2009 — 2010 |
Smith, Elizabeth R |
R03Activity Code Description: To provide research support specifically limited in time and amount for studies in categorical program areas. Small grants provide flexibility for initiating studies which are generally for preliminary short-term projects and are non-renewable. |
Prevention of Menopause-Related Ovarian Epithelial Cancer @ University of Miami School of Medicine
DESCRIPTION (provided by applicant): Ovarian cancer is the leading cause of death from a gynecologic malignancy among women in North America and the fifth most frequently occurring cancer among women. Most (about 70%) ovarian cancers are diagnosed when the cancer has spread outside the ovary, having disseminated to the peritoneal lining of the abdomen, and most (about 85%) are diagnosed in women post-menopause. If detected while still localized in the ovary, the success rate of treatment is high, with a 5-year survival rate over 90%. However, current detection methods are unreliable or poor, and viable prevention strategies are imperative. The risk of epithelial ovarian cancer is well linked with reproductive history, where uninterrupted ovulation frequency and non-parity increase the risk, and parity and the use of oral contraceptives clearly reduce the risk. Epidemiological evidence suggests that progesterone, which is elevated by both pregnancy and oral contraceptives, is the critical agent, acting to reduce ovulation and provide an independent risk reduction. The effects of progesterone may differ depending upon timing and duration of use, and between pre- and post-menopausal women. Some studies suggest that hormone-related risk factors may provide a greater protective effect against pre-menopausal than post-menopausal ovarian cancers. This is an important question, since women can expect to live more one-third or more of their lives after their reproductive years. In this study we will examine the ability of progesterone to prevent or reduce ovarian cancer risk using the germ cell deficient Wv mouse model. The mice mimic menopausal biology and develop epithelial lesions that resemble preneoplastic changes in human ovaries. When deletion of the cyclin-dependent kinase inhibitor p27kip1 gene, whose expression is often lost in ovarian cancer, is added to the Wv/Wv genotype, the ovarian tumors develop malignant features and resemble more nearly human ovarian tumors. Our hypothesis is depletion of ovarian follicles that occurs with menopause underlies ovarian cancer risk, and that follicle reserve and menopause status may alter the ability of progesterone to prevent ovarian cancers, such that progesterone is likely most effective when given before menopause. We will administer progesterone to Wv female mice prior to follicle depletion (pre-menopause) (Aim 1) and after (post-menopause) follicle depletion (Aim 2) to determine the effects on ovarian function, serum hormone levels, and tumor development (Aim 3). The goal is to formulate rationale preventive strategies for ovarian cancer in post-menopausal women.
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0.902 |
2012 — 2013 |
Smith, Elizabeth R |
R03Activity Code Description: To provide research support specifically limited in time and amount for studies in categorical program areas. Small grants provide flexibility for initiating studies which are generally for preliminary short-term projects and are non-renewable. |
Mechanism of Mapk Cytoplasmic Retention in Differentiation of Es Cells @ University of Miami School of Medicine
DESCRIPTION (provided by applicant): Embryonic stem (ES) and carcinoma (EC) cells undergo differentiation in culture when treated with retinoic acid. The majority of the ES cells differentiate into cells with properties that resemble the primitive endoderm of early embryos. Retinoic acid-induced primitive endoderm differentiation leads to suppression of cell growth, which we found to result from restriction of active MAPK from the nucleus and to require an intact cytoskeleton. In previous studies, we have found that in differentiated cells, activated phospho-MAPK remains principally cytoplasmic rather than entering the nucleus, in contrast to most cultured cells, in which stimulation of cells by serum mitogens results in activated MAPK readily entering the nucleus. The localization of activated MAPK correlates with the degree of phosphorylation of nuclear and cytoplasmic MAPK substrates, such as Elk1 and cPLA2, respectively. The current proposal is to investigate a potential mechanism that accounts for the cytoplasmic retention of activated MAPK in differentiated ES cells. In preliminary studies, we found that endoderm differentiation of ES cells dramatically increases expression of the nuclear envelope protein Nesprin-1. Nesprins, a family of proteins of the LINC complex that links the nuclear envelope and skeleton to the cytoskeleton, are believed to influence nuclear architecture and position as well as cytoskeletal stability and cell mobility. Nesprin-2 has been reported to bind MAPK in smooth muscle cells. The increased expression of Nesprin-1 in ES cells differentiated to primitive endoderm cells may therefore function to restrict MAPK nuclear entry. The limited expression of Nesprin-1 in undifferentiated ES cells would be permissive for MAPK nuclear entry and, as a consequence, enhance proliferation. We will test this hypothesis in the following three experimental aims: (1) Characterize Nesprin- 1/MAPK association biochemically; (2) Analyze Nesprin-1 and MAPK association in ES cell differentiation; and (3) Determine the impact of Nesprin-1 suppression on MAPK nuclear entry and signaling and cellular differentiation and proliferation. Control of cell growth and proliferation is an obligate step to attain and maintain the phenotype and function of differentiated cells in the developing embryo and in the adult organism, and requires regulation of MAPK cytoplasmic localization and nuclear entry. If the experiments suggest the hypothesis is valid, we may uncover a mechanism regulating MAPK localization and cell proliferation in differentiated cells. We speculate that regulation of nuclear entry of activated MAPK is prevalent in vivo, and this regulatory step is overcome in most cultured cells.
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0.902 |