Identification of endogenous testicular cytokines crucial in the development of chronic testicular inflammation, and their potential in future therapeutic strategies

January 30, 2008

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Infection and inflammation of the reproductive tract including the testes are widely accepted as important etiological factors of male infertility. Rodents injected with homologous testicular antigen or viable syngeneic germ cells also develop autoimmune orchitis, a widely used model known as experimental autoimmune orchitis (EAO) to study chronic inflammation of the male gonad. Several studies have provided evidence for the involvement of proinflammatory cytokines in the pathogenesis of EAO.

Objective: To identify essential cytokines that could affect orchitis. This will be performed by: 1. Induction of EAO using knock out (KO) mice, for candidate cytokines, and to be compared to wildtype mice. 2. Examine the recovery of EAO in normal mice by administration of anti inflammatory drugs or by administration of specific neutralizing antibodies to cytokines or alternatively recombinant cytokines. 3. Identification of testicular cells (SC, LC, PT, GC, MQ, DC), which produce the relevant testicular cytokines in EAO. Genechip analysis will be used to identify genes and pathways changed in testicular tissues from wildtype mice before and after EAO induction.

Scientific significance: Identifying the cells upon which the pro-inflammatory cytokines react and by understanding the role of these cytokines in EAO, would provide potential pathways to develop new diagnostic tools and therapeutic strategies to rescue the testis from the adverse effects of inflammatory damage and will give insights into underlying mechanism of idiopathic male infertility.

Methoden:
cell isolation, primary cell culture, Western blotting, gene chip arrays, qRT-PCR, immunohistochemistry, flat panel volumetric CT for small animals.

Anfangsdatum: 1. März 2008

geschätzte Dauer: 3 years

Bezahlung: BAT IIa/2

Veröffentlichungen:
O’Bryan MK, Gerdprasert O, Nikolic-Paterson DP, Meinhardt A, Muir JA, Foulds LM, Phillips DJ, de Kretser DM, and Hedger MP. (2005). Cytokine profiles in the testes of rats treated with lipopolysaccharide indicate reveal localized suppression of inflammatory responses. Am J Physiol 288:R1744-1755.

Fijak M, Iosub R, Schneider E, Linder M, Respondek K, Klug J, and Meinhardt A. (2005). Identification of Immunodominant Autoantigens in Rat Autoimmune Orchitis. J Pathol, 207:127-38.

Iosub R, Klug J, Fijak M, Schneider E, Fröhlich M, Blumbach K, Wennemuth G, Sommerhoff CP, Steinhoff M, and Meinhardt A. (2006). Development of testicular inflammation in rat involves activation of proteinase activated receptor 2. J Pathol 208:686-698.

Nayernia K, Nolte J, Michelmann HW, Lee JH, Rathsack K, Drusenheimer N, Dev A, Wulf G, Ehrmann IE, Elliott DJ, Okpanyi V, Zechner U, Haaf T, Meinhardt A, and Engel W. (2006). In vitro differentiated embryonic stem cells give rise to male gametes that can generate offspring mice. Dev Cell 11:125-132.

Fijak M and Meinhardt A. (2006). The testis in immune privilege. Immunol Rev, 213:66-81.

Held T, Paprotta I, Khulan J, Hemmerlein B, Binder L, Wolf S, Schubert S, Meinhardt A, Engel W, Adham I. (2006). Hspa4l deficient mice display increased incidence of male infertility and hydronephrosis development. Mol Cell Biol 26:8099-8108.

Rival C, Guazzone VA, von Wulffen W, Hackstein H, Schneider E, Lustig L, Meinhardt A, and Fijak F. (2007). Expression of Costimulatory Molecules, Chemokine Receptors and Proinflammatory Cytokines in Dendritic Cells from Normal and Chronically Inflamed Rat Testis. Mol Human Reprod 13:15-23.

Bhushan S, Tchatalbachev T, Klug J, Fijak M, Pineau C, Chakraborty T, and Meinhardt A. (2008). Uropathogenic Escherichia coli block MyD88 dependent and activate MyD88 independent signal ways in rat testicular cells. J Immunol, in revision.

Homepage: http://www.med.uni-giessen.de/reprobio

This is a joint project with a cooperating group at Ben-Gurion University in Beer-Sheva (Israel) and requires approx. two stays in Israel for 2 months, respectively.

Written applications are preferred over electronic applications. In case the latter cannot be avoided please send your application as one (1!) single pdf-file containing cover letter, CV and copies of all relevant ceertificates. Applications consisting of several files will not be administered.

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