Richard Leach, MD
Richard E. Leach, MD
Professor and Chair Department of Obstetrics, Gynecology and Reproductive Biology
Michigan State University College of Human Medicine
A-630 East Fee Hall
East Lansing, MI 48824-1316
Phone: 517-884-6031
Email: rleach@msu.edu
Dr. Leach received his medical degree from Wayne State University School of Medicine and completed Residency training in Obstetrics and Gynecology at William Beaumont Hospital. He completed his Fellowship in Reproductive Endocrinology and Infertility at the Mayo Clinic in 1990. Dr. Leach is Board Certified in Obstetrics and Gynecology with subspecialty certification in Reproductive Endocrinology and Infertility. He is a Fellow in the American College of Obstetrics and Gynecology, the American College of Surgeons and the American College of Clinical Endocrinologists. Dr Leach serves as an expert on in vitro fertilization (IVF) on several national committees including the Society of Assisted Reproductive Technologies. He is a national expert on early implantation and his research is supported by the National Institute of Health to study how this can cause infertility. He is as a member of the Best Doctors in AmericaR for his contributions to the practice of IVF.
Research Focus:
We are investigating EGF-Like growth factors and cognate HER receptor regulation of human trophoblast-endometrial cell survival and differentiation. This regulation is influenced by stress including hypoxia that is normally present during early implantation. We are demonstrating that generation of reactive oxygen species through hypoxia-reoxygenation recapitulates EGF-LGF dysregulation in early pregnancy loss. The response of human trophoblast cells to hypoxia has led to the discovery of novel genes over expressed in ovarian cancer. The study of adaptive mechanisms to oxidative stress in invasive trophoblasts and cancer cells is unraveling common modes of regulation and cellular phenotypes including invasion and apoptosis.
1. HBEGF: A Role in Human Implantation. The synchronous development of the endometrium during early implantation in women is highly dependent on embryonic-maternal signaling. We have shown that HB-EGF is secreted by the luminal epithelium of the human uterus during interval of implantation and is regulated in a spatiotemporal pattern in the endometrium by ovarian steroids estrogen and progesterone in the baboon. We discovered that HB-EGF stimulates human placenta villous explants to invade matrix at an accelerated rate by binding both HER-1 and HER-4 tyrosine kinase receptors. In collaboration with Randy Armant, PhD, from Wayne State University we are studying more closely the underlying molecular mechanisms that regulate HB-EGF expression and processing and its down stream control of trophoblast invasion and apoptosis.
2. HBEGF: A Role in Abnormal Human Implantation. We have shown that HB-EGF is absent in the placentas form women with preeclampsia. The cell invasion-promoting and antiapoptotic activities of HB-EGF place this molecule at a point of convergence of the pathophysiological abnormalities associated with early pregnancy loss: namely inadequate trophoblast invasion and excessive cell death. As a member (Project 4) of the U54 SCCPR (HD040093-0) centered at University of Illinois at Chicago (PI Asgi Fazleabas) we are studying how oxidative stress causes the dysregulation of trophoblast HB-EGF processing, invasion and apoptosis. Of significance, we can recapitulate the trophoblast phenotype found in some early pregnancy loss by in vitro exposure of trophoblast to hypoxia-reoxygenation.
3. Novel Human Implantation Genes that are Over-Expressed in Cancer. The human and mouse genome sequencing efforts are providing us with an opportunity to use species similarities as gene-function discovery tools. We have employed transcript profiling to characterize extra-embryonic trophoblast tissues during early human implantation. A cDNA library isolated from the ectoplacental cone region of 7.5 dpc staged mouse embryos was probed with cDNA from hypoxic cultured human trophoblast cells. This stage correlates to 20 days (Carnegie Stage 9) of human embryo development and cannot readily be studied for ethical and technical reasons. In total, 21 known and 9 unknown genes induced or attenuated in trophoblast cells after hypoxic treatment were identified. In collaboration with Steven Krawetz, PhD, from Wayne State University, we have focused on the characterization of OVCOV1 (ovarian cancer over expressed 1) since it is over expressed in ovarian cancer tissue. We are proceeding with studies to elucidate its function.
Acromite MT, Mantzoros CS, Leach RE, Hurwitz J, Dorey LG. Androgens in Preeclampsia. American Journal of Obstetrics and Gynecology 180:60-64, 1999.
Leach RE, Rout UK, Schultz JF, Saunders DE, Armant DR. Ethanol Elevates C-MYC Levels in Cultured Mouse Preimplantation Embryos. Alcoholism: Clinical and Experimental Research 23:778-784,1999.
Leach RE, Khalifa R, Ramirez ND, Das SK, Wang J, Dey SK, Romero R, Armant DR. Multiple Roles for Heparin-Binding EGF-Like Growth Factor are Suggested by its Cell-Specific Expression During the Human Endometrial Cycle and Early Placentation. Journal of Clinical Endocrinology and Metabolism 84:3355-3363, 1999.
Kilburn B, Wang J, Duniec-Dmuchowski ZM, Leach RE, Romero R, Armant Dr. Extracellular Matrix Composition and Hypoxia Regulate the Expression of HLA-G and Integrins in a Human Trophoblast Cell Line. Bio Repro 62:739-747, 2000.
Martins RP, Leach RE, Krawetz SA: Whole Body Gene Expression By Data Mining. Genomics 72:34-42, 2001.
Draghici S, Martins RP, Leach RE, Krawetz SA: Expressed Sequenced Tag Data Mining: The Reality of Virtual Gene Expression. Proceedings of Atlantic Symposium on Computational Biology, and Genome Information Systems & Technology. 39-41, 2001.
Leach RE, Khalifa R, Armant DR, Brudney A, Das S, Dey SK, Fazleabas. Heparin-Binding EGF-Like Growth Factor (HB-EGF) Modulation by AntiProgestin and Chorionic Gonadotropin in the Baboon (Papio anubis). Journal of Clinical Endocrinology and Metabolism. 86(9): 4520-4528, 2001.
Leach RE, Duniec-Dmuchowski Z, Tetsuya Tanaka, Ko M, Krawetz S. Assignment of Ovarian Cancer Over Expressed 1 (OVCOV1) to 20 Human Chromosome Band q13.1-13.2 by Fluorescent in Situ Hybridization. Cytogenetics and Cell Genetics. 94(3-4): 252-253, 2001.
Leach RE, Duniec-Dmuchowski ZM, Pezole G, Tanaka T, Ko MS, Krawetz SA. Identification, Molecular Characterization, and Tissue Expression of Ovarian Cancer Over Expressed 1 (OVCOV1). Mammalian Genome. 13:619-624, 2002.
Leach, RE, Romero, R., Kim, Y.M., Chaiworapongsa, T., Kilburn, B., Das, S.K., Dey, S.K., Johnson, A., Qureshi, F., Jacques, S. and Armant, D.R. Pre-eclampsia and Expression of Heparin-Binding EGF-like Growth Factor. Lancet, 360:1215-1219, 2002.
Leach, RE, Duniec-Dmuchowski, Z.M., Pesole, G., Tanaka, T.S., Ko, M.S.H., Armant, D.R. and Krawetz, S.A. Identification, Molecular Characterization, and Tissue Expression of OVCOV1. Mammalian Genome, 13:619-624, 2002.
Liu Z, Kilburn BA, Leach RE, Romero R, Paria BC, Armant DR. Histamine Enhances Cytotrophoblast Invasion by Inducing Intracellular Calcium Transients Through the Histamine Type-1 Receptor. Molecular Reproduction and Development, 68:345-53, 2004.
Leach, RE, Kilburn B, Wang J, Liu, Z, Romero R and Armant DR. Heparin-Binding EGF-Like Growth Factor Regulates Human Extravillous Cytotrophoblast Development During Conversion to the Invasive Phenotype. Developmental Biology, Developmental Biology 266(2): 223-37, Feb 15 2004.
Zhong W, Sun T, Wang QT, Wang Y, Xie Y, Johnson A, Leach R, Puscheck EE, Rappolee DA. (2004). SAPKgamma/JNK1 and SAPKalpha/JNK2 mRNA transcripts are expressed in early gestation human placenta and mouse eggs, preimplantation embryos, and trophoblast stem cells. Fertil Steril. 82:1140-1148.
McGovern PG, Myers ER, Silva S, Coutifaris C, Carson S, Legro RS, Schlaff WD, Carr BA, Steinkampf MP, Giudice LC, Leppert PC, Diamond MP for the National Cooperative Reproductive Medicine Network: Absence of Secretory Endometrium After False Positive Home Urine Luteinizing Hormone Testing. Fertil Steril. 82(5):1273-7. 2004.
Allon MA, Leach RE, Dunbar J, Schultz J, Diamond MP. Effects of Chronic Hyperandrogenism and/or Administered Central Nervous System Insulin on Ovarian Manifestation, Gonadotropin and Steroid Secretion: A Model for Polycystic Ovarian Syndrome (PCOS). Fertil Steril. 2005. 83 Suppl 4:1319-26. 2005.
Zhong W, Wang Q. Tian, Sun T, Wang F, Liu J, Leach R, Johnson A, Puscheck EE, Rappolee DA. FGF ligand family mRNA expression profile for mouse preimplantation embryos, early gestation human placenta, and mouse trophoblast stem cells. Molecular Reproduction and Development. 73(5):540-50. 2006
Armant RA, Kilburn BA, Petkova A, Edwin SS, Duniec-Dmuchowski ZM, Edwards HJ, Romero R, Leach RE. Human trophoblast survival at low oxygen requires metalloproteinase mediated shedding of heparin-binding EGF-like growth factor. Development. 133(4):751-9. 2006.
Mehendale, R, Hibbard, J, Fazleabas, A, Leach RE. Placental angiogenesis markers sFlt-1 and P1GF: response to cigarette smoke. American Journal of Obstetrics and Gynecology, in Press, 2007.