Mary R. Loeken, Ph.D.
Dr. Loeken is an Investigator in the Section on Developmental and Stem Cell Biology at Joslin and an Assistant Professor of Medicine at Harvard Medical School. She received her doctoral degree in Reproductive Endocrinology at the University of Maryland Medical School and did her postdoctoral training in Molecular Virology at the National Cancer Institute. In 1992, she was named a Capps Scholar in Diabetes Research at Harvard Medical School, from which she also received a Scholars in Medicine Award in 1998. She is an expert on the study of birth defects resulting from diabetic pregnancy. She currently serves on the Grant Review Panel of the American Diabetes Association, and recently completed terms on the Medical Science Review Panel of the Juvenile Diabetes Research Foundation and on the editorial board of the journal Diabetes.
Birth defects occur 2 to 5 times more frequently in the pregnancies of women who have diabetes. Until recently, the reasons for this were unknown. Dr. Loeken developed a mouse model of diabetic pregnancy to study this problem. Her laboratory showed that during episodes of maternal hyperglycemia, more glucose is delivered to the embryo. When the embryo cells break down the excess glucose, it blocks the activation of certain embryo genes that control formation of organs such as the brain, spinal cord and heart.
Most of Dr. Loeken’s research has focused on expression of one particular gene, Pax-3. Dr. Loeken has shown that oxidative stress blocks expression of Pax-3. In recent findings, Dr. Loeken’s laboratory demonstrated that the oxidative stress occurs because increased glucose metabolism causes oxygen to be consumed by the embryo more rapidly than it can be delivered. In trying to understand why blocking expression of Pax-3 leads to congenital malformations, the Loeken lab showed that the Pax-3 protein is necessary for formation of these structures because it prevents cells from dying. In recent experiments using mice with genetically engineered cells to allow visualization of Pax-3-expressing cells in the embryo, her lab found that the same process, involving Pax-3 and cell death, explains both neural tube and heart defects that are particularly prevalent in diabetic pregnancy.
Although further research is necessary, Dr. Loeken’s findings might lead to new methods to prevent high glucose damage to embryo gene expression and to identify which women might be at increased risk of having a baby with a birth defect. Furthermore, these findings might be applicable to understanding how high glucose causes abnormal gene expression in other diabetic complications such as nephropathy and vasculopathy.
The current work of the Loeken laboratory focuses on three major questions: How does increased glucose metabolism interfere with gene expression? How does Pax-3 prevent cell death? And which genes increase risk of birth defects associated with diabetic pregnancy? Experiments to answer these questions will use the diabetic mouse model of pregnancy and embryonic stem cells. The stem cell model complements the mouse model and can be used for molecular and proteomic analysis of the signals by which embryonic cells begin to become specialized and how glucose metabolism affects this process. In addition, the embryonic stem cells might be used to determine how genes regulated by glucose metabolism might regulate the immortal nature of stem cells.
Li R, Chase M, Jung SK, Smith PJ, Loeken MR. Hypoxic stress in diabetic pregnancy contributes to impaired embryo gene expression and defective development by inducing oxidative stress. Am J Physiol Endocrinol Metab 289:E591-599, 2005.
Chang TI, Horal M, Jain SK, Wang F, Patel R, Loeken MR. Oxidant regulation of gene expression and neural tube development: insights gained from diabetic pregnancy on molecular causes of neural tube defects. Diabetologia 46:538-545, 2003.
Pani L, Horal M, Loeken MR. Polymorphic susceptibility to the molecular causes of neural tube defects during diabetic embryopathy. Diabetes 51:2871-2874, 2002.
Pani L, Horal M, Loeken MR. Rescue of neural tube defects in Pax-3-deficient embryos by p53 loss of function: implications for Pax-3-dependent development and tumorigenesis. Genes Dev 16:676-680, 2002.
Fine EL, Horal M, Chang TI, Fortin G, Loeken MR. Evidence that elevated glucose causes altered gene expression, apoptosis, and neural tube defects in a mouse model of diabetic pregnancy. Diabetes 48:2454-2462, 1999.
Phelan SA, Ito M, Loeken MR. Neural tube defects in embryos of diabetic mice: role of the Pax-3 gene and apoptosis. Diabetes 46:1189-1197, 1997.
Page last updated: August 29, 2014