As early as 1927, Sampson theorized that endometriosis occurs as a consequence of the mechanical transfer of endometrial tissue to the peritoneum via retrograde menstruation, a process that occurs in most women. Using both in vivo observations and in vitro studies, our laboratory has demonstrated that, in the endometrium of endometriosis, an inflammatory-like microenvironment alters the expression ratio of progesterone receptors (PR-A and PR-B), disrupts the ability of progesterone to up-regulate transforming growth factor ? (TGF-?) expression and down-regulates cell-specific matrix metalloproteinase (MMP) expression. Many investigators now suspect that endometriosis occurs as a predictable consequence of the failure of progesterone to control the proinflammatory activity of immune cells that migrate into the endometrium prior to menstruation. In the normal endometrium, decay accelerating factor (CD55) is upregulated in response to progesterone, suggesting that this complement protective protein may play a critical role in controlling the behavior of immune cells during preparation for pregnancy. Although the relationship of reduced epithelial CD55 expression to the development of endometriosis is unknown, both TGF-? and CD55 are known to impact the activation and function of polymorphonuclear neutrophils (PMNs) during inflammation. PMNs are key trigger cells during early inflammation and can significantly increase MMP expression during menstruation. We have noted the rapid accumulation of PMNs at ectopic sites of human cell growth in our chimeric models of endometriosis using immune deficient mice. In this application, we propose that reduced expression of PR-B in endometrial stromal cells of endometriosis patients will inhibit progesterone-dependent expression of TGF-?2 and CD55 in vivo, in vitro and at ectopic sites of endometrial cell growth in experimental murine models of endometriosis. We also predict that altered expression of these factors will affect the activated state of PMNs that migrate into ectopic sites of human endometrial cell and tissue growth in mice.
Our specific aims are: 1)- to examine whether reduced endometrial responsiveness to progesterone affects the in vivo and in vitro expression of CD55 by epithelial cells in the eutopic endometrium of women with endometriosis; 2)- to utilize established in vitro and in vivo co-culture models to examine whether reduced sensitivity to progesterone affects the ability of endometrial stromal cells acquired from endometriosis patients to mediate CD55 expression in adjacent epithelial cells, and 3)- to utilize newly established in vivo models to examine whether the expression of TGF-?2 and CD55 correlates with PMN recruitment and function at ectopic sites of human cell and tissue growth in RAG2? (c) mice. ? ? ?

Agency
National Institute of Health (NIH)
Institute
Eunice Kennedy Shriver National Institute of Child Health & Human Development (NICHD)
Type
Research Project (R01)
Project #
1R01HD055648-01
Application #
7250451
Study Section
Integrative and Clinical Endocrinology and Reproduction Study Section (ICER)
Program Officer
Yoshinaga, Koji
Project Start
2007-05-01
Project End
2012-03-31
Budget Start
2007-05-01
Budget End
2008-03-31
Support Year
1
Fiscal Year
2007
Total Cost
$497,242
Indirect Cost
Name
Vanderbilt University Medical Center
Department
Obstetrics & Gynecology
Type
Schools of Medicine
DUNS #
004413456
City
Nashville
State
TN
Country
United States
Zip Code
37212
Lynn, Andrew C; Padmanabhan, Aarthi; Simmonds, Daniel et al. (2018) Functional connectivity differences in autism during face and car recognition: underconnectivity and atypical age-related changes. Dev Sci 21:
O'Hearn, Kirsten; Velanova, Katerina; Lynn, Andrew et al. (2016) Abnormalities in brain systems supporting individuation and enumeration in autism. Autism Res 9:82-96
Rana, Tanu; Hasan, Rafia J; Nowicki, Stella et al. (2014) Complement protective epitopes and CD55-microtubule complexes facilitate the invasion and intracellular persistence of uropathogenic Escherichia coli. J Infect Dis 209:1066-76
O'Hearn, Kirsten; Tanaka, James; Lynn, Andrew et al. (2014) Developmental plateau in visual object processing from adolescence to adulthood in autism. Brain Cogn 90:124-34
Pratap, Siddharth; Brown, Laura E; Izban, Michael G et al. (2013) Accurate preterm labor diagnosis using a CD55-TLR4 combination biomarker model. J Biomed Sci Eng 6:253-257
Bruner-Tran, K L; Herington, J L; Duleba, A J et al. (2013) Medical management of endometriosis: emerging evidence linking inflammation to disease pathophysiology. Minerva Ginecol 65:199-213
Herington, Jennifer L; Glore, Dana R; Lucas, John A et al. (2013) Dietary fish oil supplementation inhibits formation of endometriosis-associated adhesions in a chimeric mouse model. Fertil Steril 99:543-50
Izban, Michael G; Nowicki, Bogdan J; Nowicki, Stella (2012) 1,25-Dihydroxyvitamin D3 promotes a sustained LPS-induced NF-?B-dependent expression of CD55 in human monocytic THP-1 cells. PLoS One 7:e49318
Cakmak, Hakan; Basar, Murat; Seval-Celik, Yasemin et al. (2012) Statins inhibit monocyte chemotactic protein 1 expression in endometriosis. Reprod Sci 19:572-9
Herington, Jennifer L; Crispens, Marta A; Carvalho-Macedo, Alessandra C et al. (2011) Development and prevention of postsurgical adhesions in a chimeric mouse model of experimental endometriosis. Fertil Steril 95:1295-301.e1

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