MODELING THE FERTILIZATION CALCIUM WAVE IN MOUSE EGGS

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The overall goal of this proposal is to develop a realistic spatial model of the mouse oocyte and egg, that will allow me to examine the mechanisms underlying maturation and fertilization. I will then use this model to answer a very simple question: what happens to the immature oocyte during maturation that makes it fertilizable, and once it is fertilized, how are these maturation-induced changes important for the ensuing calcium signal? It has been known for some time that during maturation, the oocyte increases its capability to release calcium, and a number of potential mechanisms have been proposed: l) an increase in the ER's calcium-sequestering capability; 2) an increase in the ER's ability to release calcium via an increase in the number and/or density of Ip3 receptors; 3) an increase in the ER's ability to sequester and/or release calcium differentially in specific spatial regions as a result of structural rearrangement of the ER; 4) an increase in total intracellular calcium due to influx; and 5) a change in the IP3 receptor sensitivity. By dint of the model's incorporation of both maturation and fertilization mechanisms, I will test these hypotheses by examining the effects of such changes on both the pre-fertilization and post-fertilization egg, and comparing them to experiment. Additionally, I will use the model to investigate the mechanisms underlying the initiation and propagation of the fertilization wave, in a manner similar to my previous work with Xenopus. Finally, I will perform limited laboratory experiments, when reasonable, to collect data for both model calibration and, possibly, comparison of simulation results, when such data are not available in the literature. The modeling and simulation will be performed in collaboration with Dr. Les Loew and others in CBIT, and the experimental work will be greatly aided by collaboration with members of Dr. Laurinda Jaffe's lab.