As growth factors, cytokines are known mediators of both normal proliferation and aberrant cell cycle-related responses in the hematopoietic and immune systems. Deficiencies as well as inappropriate expression of specific cytokines in vivo is associated with disruptions in spermatogenesis. These findings are suggestive of their role in pro- and anti-proliferative effects within the male germ cell lineage. The biological activities of multiple cytokines and growth factors are mediated through cognate receptors and specific receptor-associated kinases (JAK). Distinct protein-protein interactions are critical for these signal transduction events leading to an induction of gene expression through a family of latent transcription factors called STAT proteins. Recent studies have identified several members of the JAK tyrosine kinases and cytokine/growth factor receptors in specific male germ cells. The working hypothesis is that an imbalance between the levels of critical growth factors can result from a hostile environment. It is proposed that such extra cellular stimuli can generate inappropriate signals within receptor-positive developing germ cells at the level of two of their kinase pathways (JAK and MAPK).
Three specific aims are proposed to test the PI's working hypothesis. (1) To characterize the effects of these growth factors on germ cell DNA synthesis and cell cycle progression and, to determine the interactions of the retinoic acid receptors and cytokine signaling on cell proliferation. (2) To establish the role of the SOCS family of cytokine-inducible inhibitors and, determine the role of intracellular compartmentalization in STAT function. (3) To characterize the cross-talk between IL6 and MAPK signaling in germ cell proliferation and, to test whether germ cells exposed to inflammation or environmental toxicants can be rescued from apoptosis by growth factor/cytokine rescue. It is the PI's long term goals to include the identification of novel sites for therapeutic intervention to prevent disruption of germ cell development during infection, inflammation and in cytokine-based male infertility.

Agency
National Institute of Health (NIH)
Institute
Eunice Kennedy Shriver National Institute of Child Health & Human Development (NICHD)
Type
Research Project (R01)
Project #
5R01HD039024-04
Application #
6704210
Study Section
Special Emphasis Panel (ZRG1-END (01))
Program Officer
Rankin, Tracy L
Project Start
2001-04-26
Project End
2006-02-28
Budget Start
2004-03-01
Budget End
2005-02-28
Support Year
4
Fiscal Year
2004
Total Cost
$294,872
Indirect Cost
Name
Population Council
Department
Type
DUNS #
071050090
City
New York
State
NY
Country
United States
Zip Code
10017
Feitosa, Weber Beringui; Hwang, KeumSil; Morris, Patricia L (2018) Temporal and SUMO-specific SUMOylation contribute to the dynamics of Polo-like kinase 1 (PLK1) and spindle integrity during mouse oocyte meiosis. Dev Biol 434:278-291
Onorato, Thomas M; Brown, Petrice W; Morris, Patricia L (2008) Mono-(2-ethylhexyl) phthalate increases spermatocyte mitochondrial peroxiredoxin 3 and cyclooxygenase 2. J Androl 29:293-303
Brown, Petrice W; Hwang, KeumSil; Schlegel, Peter N et al. (2008) Small ubiquitin-related modifier (SUMO)-1, SUMO-2/3 and SUMOylation are involved with centromeric heterochromatin of chromosomes 9 and 1 and proteins of the synaptonemal complex during meiosis in men. Hum Reprod 23:2850-7
Ishikawa, Tomomoto; Morris, Patricia L (2006) Interleukin-1beta signals through a c-Jun N-terminal kinase-dependent inducible nitric oxide synthase and nitric oxide production pathway in Sertoli epithelial cells. Endocrinology 147:5424-30
Vigodner, Margarita; Ishikawa, Tomomoto; Schlegel, Peter N et al. (2006) SUMO-1, human male germ cell development, and the androgen receptor in the testis of men with normal and abnormal spermatogenesis. Am J Physiol Endocrinol Metab 290:E1022-33
Ishikawa, Tomomoto; Morris, Patricia L (2006) A multistep kinase-based sertoli cell autocrine-amplifying loop regulates prostaglandins, their receptors, and cytokines. Endocrinology 147:1706-16
Ishikawa, Tomomoto; Hwang, Keumsil; Lazzarino, Deborah et al. (2005) Sertoli cell expression of steroidogenic acute regulatory protein-related lipid transfer 1 and 5 domain-containing proteins and sterol regulatory element binding protein-1 are interleukin-1beta regulated by activation of c-Jun N-terminal kinase and cycloo Endocrinology 146:5100-11
Walch, Laurence; Morris, Patricia L (2002) Cyclooxygenase 2 pathway mediates IL-1beta regulation of IL-1alpha, -1beta, and IL-6 mRNA levels in Leydig cell progenitors. Endocrinology 143:3276-83