Daniel B. Hardy, Ph.D.

 

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This issue of Seminars in Reproductive Medicine addresses the developing science of fetal programming. Dr. Daniel Hardy, a former colleague, has recruited the principal investigators in this area, who have provided us with an update on this relatively new area of medicine.

Dr. Hardy was first introduced to the fetal origins of adult diseases hypothesis by his high school and undergraduate cooperative supervisor, Dr. John Challis, who at that time was director of the Lawson Health Research Institute (LHRI) at the University of Western Ontario (UWO). Dr. Hardy went on to pursue an honors B.Sc. at the University of Waterloo in a specialized cooperative biology program that posted him in several research laboratories in Canada including the LHRI, Robarts Research Institute, and the National Research Council of Canada. Through these cooperative work-term placements, Dr. Hardy was exposed to a variety of types of endocrine-related research including type 1 diabetes, neuroendocrine disorders, and pregnancy.

In 1997, he came back to London and pursued his Ph.D. in physiology focused on placental glucocorticoid metabolism under the supervision of Dr. Kaiping Yang. During his doctoral work, Dr. Hardy became more interested in the role of the in utero environment on fetal development and long-term outcomes. His dissertation specifically examined how eicosanoids and hypoxia impair the expression of placental 11β-hydroxysteroid dehydrogenase type 2, the critical glucocorticoid barrier at the maternal-fetal interface.

His research interests in nuclear receptor biology then led him to pursue a postdoctoral fellowship in 2003 at the University of Texas Southwestern Medical Center at Dallas under the mentorship of Dr. Carole Mendelson, focusing on another steroid nuclear receptor, the progesterone receptor (PR). Specifically he focused on how PR plays a major anti-inflammatory role in both parturition and in breast cancer. In a first-author paper published in Molecular Endocrinology, he identified how PR, via ligand-dependent and ligand-independent mechanism, impairs the cyclooxygenase-2 (COX-2) expression in both myometrial and T47D breast cancer cells. Moreover, chromatin immunoprecipitation analysis revealed that progesterone decreased in vivo binding of nuclear factor (NF)-κB to both the proximal and distal NF-κB response elements of the COX-2 promoter. This was found to be associated with a marked increase in the expression of IκBα, a crucial inhibitor of NF-κB transactivation. This is of great interest because, to date, essentially no PR target genes have been identified in the uterus that affect myometrial quiescence. In a 2008 follow-up paper in Molecular Endocrinology, Dr. Hardy and colleagues also demonstrated that PR plays an important anti-inflammatory role in breast cancer cells by antagonizing the expression of aromatase and HER-2/neu. This exciting new role of the PR was first recognized at the ENDO 2005 Panel on Women's Health and on Reuters Health Online. At ENDO 2006, Dr. Hardy received the inaugural Endocrine Scholar Award from the Endocrine Society, followed by a Fellowship Award from the Susan G. Komen Breast Cancer Foundation. His postdoctoral fellowship also led to four coauthorships in Nature publications with Drs. Bethany Janowski at UT Southwestern demonstrating the role of PR siRNAs, PR antigene nucleic acids, or PR antigene/activating RNAs in regulating PR. Under the direction of Dr. Carole Mendelson and Dr. Bruce Carr, his collaborations with reproductive endocrinology and infertility fellow Dr. Orhan Bukulmez also led to an Endocrinology and a Journal of Clinical Endocrinology & Metabolism publication elucidating some of the molecular mechanisms underlying endometriosis.

In 2008, Dr. Hardy was recruited back to UWO by Dr. Bryan Richardson as an assistant professor in the Departments of Obstetrics and Gynecology and Physiology and Pharmacology to examine the molecular mechanisms underlying the fetal origins of adult diseases, his first passion. He is also a Scientist with the Children's Health Research Institute and the LHRI. Using animal models of undernutrition (e.g., maternal protein restriction) and hypoxia, Dr. Hardy has begun to uncover some of the transcriptional and epigenetic mechanisms involved in the long-term programming of the liver. He currently focuses on the role of yet another nuclear receptor, the liver X receptor, in the in utero origins of hepatic cholesterol and glucose homeostasis. Since his transition to UWO, Dr. Hardy has been supported by the Molly Towell Perinatal Research Foundation, the National Science and Engineering Research Council of Canada, the Sick Kids Foundation, and the Canadian Institutes for Health Research.

In addition to research, Dr. Hardy teaches fetal physiology at UWO alongside his mentors including Drs. David Hill, Bryan Richardson, Kaiping Yang, and Tim Regnault. He previously represented Canada in a German-Canadian Young Leaders Study Tour and continues to participate in community organizations such as the Irish Benevolent Society and the Canadian Diabetes Association. In 2008, in honor of the 50th anniversary of the University of Waterloo, Dr. Hardy was recognized by the Faculty of Science with an Alumni of Honor Award. He continues to participate in Canadian running clubs and has lately revitalized his passion for playing hockey.

Bruce R CarrM.D. 

Division of Reproductive Endocrinology and Infertility

Department of Obstetrics and Gynecology, University of Texas Southwestern Medical Center at Dallas, Dallas, Texas