Endometriosis Susceptibility Genes in Endometrial Stem/Progenitor Cells
Abstract
Background: Endometriosis is a serious, chronic disorder affecting up to 1 in 10 menstruating girls and women. The debilitating pain experienced by many women with endometriosis limits their participation in education, careers, and social life. Infertility is also a common symptom, which denies many women with endometriosis the opportunity to raise a family. Women with endometriosis undergo numerous surgeries to overcome the pain and increase chances of pregnancy. Many also resort to using expensive in vitro fertilization (IVF) procedures. The cause of endometriosis is unknown, and diagnosis takes at least 10 years due to lack of a non-invasive diagnostic test. In the years between symptom onset and diagnosis, endometriosis progression leads to severe disease and the need for surgery to excise lesions, often with limited success. Current drug treatments are hormonally based, often ineffective, and can only be used short term due to severe adverse effects in young women. To develop a much-needed cure for endometriosis, it is first necessary to understand the pathogenesis and evolution of the disease. Only stem/progenitor cells are sufficiently long-lived and capable to establish endometriotic growths in the pelvis. Our studies have identified and characterized rare populations of two stem/progenitor cell types of the uterine lining. Importantly, we have shown that these cells are shed into the pelvic cavity by reverse menstruation (which occurs in most women) and that the gene expression profile of one stem/progenitor type from women with endometriosis confers greater survival, enabling them to attach and initiate endometriosis lesions. Endometriosis is a complex disease where many genetic variations confer small effects in combination and through interaction with environmental factors, or are involved with the regulation of gene expression. Our studies identified 14 endometriosis risk genes, but their biological role remains unknown. We have also devised a polygenic risk score (PRS) that reflects the cumulative load of the risk genes in an individual. In this proposal, we will assess the biological role of a high PRS in endometriosis patients versus a low PRS in normal women. We will generate molecular signatures of the stem cells thought to form lesions, from patients with high and low PRS. Using new ways to culture human endometrial cells in 3D organoids, which reflects their function in the body, we will determine the biological differences between high and low PRS that allows the stem/progenitor cells to survive in the pelvis and initiate endometriosis. Some risk genes may confer greater effects than others, and we will assess several on the background of high PRS in our functional organoid model. Finally, we will examine endometrial tissues and lesions to determine the relationships between the risk genes, key gene signature genes, and stem cell locations to further understand endometriosis causation and pathogenesis. Hypothesis: High endometriosis PRS confers selective advantage to endometrial epithelial progenitor cells in initiating growth of endometriotic lesions in women with endometriosis. Endometrial mesenchymal stem cells have a role in the initiation and progression of endometriotic lesions by providing niche or support cells for epithelial stem cells. The mesenchymal stem cells also promote new blood vessel growth to sustain the lesion. Specific Aims/Objectives Aim 1: To investigate the biological effects of endometriosis risk genes by determining gene-expression signatures of endometrial epithelial and mesenchymal stem cells from women with a defined polygenic risk score. Aim 2: To determine the association between genetic risk profiles, the contribution of the endometrial niche, gene transcription, and survival of menstrual stem cells from women with high and low PRS. Aim 3: To map the temporal and spatial relationship of endometrial stem cells in endometrium from
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Nov 19, 2019
- Source ID
- W81XWH1910364
Entities
People
- Caroline E. Gargett
Organizations
- Monash University
- United States Army