Reproductive and Developmental
Sciences Training Program

 


Reproductive and Developmental

Sciences Training Program

 

artiro sen thumb

EDUCATION/DEGREE INFORMATION

PhD, Biology (CMB Program) - West Virginia University, Morgantown

MS, Biochemistry - University of Calcutta, India,

BS, Microbiology - Bangalore University, India

Postdoctoral Research, Reproductive Endocrinology – Michigan State University, East Lansing

Postdoctoral Research, Molecular Endocrinology - University of Texas Southwestern Medical Center, Dallas

Dr. Sen received his undergraduate degree in Microbiology with minor in Chemistry and Zoology from Bangalore University in 2000 followed by Masters degree in Biochemistry from University of Calcutta, India in 2002. Thereafter he joined the PhD program in Cell and Molecular Biology at West Virginia University, where he worked with Dr. Jorge Flores and Dr. Keith Inskeep. His PhD work focused on the intracellular mechanisms regulating the functions of corpus luteum, a transient endocrine gland that plays a vital role in reproduction by supporting pregnancy. Following his PhD in 2005, Dr. Sen moved to Michigan State University for a post-doctoral fellowship in Reproductive Endocrinology in the Department of Animal Sciences. At Michigan State University, he worked with Dr. George Smith on the role of a novel neuropeptide called Cocaine-and Amphetamine-Regulated Transcript on follicular development. Dr. Sen was also part of a research team that discovered a novel oocyte specific protein involved in early embryonic development. In 2008, Dr. Sen joined the laboratory of Dr. Stephen R Hammes in the Division of Endocrinology and Metabolism at University of Texas Southwestern Medical Center, Dallas for a second post-doctoral fellowship in Molecular Endocrinology and then in 2009 he moved from Dallas to Rochester in Upstate New York as Research Assistant Professor at University of Rochester Medical Center, Rochester. In 2015, Dr. Sen established his own laboratory and was promoted to Assistant Professor (Tenure Track) in the Department of Medicine, Division of Endocrinology and Metabolism at University of Rochester School of Medicine and Dentistry. He also held an Adjunct Faculty position at The College of Brockport, State University of New York and was visiting research scientist at the Center for Human Reproduction in New York City. In August of 2017, Dr. Sen joined the Reproductive and Developmental Sciences Program at Michigan State University. He currently holds an Assistant Professor position in the Department of Animal Sciences at MSU. Dr. Sen has two patents related to a cancer biomarker and an infertility treatment option in women. His research is currently funded by the National Institute of Health (NIH), Michigan State University, Ferring Pharmaceuticals and the Foundation for Reproductive Medicine. He has published more than 25 peer-reviewed manuscripts and invited-reviews in leading scientific journals such as Proceeding of the National Academy of Sciences of the United States of America (PNAS), Journal of Clinical Investigation, Nature Reviews Endocrinology, Journal of Biological Chemistry, Endocrinology and Molecular Endocrinology. Dr. Sen has been awarded the Endocrine Society’s Pfizer Early Career Investigator Award. He is also the recipient of the Endocrine Society’s outstanding abstract award, Larry Ewing trainee award from the Society for the Study of Reproduction as well as outstanding graduate student HERF fellowship from West Virginia University. Dr. Sen serves on NIH study sections and has served as an external expert for the French National Research Agency. He also serves as a reviewer for numerous scientific journals including FASEB, JBC, PLoS Genetics, Biology of Reproduction, Neuroscience and Developmental Biology. He is currently an Editorial Board member for Endocrinology and has previously served as an editorial board member for the Journal of Endocrinology and the Journal of Molecular Endocrinology. Dr. Sen has been invited to present his work in numerous international meetings, universities and pharmaceutical companies. Dr. Sen loves to cook and watch movies in his spare time.

RESEARCH INTEREST

The main focus of the lab is to understand the role of steroids and hormones in health and disease. Specifically, the lab is interested in understanding the cross-talk between steroid-induced extranuclear kinase signaling and intranuclear transcription and its downstream physiological effects. To elucidate this “outside-inside” communication of steroid signaling, we initially concentrated towards understanding androgen actions in ovarian physiology and female fertility. Through development of different ovarian cell-specific knockout mouse models our laboratory established for the first time that androgens play a critical role female fertility. The lab has further elucidated that the physiological effects of androgen are mediated through a synergistic action between the androgen receptor-mediated nuclear and extra-nuclear signaling and this phenomenon is highly conserved across tissues (ovary and prostate cancer) and species (mouse to humans). Most recently, we have turned our attention towards understanding steroid-induced epigenetic modulation. We are trying to understand how prenatal exposure to steroids and hormones in the form of maternal/fetal pathologies, nutritional deficits/excess, lifestyle choices/stress, as well as medical interventions, re-programs the epigenome that in turn alters the developmental course of the fetus or offspring leading to long-term harmful outcomes that often culminate in adult pathologies. We have created animal models for steroid hormone prenatal exposure and are studying the underlying mechanism(s) and its effect on metabolism and fertility. The lab uses a wide range of mouse models, primary cell culture and cell lines as well as cell and molecular techniques, genomic and physiological tools.

RESEARCH TOPICS

Currently there are three ongoing projects in the laboratory that are inter-connected, yet independent in nature.

Project 1: Steroid Signaling: Through the development of an ovarian granulosa cell -specific and oocyte-specific androgen receptor knockout mouse model our laboratory established for the first time that androgen actions regulating female fertility and follicle growth are mediated in large part through androgen receptors expressed in the ovarian granulosa cells (Mol Endo 2010, Nat Rev Endocrinol 2015). Furthermore, we reported (JBC 2010, JCI 2012, PNAS 2014, J Endocrinol 2014) that the physiological effects of androgen are mediated through a synergistic action between the androgen receptor-mediated nuclear and extra-nuclear signaling and this phenomenon is highly conserved across tissues (ovary and prostate cancer) and species (mouse to humans).

At present the primary focus of this project is to understand how steroids (estrogen, glucocorticoid and androgen) bring about epigenetic changes under normal and pathophysiological conditions and its physiological significance with respect to fertility and metabolism in women. We have found that in both mouse and human, steroids through membrane-initiated kinase signaling and nuclear actions regulate the expression and activity of various histone methylases and demethylases. Currently we are trying to understand the underlying mechanism by which steroids through epigenetic modulation regulates the expression of various genes and its long tern physiological implications in normal and in the developmental of pathophysiological conditions.

Project 2: Underlying mechanism of Anti-Müllerian Hormone in female fertility and its role in onco-fertility: The role of Anti-Müllerian hormone (AMH) across the female reproductive lifespan has only more recently come to light. In women, AMH is currently exclusively used as a diagnostic and/or prognostic marker for infertility and reproductive disorders like polycystic ovary syndrome (PCOS), diminished ovarian reserve (DOR) and primary ovarian insufficiency (POI). AMH is also routinely used as a predictor for ovarian reserve and ovarian response in fertility treatments. However, absence of mechanistic insights into AMH actions or knowledge of how AMH expression is regulated during follicular development is a significant limitation towards using AMH as a potential therapeutic option/target. Recently (Mol Cell Endocrinol 2016), we have reported that AMH is a stalling/inhibitory factor for folliculogenesis and ovulation and its actions are mediated at least in part through induction of two microRNAs, miR-181a and miR-181b, which target activin-receptor2A and adenylate cyclase-9, leading to decline in FSH signaling/sensitivity, ovarian gene expression and follicular growth. Moreover, as a proof of concept, we have shown that AMH pre-treatment of mice prior to superovulation improves oocyte yield and thus, AMH can, indeed, be a potential therapeutic option for women with low functional ovarian reserve. Currently the focus of this project is to determine the regulation of AMH expression in granulosa cells. Another aspect of this project is to investigate the role of AMH in onco-fertility.

Project 3: Obesity and Infertility: Obesity is detrimental to women's reproductive health. While the mechanisms of obesity related infertility are multi-factorial, obesity-induced hyperleptinemia is clearly a major contributing factor. Leptin actions affecting fertility are mediated both centrally (in the hypothalamus) and peripherally (in the ovary). Our studies are focused on the ovary, where leptin is known to directly alter ovarian function through mechanisms that to date, are unknown. Recently, we have shown that (Endocrinology 2016) in mouse and human samples elevated leptin levels associated with obesity induce the expression of a neuropeptide called CART (Cocaine and Amphetamine Regulated Transcript) in granulosa cells of follicles. CART negatively affects intra-cellular cAMP levels, MAPK signaling, and aromatase gene expression causing ovarian dysfunction and reduced fertility in both bovine and mouse models (Endocrinology 2007, Mol Endocrinology 2008 and Endocrinology 2016). We also found a significant positive correlation between IVF patient BMI and ovarian CART levels. Currently, work is under way to determine the regulation of CART expression in the ovary and its long-term effect on female fertility.  

RECENT PUBLICATIONS

  1. Xiaoting Ma, Emily Hayes, Anindita Biswas, Christina Seger, Hen Prizant, Stephen R Hammes, Aritro Sen. Androgen Induced Epigenetic Modulation in Mouse Ovaries Through Rapid and Long Term Inhibition of Ezh2. Endocrinology 2017.
  2. Emily Hayes, Vitaly Kushnir, Xiaoting Ma, Anindita Biswas, Hen Prizant, Norbert Gleicher, Aritro Sen. Intracellular mechanism of Anti-Müllerian Hormone (AMH) in regulation of follicular development. Molecular and Cellular Endocrinology, 2016 Sep 15;433:56-65.
  3. Xiaoting Ma, Emily Hayes, Hen Prizant, Rajesh K Srivastava, Stephen R Hammes, Aritro Sen. Leptin-induced CART (Cocaine-and Amphetamine-Regulated Transcript) is a novel intra-ovarian mediator of obesity-related infertility. 2016 Mar;157(3):1248-57.
  4. Sellix MT and Aritro Sen. Finding the Right Balance: Androgens at the Tipping Point of Fertility and Metabolism in Women. Endocrinology 2017 Mar1;158(3):467-469.
  5. Aritro Sen, Hen Prizant, Allison Light, Anindita Biswas, Emily Hayes, Ho-Joon Lee, David Barad, Norbert Gleicher, Stephen R Hammes. Androgens Regulate Ovarian Follicular Development by Increasing Follicle Stimulating Hormone Receptor and microRNA-125b Expression. Proc Natl Acad Sci U S A. 2014 Feb 25;111(8):3008-13.