP, Behringer RR, DeMayo FJ, Tsai M-J and Tsai SY. (2007). Deletion of the orphan nuclear receptor COUP-TFII in uterus leads to placental deficiency. Proc. Natl. Acad. Sci. USA 104: 6293-6298 PMCID: PMC1851059.
  9. You LR, TakamotoN, Yu CT,Tanaka T, Kodama T, DeMayo FJ, Tsai SY and Tsai MJ.(2005). Mouse lacking COUP-TFII as an animal model of Bochdalek-type congenital diaphragmatic hernia. Proc.Natl.Acad.Sci., 102(45):16351-16356 PMCID: PMC1283449.
  10. You L-R, Lin F-J, Lee CT, DeMayo FJ, Tsai M-Jand Tsai SY. (2005). COUP-TFII suppression of Notch signaling regulates vein identity. Nature, 435, 98-104 PMID: 15875024

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