Grant: Project Grant

Endometriosis (EM) is a disease where normal lining of the uterus, called endometrium, grows outside on the organs (bowel, bladder, ovaries) in pelvic cavity. It is estimated to affect ~200 million women worldwide and more than 50% of them experience infertility and disease recurrence. There is no cure. The disease can be definitely diagnosed through an invasive surgical procedure (laparoscopy). Most of the current treatments include hormone therapy and anti-inflammatory drugs that provide only temporary relief and have significant side effects. There is an urgent need to develop new non-invasive diagnostic methods and new generation of treatments that will target EM lesion growth and pain without affecting fertility. In this context, interleukin 33 (IL-33) has emerged as a major cytokine that regulates multiple processes associated with EM lesion growth, blood supply and pain. We have provided evidence that EM lesions produce IL-33 and that IL-33 mediates its disease promoting effects via a cell type called Innate Lymphoid Cells 2 (ILC2). Here, we seek to understand the molecular mechanisms by which IL-33 drive expansion of ILC2 cells to promote disease specific effects. We will also test whether blocking IL-33 or its primary receptor, ST2 present on ILC2 cells will impact endometriosis lesion survival. We will first establish whether IL-33 and ILC2 cell numbers will correlate with EM disease severity. We will then conduct studies in mice that lack ILC2 cells and prove the molecular basis of how and whether IL-33 and ILC2 cells contribute to EM development and associated symptoms. Finally, we will evaluate therapeutic efficacy by blocking either IL-33 or its primary receptor ST2 present on ILC2 to determine effects on lesion growth and survival in mouse models. The outcome from this proposal will inform us on the foundational knowledge on IL-33-ILC2 axis, its diagnostic potential and therapeutic utility as a new generation immune based drug target for EM.