Characterization and Validation of a New Mouse Model of Spontaneous Endometriosis to Implement Translation of Basic Research to the Clinic
Abstract
Background: Endometriosis is a chronic, debilitating disease in which endometrial tissue, which normally lines the uterus, grows outside the uterus. Endometriosis is associated with infertility, severe pain and reduced quality of life and is estimated to affect 10% of women worldwide. Despite its prevalence, the causes of endometriosis remain poorly understood. The most accepted theory is that endometriosis is the result of a process called retrograde menstruation, where endometrial cells are sloughed off into menstrual fluid, flow backwards through the fallopian tubes and implant into tissues in the peritoneal cavity. In support of this theory, endometriosis develops in over half of women affected by uterine obstruction, which can occur during embryonic development. In these women, retrograde menstruation is greatly exacerbated because outflow of menstrual fluid is impeded. For reasons that are still unclear, although retrograde menstruation occurs in most women, only a minority will develop endometriosis. Hence, there is a pressing need for an improved understanding of the mechanisms underlying endometriosis in order to deliver better diagnostic and therapeutic options for patients, as invasive surgery is currently the only means to definitively diagnose this condition. One reason that endometriosis is poorly understood is that there are currently no small animal models of spontaneous endometriosis. This negatively impacts our ability to study this disease, test potential treatments, and find new diagnostic strategies. Because laboratory mice do not normally develop endometriosis, most research has been conducted by artificially introducing uterine tissue into the peritoneal cavity. These experiments typically require surgical removal of the ovaries and injection of hormones to support endometriosis growth. This has made it difficult to study the most common form of endometriosis in humans, which are lesions that grow directly on the ovaries called endometriomas. While endometriomas greatly reduce fertility and increase the risk of ovarian cancer, the exact mechanisms by which this occurs are still unclear. Recently, we have developed the first mouse model of spontaneously occurring endometriosis. We have done this by suppressing a gene called Hnf1b in the mouse uterus, which causes uterine obstruction. We have found that Hnf1b mutant mice develop endometriosis and show signs of ovarian disease also observed in humans, offering a world-first model to study the pathological mechanisms of endometriosis as they arise spontaneously without surgical or pharmacological interventions. Here, we will extend our breakthrough by using our Hnf1b mutant mice to address two major knowledge gaps in the endometriosis field. We will: 1) Define the mechanisms of endometriosis in the Hnf1b mutant mouse model. 2) Determine the impact of endometriomas on fertility and ovarian health. By answering these questions, we will address the Strategic Goal to Improve understanding of long-term complications and comorbidities of associated diseases and conditions within the Fiscal Year 2022 Peer Reviewed Medical Research Program Topic Area of Endometriosis (Internal Medicine portfolio). We anticipate that comprehensive analyses of our Hnf1b mutant model will reveal new mechanisms of disease progression and improve our understanding of the impact that endometriosis has on fertility and cancer risk. Innovation: A new strategy is needed to address long-standing limitations in endometriosis research and fill critical knowledge gaps, especially in the fields of infertility and ovarian cancer. We have developed the first mouse model of spontaneous endometriosis. With this innovation, we have established the necessary resources to place our work at the forefront of endometriosis research. The implementation of our animal model will open new research avenues, including the validation of findings from previous models, the refinement of research
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Jan 04, 2024
- Source ID
- HT94252310147
Entities
People
- Emanuele Pelosi
Organizations
- United States Army
- University of Queensland