Integrative physiology of ovarian follicular development and ovulation

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The last several decades have born witness to a global decline in reproductive efficiency within the bovine industry which has translated into significant economic losses for producers. The causes of this reduced fertility are multifactorial; central to the problem on the female side is ovarian physiology. The long-term goal of this research program is to better comprehend the development of ovarian follicles by studying the physiology of granulosa cells (GC) during the final stages of follicular growth, ovulation and early luteinisation. In previous studies, we have established a differentially expressed gene index for GC at critical stages of follicular development. The objectives of this proposal are to determine the biological functions of these novel and differentially expressed genes previously identified, including the low-density lipoprotein receptor-related protein 8 (LRP8) and two long non-coding RNAs (lncRNA). Our specific objectives will test the hypothesis that a paracrine interaction between Reelin (a ligand of LRP8) released from the theca layer and the membrane receptor LRP8 expressed by GC regulate the final stages of follicular growth. We will: 1) define proteins that bind the intracellular and extracellular domains of LRP8 expressed by GC; 2) comprehend how LRP8 gene expression is activated; and 3) demonstrate the physiological effects of extracellular ligands on GC physiology following activation of the membrane receptor LRP8. For the two novel lncRNAs, we hypothesize that they represent RNA regulators controlling transcription of specific genes. The short-term objective is to uncover their biological function in GC by defining: 1) their protein binding partners; and 2) their binding sites within the bovine genome to determine which genes are under their control. This research program will significantly advance our understanding of key biochemical processes involved in GC proliferation and differentiation regulating final follicular growth, a stage of development at which follicles are most sensitive to metabolic stresses that impact fertility. Understanding which ligands activate the LRP8 membrane receptor and how LRP8 transduces its extracellular signals within GC will provide insights into the development of agonists to stimulate the LRP8 activity that may in turn help contravene the effects of metabolic stresses. This research program will further advance our understanding: 1) To enhance the efficacy of treatments that aim at follicle synchronization and ovarian stimulation programs in cattle; 2) To increase the production of competent oocytes used for in vitro fertilization, nuclear transfer and genome editing; 3) To identify candidate genes associated with fertility that can be used as molecular markers for genetic assisted-selection in breeding programs of industries involved in commercializing and distributing male and female gametes; and 4) To promote the training of highly qualified personnel in the science.