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Mary Loeken, Ph.D.

Associate Professor of Medicine (Physiology)

Joslin Diabetes Center
Research Division
One Joslin Place
Boston, MA 02215
Telephone: 617-732-2525
Fax: 617- 732-2541
Email: mary.loeken@joslin.harvard.edu
Predocs: 0 Postdocs: 4 Completed PhD's: 1

 Mary Loeken

The neural tube forms the scaffolding upon which the central nervous system forms. Therefore, proper formation of the neural tube is essential for successful development of the brain and spinal cord. The Loeken lab seeks to understand the molecular regulation of early neural tube formation, and to understand the mechanisms by which neural tube defects occur in a mouse model of diabetic pregnancy. We have demonstrated that congenital malformations result from impaired expression of genes in the embryo that control developmental programs. We have focused on Pax3, a gene that is essential for neural tube closure, how energy metabolism regulates expression of Pax3, and in how deficient expression of Pax3 leads to neural tube defects. Using a variety of molecular and genetic approaches, we have shown that Pax3 inhibits p53-dependent apoptosis, apparently by destabilizing p53 protein, during neural tube development, and that neural tube defects in Pax-3-deficient embryos results from derepression of p53-dependent apoptosis.

The current research in my laboratory is focused on understanding how Pax3 is regulated during normal development and in response to oxidative stress, and how Pax3 regulates p53-dependent apoptosis. We have found that transport and metabolism of excess glucose to the embryo during diabetic pregnancy generates oxidative stress, and that oxidative stress inhibits Pax3 expression. We are investigating how increased oxidant status inhibits transcription factor induction or activation. To investigate how Pax3 regulates p53, we are using mutant mouse strains to fate map Pax3-transcribing cells when they are Pax3-deficient, p53-deficient, or both. We are also employing embryonic stem cells with mutant Pax-3 and p53 alleles to investigate the regulation of p53 by Pax-3 on a biochemical level.

 

References:

  • 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, 2003; 46:538-45.
  • Horal, M, Zhang, A, Stanton, R., Virkamaki, A, Loeken, MR. Activation of the hexosamine pathway causes oxidative stress and abnormal embryo gene expression: Involvement in diabetic teratogenesis. Birth Defects Research Part A: Clinical and Molecular Teratology, 2004; 70: 519-527.
  • 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 Encrinol Metab, 2005; 289:E591-599. E-Pub May 31, 2005.
  • Wang, F, Thirumangalathu, S, Loeken, MR Establishment of new mouse embryonic stem cell lines is improved by physiological glucose and oxygen. Cloning and Stem Cells, 2006; 8(2):108-16.
  • Loeken MR. Advances in understanding the molecular causes of diabetes-induced birth defects. J. Soc. Gynecol. Invest., 2006;13: pp. 2-10; Epub Nov 21, 2005.