REGULATION AND CONTROL OF HUMAN SPERM MOTILITY

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The goal of this application is to determine the biochemical basis for the loss of human sperm motility following cryopreservation and to prevent or reverse this loss. We will first characterize in detail the motility characteristics of freshly ejaculated and cryopreserved human sperm with a new fully computerized method capable of generating a "complete motility profile" of both head and flagellar wave parameters. This study will provide the first complete description of the effects of cryopreservation on human sperm motility. To determine the biochemical basis for loss of motility on cryopreservation we will provide the first overview of how human sperm motility is regulated. To do this we will determine the roles played by and interrelationships among calcium ion, cyclic AMP, adenosine and the phosphorylation of "axokinin-like motility proteins. All studies will be carried out in intact sperm. We will emphasize studies on the role of the nucleoside adenosine in initiating motility in immotile sperm by coupling the actions of calcium and cyclic AMP, the mechanism of efflux of adenosine efflux from sperm through a nucleotide transport system, and it intra-cellular elevation by adenosine deaminase inhibition. These studies may lead to the development of a new class of compounds, adenosine deaminase inhibitors, which selectively increase the motile density of human sperm in semen. We will document that adenosine lowers cytosolic calcium levels and determine the mechanism by which this takes place. Further, we will define the singular effects of varying intra-cellular levels of cyclic AMP and calcium on complete motility profiles. These studies will document hoe key regulators of human sperm motility control the multiple parameters of motility and will provide the basis for describing in detail the changes in motility parameters during cryopreservation. Confirmation of the basis for loss of any individual parameter will be obtained by determining how regulation of this parameter changes during cryopreservation. Recovery of motility in cryopreserved sperm will be carried out by returning intracellular messengers in cryopreserved sperm to their freshly ejaculated state and prevention of motility loss by use of cryoprotectants which selectively protect that part of the motility machinery damaged during cryopreservation.