The overall goal of this project is to understand the mechanism of action and clinical potential of retinoids in endometriosis. We propose that retinoids play both a causative role in the development of endometriosis and have therapeutic potential for its treatment. In support of these hypotheses, our previous work has demonstrated that retinoids have profound effects on certain endometrial and immune cell functions that are abnormal in endometriosis, and thought to be related to its pathogenesis and/or progression. Of particular importance, we provide evidence that retinoids can alter endometrial cell and macrophage activity in ways that would be expected to be beneficial to endometriosis subjects. Our overall goal will be accomplished by four specific aims.
Aim 1 will assess whether retinoid levels are altered in endometriosis. This question will be addressed by detailed analyses of retinoid storage and metabolism in endometrial tissue, peritoneal immune cells, and the peritoneal milieu in which the cells reside.
Aim 2 will determine the physiologic implications of retinoid action on CD36 as relates to peritoneal macrophages from women with endometriosis. This type-B scavenger receptor plays a primary role in the uptake and clearance of apoptotic cells and cell debris which seed the peritoneum as a result of retrograde menstruation. We have shown that this receptor is reduced in peritoneal macrophages from women with endometriosis and that retinoic acid (RA) can upregulate its expression. We will now determine the nature of the aberrant regulation of CD36 in endometriosis macrophages and whether RA can be used to normalize the expression and function of this receptor. Through our demonstration that retinoids can also alter the expression of certain connexins (Cxs) involved in endometrial gap junction communication, Aim 3 will test our hypothesis that Cxs play fundamental roles in endometriosis through their involvement in endometrial cell growth, apoptosis, and invasive potential. These studies will establish the cause and effect relationship between aberrant Cx expression in endometriotic lesions and the etiology/progression of this disease, and determine the ability to regulate Cxs in endometrial cells by retinoid compounds. Finally, Aim 4 will evaluate the effects of retinoids on the development of endometriosis in an immunocompetent mouse model. Using methodology that simulates a massive retrograde menses, this model will also shed light on the relationship between immune modulation and ectopic growth of endometrial cells. Project Narrative: Endometriosis is a major public health issue. Since current medical therapy has limitations, more effective treatment options are desperately needed. The information gained from our studies will provide the basic framework for the therapeutic use of retinoid compounds to impede the genesis and growth of endometriotic lesions.
|Schutte, Stacey C; James, Christopher O; Sidell, Neil et al. (2015) Tissue-engineered endometrial model for the study of cell-cell interactions. Reprod Sci 22:308-15|
|Taylor, Robert N; Kane, Maureen A; Sidell, Neil (2015) Pathogenesis of Endometriosis: Roles of Retinoids and Inflammatory Pathways. Semin Reprod Med 33:246-56|
|Best, Monica W; Wu, Juanjuan; Pauli, Samuel A et al. (2015) A role for retinoids in human oocyte fertilization: regulation of connexin 43 by retinoic acid in cumulus granulosa cells. Mol Hum Reprod 21:527-34|
|Wu, Juanjuan; Williams, Devin; Walter, Grant A et al. (2014) Estrogen increases Nrf2 activity through activation of the PI3K pathway in MCF-7 breast cancer cells. Exp Cell Res 328:351-60|
|Pierzchalski, Keely; Taylor, Robert N; Nezhat, Ceana et al. (2014) Retinoic acid biosynthesis is impaired in human and murine endometriosis. Biol Reprod 91:84|
|Wu, Juanjuan; Taylor, Robert N; Sidell, Neil (2013) Retinoic acid regulates gap junction intercellular communication in human endometrial stromal cells through modulation of the phosphorylation status of connexin 43. J Cell Physiol 228:903-10|
|Pauli, Samuel A; Session, Donna R; Shang, Weirong et al. (2013) Analysis of follicular fluid retinoids in women undergoing in vitro fertilization: retinoic acid influences embryo quality and is reduced in women with endometriosis. Reprod Sci 20:1116-24|
|Zhang, Huanchun; Taylor, W Robert; Joseph, Giji et al. (2013) mRNA-binding protein ZFP36 is expressed in atherosclerotic lesions and reduces inflammation in aortic endothelial cells. Arterioscler Thromb Vasc Biol 33:1212-20|
|Brahma, Pavna K; Zhang, Huanchun; Murray, Betsy S et al. (2012) The mRNA-binding protein Zfp36 is upregulated by ?-adrenergic stimulation and represses IL-6 production in 3T3-L1 adipocytes. Obesity (Silver Spring) 20:40-7|
|Wieser, Friedrich; Wu, Juanjuan; Shen, Zhaoju et al. (2012) Retinoic acid suppresses growth of lesions, inhibits peritoneal cytokine secretion, and promotes macrophage differentiation in an immunocompetent mouse model of endometriosis. Fertil Steril 97:1430-7|
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