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Developmental biology

 

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Mirja Konrad

Semester: 10

 

Project description

 

Preterm infants are at high risk for developing a „respiratory distress syndrome“ (RDS) as a result of insufficient surfactant production [1]. The erbB4 receptor and its ligand NRG play an important role in fetal lung development. They contribute to the onset of fetal surfactant synthesis [2, 3] and are also critical for the alveolarisation. ErbB receptors interact with nuclear receptors and it has been shown that erbB4 coregulates estrogen receptor α in breast cells [4]. Since estrogen receptor β (ERβ) is highly expressed in pneumocytes (type I and II) and deletion of ERβ in adult mice leads to fewer alveoli and reduced elastic recoil [5], similar to the picture we have detected in erbB4 deleted lungs [6] we want to study the role of the estrogen receptor (ER) and its interaction with erbB4 in epithelial type II cells.

The delay in surfactant synthesis [7] as well as the increased risk for the development of respiratory distress syndrome (RDS) [8] in the male fetus are well known. High androgen levels have been implicated in the mechanism of delay in lung maturation [9]. Also, the fetus is exposed to increased levels of estradiol and progesterone [10] and replacement of these placental hormones after preterm birth seems to be related with a lower incidence of chronic lung disease [11].

 

Thus, we hypothesize that there is a co-regulation of ERβ and erbB4 in type II epithelial cells regulating the fetal surfactant system.

 

Methods

 

Cell culture, Transfection of ER, Protein- and RNA-isolation, Co-Immunoprecipitation and Western Blotting, Confocal microscopy, RT-PCR for the surfactant proteins.

 

References

 

1. Jobe, A.H. and M. Ikegami, Surfactant metabolism. Clin Perinatol, 1993. 20(4): p. 683-96.

 

2. Dammann, C.E., H.C. Nielsen, and K.L. Carraway, Role of Neuregulin1{beta} in the Developing Lung. Am J Respir Crit Care Med, 2003. 167: p. 1711-1716.

 

3. Zscheppang, K., Korenbaum, E., Bueter, W., Ramadurai, S. M., Nielsen, H. C., Dammann, C. E., ErbB receptor dimerization, localization, and co-localization in mouse lung type II epithelial cells. Pediatr Pulmonol, 2006. 41(12): p. 1205-12.

 

4. Zhu, Y., Sullivan, L. L., Nair, S. S., Williams, C. C., Pandey, A. K., Marrero, L., Vadlamudi, R. K., Jones, F. E., Coregulation of Estrogen Receptor by ERBB4/HER4 Establishes a Growth-Promoting Autocrine Signal in Breast Tumor Cells. Cancer Res, 2006. 66(16): p. 7991-8.

 

5. Morani, A., Barros, R. P., Imamov, O., Hultenby, K., Arner, A., Warner, M., Gustafsson, J. A., Lung dysfunction causes systemic hypoxia in estrogen receptor beta knockout (ERbeta-/-) mice. Proc Natl Acad Sci U S A, 2006. 103(18): p. 7165-9.

 

6. Purevdorj, E., Zscheppang, K., Hoymann, H.G., Braun, A., Von Mayersbach, D., Acevedo, C., Brinkhaus, M., Schmiedl, A., Dammann, C.E., Hyperreactive Airways and Alveolar Simplification in Pulmonary ErbB4-Deleted Transgenic Mice. Proc Am Thor Soc, 2007. A90: 3222.

 

7. Torday, J.S., H.C. Nielsen, and M. Fencl, Sex differences in fetal lung maturation. Am Rev Respir Dis, 1981. 123: p. 205-8.

 

8. Miller, H.C. and P. Futrakul, Birth weight, gestational age, and sex as determining factors in the incidence of prematurely born infants. J Pediatr, 1968. 72: p. 628-95.

 

9. Dammann, C.E., Ramadurai, S.R., McCants, D., Pham, L.D., Nielsen, H. C., Androgen regulation of signaling pathways in late fetal mouse lung development. Endocrinology, 2000. 141: p. 2923-29.

 

10. Tulchinsky, D., Hobel, C. J., Yeager, E., Marshall, J. R., Plasma estrone, estradiol, estriol, progesterone, and 17-hydroxyprogesterone in human pregnancy. I. Normal pregnancy. Am J Obstet Gynecol, 1972. 112(8): p. 1095-100.

 

11. Trotter, A., Maier, L., Grill, H. J., Kohn, T., Heckmann, M., Pohlandt, F., Effects of postnatal estradiol and progesterone replacement in extremely preterm infants. J Clin Endocrinol Metab, 1999. 84(12): p. 4531-5.

 

Supervisor

 

Christiane Dammann

 

Katja Zscheppang

V.i.S.d.P: Christiane Dammann, aktualisiert am: 12.12.2006