Document text
Principal Investigator: Anne E Carlson
Organization: UNIVERSITY OF PITTSBURGH AT PITTSBURGH
Fiscal Year: 2024
Award: $441,505
Funding agency: Eunice Kennedy Shriver National Institute of Child Health and Human Development
Zinc is the most abundant trace metal in the body, and the highest zinc concentrations are found
in semen. Human semen is enriched with 1-3 mM zinc, a 100-fold higher concentration than the
zinc contents of other parts of the body. Moreover, low seminal zinc has been correlated with
male infertility. High concentrations of zinc are also found surrounding newly fertilized eggs.
Despite several observations documenting that sperm encounter high concentrations of zinc
multiple times between mating and fertilization, how zinc regulates sperm is unknown. The
overall objectives of this application are to uncover how zinc alters sperm swimming and
establish the mechanism by which zinc homeostasis changes between when sperm are first
mixed with the seminal fluids and when sperm arrive at the site and time of fertilization. The
central hypothesis is that zinc derived from the seminal fluid and released by the egg at
fertilization regulates sperm swimming and their ability to fertilize. The rationale for this project is
that uncovering a role for zinc in the processes that sperm undergo between mating and
fertilization will provide the conceptual foundation needed to develop strategies for fertility
treatments, and the development of non-hormonal contraception can be developed. The central
hypothesis will be tested by pursuing three specific aims: 1) Establish the mechanisms by which
zinc regulates sperm at mating; 2) Delineate the mechanisms of zinc depletion during
capacitation; and 3) Define how zinc alters hyperactivation of mouse and human sperm. Under
the first aim, we will use proteomics, computer-assisted semen analysis, and biochemistry
approaches to define how zinc enters and regulates sperm at mating. For the second aim, we
will use fluorescence-based experiments to understand how intracellular zinc is depleted during
capacitation. For the third aim, we will use electrophysiology and computer-assisted semen
analysis to understand how zinc regulates the Ca2+ channel CatSper and the swimming pattern
known as hyperactivation. The research proposed in this application is innovative because it
focuses on zinc as a central regulator of sperm physiology, combines experimentation on both
mouse and human sperm, and uses mass spectrometry to identify plasma membrane-localized
proteins in sperm. The proposed research is significant because it is expected to change our
understanding of the essential events of fertilization. Ultimately, this knowledge has the potential
to offer new opportunities for the development of innovative fertility interventions.
Terms: <3,5 cyclic AMP synthetase><Abscission><Adenyl Cyclase><Adenylate Cyclase><Adenylyl Cyclase><Autoregulation><Bicarbonates><Biochemistry><Biological Chemistry><Biology><Body part><Cannot achieve a pregnancy><CatSper><Cell Communication and Signaling><Cell Signaling><Cell membrane><Computer Assisted><Contraception><Contraceptive methods><Cytoplasm><Cytoplasmic Membrane><Data><Development><Diethyl Dicarbonate><Diethyl Oxydiformate><Diethyl Pyrocarbonate><Diethylpyrocarbonate><Difficulty conceiving><Electrophysiology><Electrophysiology (science)><Endowment><Enzyme Gene><Enzymes><Ethoxyformic Anhydride><Event><Excision><Exhibits><Extirpation><Family><Family suidae><Fecundability><Fecundity><Fertility><Fertility Control><Fertilization><Fertilized Egg><Fertilized Ovum><FluoZin-3><Fluorescence><Fluorometry><Foundations><HCO3><Homeostasis><Human><Human Figure><Human body><Hydrogen Carbonates><In Vitro><Incubated><Infertility><Inhibition of Fertilization><Intracellular Communication and Signaling><Knowledge><Link><Male Infertility><Mass Photometry/Spectrum Analysis><Mass Spectrometry><Mass Spectroscopy><Mass Spectrum><Mass Spectrum Analyses><Mass Spectrum Analysis><Mediating><Mice><Mice Mammals><Mission><Modern Man><Molecular><Motility><Murine><Mus><NICHD><National Institute of Child Health and Human Development><National Institute of Children's Health and Human Development><Neurophysiology / Electrophysiology><Partner in relationship><Pattern><Penetration><Physiological Homeostasis><Physiology><Pigs><Plasma Membrane><Play><Process><Property><Proteins><Proteomics><Public Health><Publishing><Pyrocarbonic Acid Diethyl Ester><Recombinants><Regulation><Removal><Research><Role><Route><Semen><Seminal><Seminal fluid><Signal Transduction><Signal Transduction Systems><Signaling><Site><Sperm><Sperm Motility><Sperm Penetration><Sperm-Egg Penetration><Sperm-Oocyte Penetration><Sperm-Ovum Penetration><Sperm-Zona Pellucida Penetrations><Spermatozoa><Suidae><Surgical Removal><Swimming><Swine><Testing><Time><Trace metal><Zinc><Zn element><Zona Pellucida><biological signal transduction><computer aided><developmental><diethyl ester Dicarbonic acid><egg><electrophysiological><experiment><experimental research><experimental study><experiments><extracellular><fertility assistance><fertility cessation><fertility interventions><fertility loss><fertility treatment><fertilizations><in vivo><infertile><infertility treatment><innovate><innovation><innovative><insight><mate><meter><new approaches><novel approaches><novel strategies><novel strategy><plasmalemma><porcine><prevent><preventing><reproductive success><resection><social role><sperm analysis><sperm cell><sperm mobility><sperm specific ion channel><suid><uptake><zoosperm><zygote>