Neuregulin-1 (NRG1) in preovulatory granulosa cell survival and anti-inflammatory role

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 DESCRIPTION (provided by applicant): Despite considerable epidemiological and clinical research, the initiation and trajectory of ovarian dysfunction remain unclear. Ovulation is the unique biological process by which a mature oocyte and surrounding cumulus cells are released from the surface of the ovary. Luteinizing hormone (LH)-induced ovulation is similar to an inflammatory response. Relationships between the LH, ovarian steroid hormones and inflammatory markers have been well established in human and animal models (1). While plethora of pro-inflammatory factors are essential for the process of follicle rupture, whereas to protect its surrounding cells/tissues, ovulation requires multiple anti-inflammatory and cellular protective or survival factors including EGF-family members, cytokines, matrix factors. Our preliminary studies detected the epidermal growth factor (EGF) family member, neuregulin- 1 (NRG1) in rat pre-ovulatory granulosa cells (PO-GC), preovulatory follicular fluid (FF) and corpus lutea (CL). Our results also provided novel evidence that NRG1 plays an important role in PO-GC survival and inhibition of inflammatory cytokines secretion, and suggest a possible role in granulosa cells (GCs) differentiation and an anti-inflammatory factor in pre-ovulatory follicle and may act through autocrine and/or paracrine manner. Furthermore, NRG1 is known to have neuroprotective and anti-inflammatory properties, and cardiovascular functions (2,3). However, the anti-inflammatory and pro-survival function of NRG1 and its underlying mechanism of action in GCs of pre-ovulatory follicles are yet to be defined. Understanding the intracellular signaling pathways utilized by the NRG1 in governing PO-GC functions are likely to help identify strategies to overcome ovarian dysfunction. Based on our preliminary studies and on the literature, the goal of this application is to unravel the anti-inflammatory and pro-surviva role of NRG1 in mechanistic detail. Thus, the central hypothesis to be tested in this proposal is that NRG1 is critical intracellular mediators of LH stimulation of PO-GCs, which supports preovulatory follicular maturation.