The second messenger cyclic AMP (cAMP) regulates a broad spectrum of cellular activities. It is critical for mammalian spermatogenesis, maturation of sperm in the epididymis, and capacitation, the post-epididymal maturational process that sperm undergo prior to fertilization. The bicarbonate- and calcium-responsive `soluble'adenylyl cyclase (SACY) is the predominant source of cAMP in both mouse germ cells and sperm. When the Sacy gene is ablated by homologous recombination, the result is male infertility. Although spermatogenesis in the testis appears to proceed undisturbed, the morphologically normal sperm are immotile. Motility can be partially rescued with membrane permeable cAMP analogs, highlighting the importance of cAMP in this process. However, these sperm are not able to fertilize eggs in vitro, indicating that the sperm are still defective. To address our long-term goal of understanding the role of cAMP and its signaling pathways in promoting fertilization-competence of mammalian sperm, we will: 1) establish whether the Sacy-null phenotype is the result of events occurring during spermatogenesis and/or the course of epididymal maturation using reciprocal spermatogonial transplantation;2) examine the molecular bases for the flagellar angulation and immotility seen in Sacy-null sperm by identifying protein differences in the sperm of the two genotypes, and, 3) determine the role that EPACs, a family of cAMP-activated proteins, have on sperm motility. The fact that fertilization does not occur without proper sperm maturation in the epididymis and sperm capacitation emphasizes the clinical significance of this project. Although this block to fertilization can be circumvented by assisted reproductive technologies such as intracytoplasmic sperm injection, the findings from the research detailed in this application may allow the clinician to modify in vitro fertilization and artificial insemination methodologies to enhance capacitation. These studies may identify new pathways and targets for contraceptive development. Project Narrative: The relevance of this project to public health is that if sperm do not 'capacitate', they can not fertilize an egg. Understanding the role of SACY during spermatogenesis in the testis, sperm maturation in the epididymis, and sperm capacitation will allow us to improve the efficacy of sperm becoming fertilization-competent. Project Narrative The relevance of this project to public health is that if sperm do not 'capacitate', they can not fertilize an egg. Understanding the role of SACY during spermatogenesis in the testis, sperm maturation in the epididymis, and sperm capacitation will allow us to improve the efficacy of sperm becoming fertilization-competent.

Agency
National Institute of Health (NIH)
Institute
Eunice Kennedy Shriver National Institute of Child Health & Human Development (NICHD)
Type
Research Project (R01)
Project #
5R01HD051999-05
Application #
8206606
Study Section
Cellular, Molecular and Integrative Reproduction Study Section (CMIR)
Program Officer
Taymans, Susan
Project Start
2008-03-04
Project End
2013-12-31
Budget Start
2012-01-01
Budget End
2013-12-31
Support Year
5
Fiscal Year
2012
Total Cost
$321,300
Indirect Cost
$117,300
Name
University of Pennsylvania
Department
Obstetrics & Gynecology
Type
Schools of Medicine
DUNS #
042250712
City
Philadelphia
State
PA
Country
United States
Zip Code
19104
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Vadnais, Melissa L; Cao, Wenlei; Aghajanian, Haig K et al. (2014) Adenine nucleotide metabolism and a role for AMP in modulating flagellar waveforms in mouse sperm. Biol Reprod 90:128
Buffone, Mariano G; Hirohashi, Noritaka; Gerton, George L (2014) Unresolved questions concerning mammalian sperm acrosomal exocytosis. Biol Reprod 90:112
Ijiri, Takashi W; Vadnais, Melissa L; Lin, Angel M et al. (2013) Male mice express spermatogenic cell-specific triosephosphate isomerase isozymes. Mol Reprod Dev 80:862-70
Vadnais, Melissa L; Aghajanian, Haig K; Lin, Angel et al. (2013) Signaling in sperm: toward a molecular understanding of the acquisition of sperm motility in the mouse epididymis. Biol Reprod 89:127
Buffone, Mariano G; Ijiri, Takashi W; Cao, Wenlei et al. (2012) Heads or tails? Structural events and molecular mechanisms that promote mammalian sperm acrosomal exocytosis and motility. Mol Reprod Dev 79:4-18
Kim, Kye-Seong; Foster, James A; Kvasnicka, Kevin W et al. (2011) Transitional states of acrosomal exocytosis and proteolytic processing of the acrosomal matrix in guinea pig sperm. Mol Reprod Dev 78:930-41
Ijiri, Takashi W; Merdiushev, Tanya; Cao, Wenlei et al. (2011) Identification and validation of mouse sperm proteins correlated with epididymal maturation. Proteomics 11:4047-62