ln response to the ovarian secretion of progesterone and estrogen during early pregnancy, the mammalian uterus develops the capacity to perform complex cellular activities required for blastocyst implantation. Luminal epithelial cells maintain the intrauterine environment of the blastocyst by secretion and endocytosis, provide an appropriate matrix for the adhesion of the blastocyst, and appear to transmit information from the blastocyst to the underlying stroma to initiate decidualization. As implantation proceeds, luminal epithelial cells undergo autolysis within the implantation chamber and extensive restructuring peripherally. These cellular functions require the active participation of lysosomes and precise hormonal control of the synthesis and compartmentalization of lysosomal enzymes. Our past studies have shown that progesterone increases lysosomal cathepsin D activity and rates of synthesis of this enzyme in luminal epithelial cells. Following progestin pretreatment, estradiol alters the capacity of these cells to respond to deciduogenic stimuli. Epithelial cell functions during early pregnancy may depend upon the content of lysosomal proteases as well as changes in the intracellular function of lysosomes within these cells. To elucidate the biochemical mechanisms by which progesterone and estradiol control the enzyme content and intracellular activity of epithelial lysosomes, the following specific aims are proposed: (1) Changes in the activity of uterine mRNA coding for cathepsin D will be measured after progestin and estrogen treatment. (2) Precursor- product relationships between the various molecular weight forms of uterine cathepsin D will be established so that the hormonal control of cathepsin D processing and activation can be determined. (3) The glycosylated forms of cathepsin D will be identified and the hormonal control of their glycosylation determined. (4) We will examine the intracellular function of cathepsin D in protein degradation. These studies of the control of lysosomal enzyme synthesis and intracellular activity during early pregnancy should provide further elucidation of the biochemical mechanisms by which progesterone and estrogen control epithelial function and the development of the endometrial capacity for response to the implanting blastocyst. Better understanding of cellular control mechanisms in the endometrium should contribute to our fundamental knowledge of the earliest stages of pregnancy and to the development of means by which to limit population growth.
NIH ExPorter
NIH ExPorter