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Program Objectives
Implications for the research in our laboratory pertain to both improving women's reproductive health, together with the broader objective of understanding patterns of ovarian function and follicle development among vertebrates whose reproductive strategy consists of producing a limited number of offspring combined with considerable maternal investment (e.g., mammals, birds and a few reptiles). Applications include the potential for enhancing the reproductive potential of threatened/endangered plus domesticated avian species, particularly broiler breeders in which an aberrant regulation of the follicular hierarchy results in suboptimal egg production.
Ovarian Follicle Selection
A major focus is to define the endocrine, cellular and molecular mechanisms that accomplish follicle selection, a process as yet undefined in any vertebrate. The selection of preovulatory follicles represents an event by which a species-specific number of ovarian follicles progresses from an undifferentiated to differentiated state in preparation for ovulation. This process is critical for maintaining normal reproductive cycles and is dependent upon a balance between the maintenance of follicle viability and the loss of excessive or nonviable follicles via follicle atresia. Notably, excessive atresia can ultimately result in infertility and/or early reproductive senescence (e.g., menopause). The domestic hen represents a unique and important animal model system for such studies due to the ability to reliably identify a small cohort of prehierarchal follicles from which a single follicle per day is recruited into the preovulatory hierarchy.
The working hypothesis of our ongoing studies is that follicle selection and final differentiation prior to ovulation results from the removal of inhibitory cell signaling within the granulosa cell layer. To date, the nature of inhibition has focused on MAPK/Erk and protein kinase C (PKC) cell signaling maintained by epidermal growth factor ligands (EGFL) produced in an autocrine and paracrine fashion. The alleviation from this inhibitory signaling within the selected follicle subsequently enables FSH-induced LH receptor (LHR) induction and the initiation of steroid production. Of particular note is the recent finding that following follicle selection, MAPK/Erk and PKC signaling transitions to become obligatory for the expression and optimal activity of steroidogenic acute regulatory (STAR) protein and maximal steroidogenesis required for ovulation.
Significantly, the selective loss of ovarian follicles by atresia occurs via apoptosis and this process is first evident within the granulosa cell layer. We have established that granulosa cells from atresia-susceptible prehierarchal follicles are highly susceptible to undergoing apoptosis, in vitro. By contrast, following selection for final differentiation preceding ovulation, preovulatory follicles are not normally subject to atresia, and cultured granulosa cells from such follicles are known to be highly resistant to apoptosis. Such studies are conducted using transfection to over-express single or multiple gene products in cultured cells as well as by the targeted decrease in expression following transfection with antisense constructs. For additional information and related publications pertaining to ovarian follicle growth, development and atresia mediated via apoptosis visit our web site at: AVIANOVA Web Site. On the other hand, a decrease or absence of normal apoptotic cell death can contribute to tumor formation. Accordingly, a second and related focus utilizes human granulosa tumor cell lines to assess the role of cell survival proteins and cell death pathways in tumor formation and resistance to chemotherapeutics.
Implications for the research in our laboratory pertain to both improving women's reproductive health, together with the broader objective of understanding patterns of ovarian function and follicle development among vertebrates whose reproductive strategy consists of producing a limited number of offspring combined with considerable maternal investment (e.g., mammals, birds and a few reptiles). Applications include the potential for enhancing the reproductive potential of threatened/endangered plus domesticated avian species, particularly broiler breeders in which an aberrant regulation of the follicular hierarchy results in suboptimal egg production.
Ovarian Follicle Selection
A major focus is to define the endocrine, cellular and molecular mechanisms that accomplish follicle selection, a process as yet undefined in any vertebrate. The selection of preovulatory follicles represents an event by which a species-specific number of ovarian follicles progresses from an undifferentiated to differentiated state in preparation for ovulation. This process is critical for maintaining normal reproductive cycles and is dependent upon a balance between the maintenance of follicle viability and the loss of excessive or nonviable follicles via follicle atresia. Notably, excessive atresia can ultimately result in infertility and/or early reproductive senescence (e.g., menopause). The domestic hen represents a unique and important animal model system for such studies due to the ability to reliably identify a small cohort of prehierarchal follicles from which a single follicle per day is recruited into the preovulatory hierarchy.
The working hypothesis of our ongoing studies is that follicle selection and final differentiation prior to ovulation results from the removal of inhibitory cell signaling within the granulosa cell layer. To date, the nature of inhibition has focused on MAPK/Erk and protein kinase C (PKC) cell signaling maintained by epidermal growth factor ligands (EGFL) produced in an autocrine and paracrine fashion. The alleviation from this inhibitory signaling within the selected follicle subsequently enables FSH-induced LH receptor (LHR) induction and the initiation of steroid production. Of particular note is the recent finding that following follicle selection, MAPK/Erk and PKC signaling transitions to become obligatory for the expression and optimal activity of steroidogenic acute regulatory (STAR) protein and maximal steroidogenesis required for ovulation.
Significantly, the selective loss of ovarian follicles by atresia occurs via apoptosis and this process is first evident within the granulosa cell layer. We have established that granulosa cells from atresia-susceptible prehierarchal follicles are highly susceptible to undergoing apoptosis, in vitro. By contrast, following selection for final differentiation preceding ovulation, preovulatory follicles are not normally subject to atresia, and cultured granulosa cells from such follicles are known to be highly resistant to apoptosis. Such studies are conducted using transfection to over-express single or multiple gene products in cultured cells as well as by the targeted decrease in expression following transfection with antisense constructs. For additional information and related publications pertaining to ovarian follicle growth, development and atresia mediated via apoptosis visit our web site at: AVIANOVA Web Site. On the other hand, a decrease or absence of normal apoptotic cell death can contribute to tumor formation. Accordingly, a second and related focus utilizes human granulosa tumor cell lines to assess the role of cell survival proteins and cell death pathways in tumor formation and resistance to chemotherapeutics.
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General and comparative endocrinology (2018): 41-47
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