Entwicklungsbiologie

Project description

Neuroprotection by Neuregulin-1 in the setting of perinatal inflammation

Despite the enormous progress with markedly increased overall survival rates, preterm birth still continues being a strong risk factor for neonatal brain damage and consecutive neurological deficits. Pathogenetically subclinical maternal intrauterine infections seem to be capable of inducing a systemic inflammatory response within the fetal circulation and thereby contribute to both preterm birth and consecutive organ damage [1, 2]. However, underlying mechanisms still remain fragmentary.

Neuregulin-1 has recently been suggested to serve as an endogenous neuroprotector [3]. It is one member of a large family of growth factors. These growth factors hold an EGF-like domain which directly binds to its specific receptors, the ErbB receptors, and play crucial roles during development and differentiation of various organ systems. Their major importance during fetal development becomes evident while NRG as well as ErbB4-receptor deficient animals are not viable but die during mid-embryogenesis from heart malformations [4].

This current project aims to further investigate potential neuroprotective abilities of NRG1, in particular in a setting of inflammation induced neonatal brain damage. Therefore we use a well established animal model of LPS-induced perinatal brain injury [5, 6] in wild type and ErbB4 deleted mice (rescued from intrauterine death by allowing ErbB4 expression in the heart [7]). We hypothesize that NRG1 attenuates and that ErbB4-deletion potentiates inflammatory damages.

Literature

1. Romero, R., et al., The role of inflammation and infection in preterm birth. Semin Reprod Med, 2007. 25(1): p. 21-39.

2. Dammann, O. and A. Leviton, Infection remote from the brain, neonatal white matter damage, and cerebral palsy in the preterm infant. Semin Pediatr Neurol, 1998. 5(3): p. 190-201.

3. Dammann, O., et al., Neuregulin-1: A Potential Endogenous Protector in Perinatal Brain White Matter Damage. Neonatology, 2007. 93(3): p. 182-187.

4. Meyer, D. and C. Birchmeier, Multiple essential functions of neuregulin in development. Nature, 1995. 378(6555): p. 386-90.

5. Elovitz, M.A., et al., A new model for inflammation-induced preterm birth: the role of platelet-activating factor and Toll-like receptor-4. Am J Pathol, 2003. 163(5): p. 2103-11.

6. Wang, X., et al., Lipopolysaccharide-induced inflammation and perinatal brain injury. Semin Fetal Neonatal Med, 2006. 11(5): p. 343-53.

7. Tidcombe, H., et al., Neural and mammary gland defects in ErbB4 knockout mice genetically rescued from embryonic lethality. Proc Natl Acad Sci U S A, 2003. 100(14): p. 8281-6.

Publications

1. Hoffmann, I. et al., Developmental and Genetic Influence on LPS-induced Neuregulin-1ß production (Abstract: Pediatric Academic Societies´ Annual Meeting 2007)

2. Hoffmann, I. et al., Neuregulin-1, the fetal endothelium, and brain damage in preterm newborns. Brain Behav Immun. 2010 Jul;24(5): p. 784-91.

Supervisor

Christiane Dammann

Olaf Dammann

Contact

Dr. med. Insa Hoffmann

Tel.: 0176/ 1532 6112 (mobil)

17-6112 (MHH intern)

Fax.: 0511/ 532 6827

Email: Hoffmann.Insa@mh-hannover.de