From a global perspective, we are obliged to confront and deal with the "sustainability" of a growing world population by developing social and therapeutic strategies that effectively control pregnancy rates. Alternatively, a significant number of couples in the US and other developed countries confront issues of infertility. The impact of infertility and unintended pregnancy-related health and social issues strains US health care resources and contributes to human suffering worldwide. Our understanding of fertility in mammals requires an extensive appreciation of the mechanisms of communication between the brain, pituitary gland and the gonad through the actions of gonadotropin releasing hormone (GnRH), gonadotropins and gonadal hormones. Integration of cell signaling by GnRH is initiated through a compartmentalized signaling platform specifically associated within discrete membrane compartments. The central signaling "pillar" within the GnRH signaling network is the ERK cascade. My lab has developed a critical mouse model examining the role of ERK signaling within the reproductive axis. These studies reveal an absolute requirement for ERKs within pituitary gonadotropes for normal fertility in female mice. These exciting observations support our central hypothesis that membrane raft-associated compartmentalization of the GnRHR is obligatory for GnRHR coupling to a broad signaling network exemplified by ERK pathway activation. Moreover, a gender- specific requirement for GnRH-induced ERK signaling within pituitary gonadotropes exists and is necessary for fertility in mammals.
Two Aims are proposed:
Aim 1. Determine the organization and composition of the signaling complex present within membrane rafts that is necessary for signaling through the GnRHR.
Aim 1 examines the domains within ERK2 necessary and sufficient for membrane raft localization and if the raft serves as a signaling "hub" for ERK activation in male and female mice. We will use GnRHR immunoprecipitation to isolate membrane rafts proteins;proteomic and mass spectroscopy approaches will then be used to identify the cohort of proteins that occupy and facilitate productive signaling from this discrete membrane compartment.
Aim 2. Examine the requirement for ERK1 and ERK2 in pituitary gonadotrope function in vivo.
Aim 2 focuses on a novel mouse model to examine the in vivo requirements for ERKs within the GnRH signaling network. Studies investigate potential developmental abnormalities associated with the loss of ERKs on cell lineage specification during pituitary organogenesis. We will directly examine the ability of GnRH to promote gene transcription in the absence of ERKs in vivo, including assessment of variable GnRH interpulse intervals;and we will determine if varying the timing of Cre-mediated ERK gene excision in the pituitary affects gender-specific infertility. Finally, our mouse model provides the opportunity to examine the ERK- dependent pituitary-specific gene network that is induced by a pulse of GnRH using microarray analyses.
Gonadotropin-releasing hormone (GnRH) controls the reproductive axis and fertility by modulating hormone synthesis and secretion from the pituitary gland. Pituitary-derived gonadotropic hormones in turn regulate the function of the ovary and testis. Manipulation of this system using specific drugs to affect GnRH action can have a large impact on fertility. The studies proposed examine the role of intracellular compartmentalization of important signaling molecules within the pituitary gland and how this compartmentalization affects signaling from of the GnRH receptor. Moreover, these studies will define the in vivo impact of genetic loss of key GnRH-regulated signaling molecules on fertility.
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