Jon D. Hennebold

Within the past several years, the resultant data generated from genome-sequencing projects have provided scientists with the opportunity to identify most, if not all, genes that determine the physiology of a particular organism.  For reproductive biologists, such genomic databases allow for the systematic identification and characterization of molecular pathways that are critical for fertility.  The information gained from such studies can be used to further our understanding of the causes of infertility and diseases of the reproductive tract, as well as to identify novel targets for the control of fertility.
 

Proper ovarian function depends on highly orchestrated molecular events that control the development of a pre-ovulatory follicle during the first half of the menstrual cycle, its rupture midcycle to allow for the release of a fertilizable oocyte, and the subsequent development of the corpus luteum from the remnants of the ruptured follicle.  The newly formed corpus luteum produces the steroid hormone progesterone, which is required for the maintenance of pregnancy if fertilization occurs.  In the absence of fertilization, the corpus luteum regresses and progesterone production ceases, which in turn, allows for the initiation of the next menstrual cycle.  While the hormonal signals produced by the pituitary responsible for controlling ovarian function have received considerable attention, the intraovarian processes that they regulate are only poorly characterized.  Thus, Dr. Hennebold's laboratory team has utilized recently developed molecular and genomic approaches to systematically identify novel or previously unappreciated processes that contribute to proper ovarian function.
 
One particular area of interest for Dr. Hennebold's research team includes the characterization of the molecular and cellular events necessary for the development, function, and regression of the corpus luteum.  Using techniques that allow for the identification of nearly all differentially expressed mRNAs, Dr. Hennebold and his group have systematically determined which genes change in expression within the corpus luteum throughout the luteal phase.  From such studies, it was discovered that genes involved in the synthesis, metabolism, and response to prostaglandins are dynamically regulated in the primate corpus luteum through the luteal phase.  As prostaglandins are potent bioactive lipids capable of regulating numerous cellular activities, these results suggest that they may be critical for luteal physiology.  As such, the focus of the Hennebold laboratory is to determine what specific role prostaglandins play in regulating cellular function within the primate corpus luteum.  The end result of these studies will be a better understanding of events necessary for luteal formation and function, as well as the underlying cause of infertility that is related to luteal dysfunction or insufficiency.

Another area of interest for Dr. Hennebold involves identifying and characterizing the molecular events that are necessary for follicle rupture and detachment of the oocyte from the inner cell layer of the follicle.  These events, leading to ovulation, require significant cellular reorganization and extracellular matrix remodeling.  Detachment and release of the oocyte must be preceded by loss of cell-to-cell contacts and formation of an extracellular matrix between the cells surrounding the oocyte.  The individual genes responsible for initiating and executing these processes have yet to be fully elucidated.  Recent genomic studies conducted in a collaborative effort involving Dr. Hennebold and the Center's Dr. Richard Stouffer have led to the identification of genes whose expression increases through the period preceding follicle rupture and, as a consequence, are likely involved in the requisite cellular and extracellular matrix remodeling necessary for ovulation.  Currently, Dr. Hennebold's team and colleagues are studying the exact contribution these genes play in allowing for the rupture of the ovulatory follicle and the release of the oocyte.  The results of these studies may lead to the development of novel non-hormonal forms of contraception for women.

Key Publications

Peluffo MC, Murphy MJ, Baughman ST, Stouffer RL, Hennebold JD. Systematic analysis of protease gene expression in the rhesus macaque ovulatory follicle: metalloproteinase involvement in follicle rupture. Endocrinology, 152:3963-74, 2011.

Xu F, Stouffer RL, Muller J, Hennebold JD, Wright JW, Bahar A, Leder G, Peters M, Thorne M, Sims M, Wintermantel T, Lindenthal B. Dynamics of the transcriptome in the primate ovulatory follicle. Mol Hum Reprod, 17:152-65, 2011.

Bogan RL, Hennebold JD. The reverse cholesterol transport system as a potential mediator of luteolysis in the primate corpus luteum.  Reproduction, 139:163-176, 2010.

Bogan RL, Murphy MJ, Hennebold JD.  Dynamic changes in gene expression that occur during the period of spontaneous functional regression in the rhesus macaque corpus luteum.  Endocrinology,150:1521-1529, 2009.

Bogan RL, Murphy MJ, Stouffer RL, Hennebold JD.  Prostaglandin synthesis, metabolism, and signaling potential in the rhesus macaque corpus luteum throughout the luteal phase of the menstrual cycle. Endocrinology  149:5861-5871, 2008.

Bogan RL, Murphy MJ, Stouffer RL, Hennebold JD.  Systematic determination of differential gene expression in the primate corpus luteum during the luteal phase of the menstrual cycle.  Molecular Endocrinology,  22:1260-1275, 2008.