The goal of the UC San Diego P50 Center for Reproductive
Science and Medicine is to understand the fundamental mechanisms that govern
normal and abnormal function of the hypothalamic-pituitary-gonadal axis with a
central theme of infertility.
Our research program in Reproductive Endocrinology was initiated at the inception of the Department of Reproductive Medicine at UC San Diego in 1970. In the beginning, under the direction of Dr. Kenneth Ryan and Dr. Samuel S. C. Yen, the program included Drs. Fred Naftolin, Howard Judd, John Davies, and Kurt Benirschke. Initially, the Rockefeller Foundation supported the Department research in reproduction. The P50 NICHD Specialized Population Research Center Grant was awarded in 1979, and Dr. Yen directed the Center for 19 years. Under his leadership, the center produced numerous important discoveries; many of which had major impact on the fields of basic and clinical reproductive endocrinology. Investigators associated with the Center during this period were: Gregory Erickson, Aaron Hsueh, Eli Adashi, James Schreiber, Jim Liu, Jim Schaffer, Allen Lein, Robert Rebar, Bruce Kessell, Robert Caspar, Robert Reid, Ralph Kazer, Ken Muse, Sarah Berga, Joseph Mortola, and Ana Murphy. In 1992, Dr. Pamela Mellon was recruited to UCSD to serve as Co-Director of the P50 grant for years 15-19. The four projects were headed by Drs. Yen, Mellon, Erickson, and Jerrold Olefsky. In 1997, the transition of the P30/50 Centers to the U54 Specialized Cooperative Center in Reproduction Research was accompanied by transitions in the leadership, the faculty and the research directions of the Center at UC San Diego. The Center incorporated the most advanced molecular and clinical approaches, yet our traditional research strength of integrating clinical and basic science was carefully preserved. New faculty recruited to the Center included Drs. Jeffrey Chang, Shunichi Shimasaki, and Mark Lawson. Dr. Mellon assumed the Directorship for years 20-24, with Dr. Chang as the Co-Director. The Center contained five projects headed by Drs. Mellon, Erickson, Olefsky, Shimasaki, and Chang, with Drs. Yen, Lawson, and Nicholas Webster as Co-Investigators. The Center was designed to ensure a balance of basic and clinical research. This transition afforded a unique opportunity to fulfill our ultimate aim in bringing the most advanced approaches to bear on fundamental questions of mechanisms regulating the hypothalamic-pituitary-ovarian axis in health and disease.
The distinguishing theme of our Center has always been the translation of basic research to clinical medicine. Among the historic achievements of Dr. Yen and his group was the rigorous examination of gonadotropin secretory dynamics together with characterization of LH and FSH responses to GnRH through the menstrual cycle, seminal contributions, upon which mechanisms of ovarian steroid feedback were based. Subsequently, the specific relationships between estrogen and progesterone to gonadotropin release were identified which clearly established the precise temporal endocrine signals that regulate menstrual cyclicity. Dr. Yen initiated the extensive use of neuropeptides to elucidate the role of hypothalamic control of pituitary function. Notably, most of these collective efforts were performed in vivo in normal women and women with a variety of ovulatory disorders. The spectrum of study included the transitional intervals of puberty and menopause, and pathologic anovulatory conditions, including polycystic ovary syndrome.
Our Center also pioneered development of serum-free cell culture models for granulosa and theca cells, now used by investigators worldwide discovering interaction of oocytes, theca, and granulosa cells in follicle development. This research done by Drs. Hsueh, Erickson, and Shimasaki, stands as an example of how major breakthroughs in basic research were translated to humans. The novel concepts that IGF-I, IGF-BPs, and their proteases play critical roles in regulating FSH- and LH-dependent follicle cytodifferentiation have proven clinically relevant in normal women and patients with PCOS. Drs. Erickson and Shimasaki then established crucial roles of the BMPs and GDF-9 in ovarian physiology, and demonstrated the central role played by the oocyte in controlling normal folliculogenesis.
Our Center also established key neuroendocrine model systems for investigation of hypothalamic and pituitary control of reproduction in the GT1-7, αT3-1, and LβT2 cell lines for investigation of GnRH and the gonadotropin hormones. These cell lines are utilized by numerous investigators in the NCTRI program and world-wide to advance understanding of fundamental mechanisms of hypothalamic secretion of GnRH, neuropeptide and neurotransmitter control of GnRH, developmental origins of GnRH neurons and pituitary gonadotropes, hormonal regulation in gonadotropes, and the molecular basis of gonadotropin gene regulation. These are examples of the types of translational research that led, in part, to the distinguished reputation of the Center at UC San Diego in linking basic and clinical reproductive research.
In years 25-33, the UC San Diego Center focused on three highly integrated and collaborative projects led by Drs. Mellon, Olefsky, and Chang, with Drs. Webster, Lawson, Kauffman, Thackray, Breen, Duleba, and Shimasaki as Co-Investigators. This multidisciplinary team placed special emphasis on hormonal regulation of hypothalamic-pituitary-ovarian axis in human and animal models. The currently funded grant, years 34-38, included a new Project II led by Dr. Lawson that studied the impact of free fatty acids and androgens and continued our ground-breaking translational discoveries within the UC San Diego Center for Reproductive Science and Medicine along with those led by Drs. Mellon and Chang. Our progress in the most recent period (years 34-38) has been exceptional. The scientific accomplishments include 77 publications; 21 co-authored within the center, and 3 co-authored with other NCTRI Centers during this most recent granting period (2017-2021).
For the upcoming years 39-43, we have proposed three innovative Research Projects, all with experienced, internationally renowned leaders and impressive teams of outstanding investigators. Our focus has transitioned from the study of polycystic ovary syndrome to studying genetic, epigenetic, and hormonal causes of infertility in both women and men. We have 10 participating faculty from the Department of Obstetrics, Gynecology and Reproductive Sciences, all located together at the La Jolla campus of UC San Diego in close proximity and with long-term close and collaborative relationships. The natural evolution of the Center has allowed two new project leaders to emerge to take the leads on Projects I and II. Dr. Varykina Thackray is a Co-Investigator on the currently funded Project I and has taken the lead on this project in this renewal application. Dr. Pamela Mellon remains as Co-Investigator and Dr. Kellie Breen will join the project as Co-Investigator. Dr. Mark Lawson will similarly transition from Project leader to Co-Investigator on Project II. The previous Co-Investigator, Dr. Alexander Kauffman, has taken the lead for the renewal of Project II and Dr. Mellon will also join the project as Co-Investigator. Project III will be led by Dr. R. Jeffrey Chang as before, with Dr. Tracy Harrison, a new faculty member currently a K12 WRHR Scholar, and Drs. Duleba and Shimasaki continuing as Co-Investigators. Dr. Irene Su, the previous Co-Director of the Outreach Education Core will similarly step up to become the Director, with the previous Core Director, Dr. Chang, becoming the Co-Director. All three Projects are focused on fundamental mechanisms of infertility, creating an integrated, coherent Center with translational approaches within the central theme of fertility. We envision that this integrated basic/clinical translational research Center will now advance to the next level to generate important discoveries that will provide comprehensive understanding of the molecules, cells, hormones, and systems involved in controlling reproduction and lead to improved treatment of infertility.
The support provided by the NICHD Center grant and the synergy between the Center investigators has permitted substantial progress in our understanding of how neuroendocrine and ovarian pathways lead to normal and abnormal reproduction. We believe the scientific achievements made during the past 38 years of funding have fulfilled the mission set forth by the Fertility and Infertility Branch of NICHD. The UC San Diego Center has spawned a critical new generation of reproductive scientists, many of whom occupy leadership positions throughout the nation and who have expanded the reproductive program at UC San Diego.
The UC San Diego Center's scientists have held leadership positions in the Centers program, consistently participated in and presented at the research and Director's meetings, and established extensive collaborative projects with other Centers. We have provided key model systems utilized worldwide to advance the field of reproductive biology, and translated basic discoveries made in these models to clinical medicine. The Center continues to support those goals of excellence in basic and clinical research that have built this highly integrated, translational, productive, and valuable Center at UC San Diego.