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The Department of Obstetrics and Gynecology Division of Reproductive Sciences

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Jansson-Powell Lab


The placenta determines life-long health

Our research is focused on exploring the cellular and molecular mechanisms that regulate placental function in normal pregnancy and in pregnancy complications and to investigate the role of the placenta in determining fetal growth and long-term health. We employ physiological, molecular and translational approaches, ranging from functional and molecular studies to interventions in high-risk human pregnancies. Our lab utilizes a wide variety of model systems including primary human trophoblast cells and explants, human placental tissue, mice, rats, and non-human primates. A large body of evidence shows that diseases of major importance to public health, including obesity, diabetes and cardiovascular disease originate in early life. In particular, changes in fetal nutrient availability and growth have been shown to strongly associate with chronic diseases in adult age. Fetal nutrient availability is largely controlled by placental function and we have proposed that placental nutrient sensing, a novel function of the placenta, determines life-long health.
 
Achievements:
Thomas Jansson    
The 2005 International Federation of Placenta Associations (IFPA) award 'in recognition of outstanding contributions to the field of placentology'
 
Theresa Powell
Giorgio Pardi Foundation Senior Scientist Award (Society for Gynecologic Investigation, 2010)
 
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Normal fetal growth and development are dependent on nutrient availability, which is a critical 
function of the placenta Both inadequate and excess fetal nutrition lead to the development of pregnancy complications, such as intrauterine growth restriction (IUGR) and fetal overgrowth. Epidemiological data suggests that pathological fetal growth, and therefore altered placental function, increases the risk of obesity, diabetes, cardiovascular disease and cancer in adult life. This offers unprecedented opportunities to develop novel strategies targeting the placenta to treat complications in pregnancy and to prevent the development of disease in childhood and in adult life.  However the underlying mechanisms remain elusive. Our research program addresses this significant gap in knowledge. In particular, we systematically study placental function in animal models and in the human.
 

 
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Faculty:
Thomas Jansson, MD/PhD, Professor, Principal Investigator
Theresa Powell, PhD, Professor, Principal Investigator
Frederick Rosario Joseph, PhD, Instructor
Veronique Ferchaud-Roucher, PhD, Visiting Scientist 
 
Professional Research Assistants:
Anita Kramer, BS, Senior PRA, Lab Manager
Nate Anderson, BS, Senior PRA, Animal Lab Manager
Soumini Vasan, MS
Brian Jang, BA
 
Post-Doctoral Fellows:
Priyadarshini Pantham, PhD
Paige Cooper, PhD
Yi-Yung Chen, MD, Visiting Scientist
 
Clinical Fellows:
Natalia Grindler, MD
Rebecca Jessel, MD
Stephanie Skuby, MD
Megan Gossling, MD

Placental insufficiency is more than decreased blood flow. 

A lack of normal increase of maternal placental blood flow (sometimes referred to as “placental insufficiency”) constitutes the most common cause of intrauterine growth restriction in Western societies.
We demonstrate
d that IUGR is associated with down-regulation of specific placental nutrient transporters in humans and animal models. This finding directly supported the emerging concept that placental responses to reduced placental blood flow are highly complex and, in fact, contribute directly to reduced fetal growth.
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Discovery of novel regulators of amino acid transporters.

Following our demonstration that IUGR and fetal overgrowth are associated with specific changes in placental nutrient transport activity, we performed a number of studies in animal models and primary human cultured trophoblast to identify factors regulating key placental nutrient transporters. This work led to the discoveries that placental amino acid transporters are regulated by leptin, adiponectin and mTOR signaling. Using siRNA to target specific genes in primary human trophoblast cells, we demonstrated that post translational mechanisms under the influence of mTOR Complex 1 and 2 regulate trophoblast amino acid transporters.




Placental nutrient sensing model.

We have developed a novel model for regulation of placental function highlighting maternal signals that impinge upon the syncytiotrophoblast, the placental epithelium, due to the intimate contact with maternal blood.  Formerly the placenta was thought to be regulated predominantly by the fetus and that the fetus acts as a parasite.  We propose that the placenta integrates a multitude of maternal and fetal nutritional cues through intrinsic nutrient sensing signaling pathways to match fetal growth rates with the maternal ability to supply nutrients.  This complex integration of maternal physiology, placental growth and nutrient transport we have called placental nutrient sensing. This ensures optimal allocation of resources between the mother and the fetus to maximize the propagation of parental genes without jeopardizing maternal health. Thus, placental nutrient sensing modulates maternal-fetal resource allocation to increase the likelihood of reproductive success.  


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mTOR as a novel folate sensor.

We recently discovered that mTOR functions as a folate sensor. Folate deficiency in pregnant mice causes inhibition of mTOR Complex 1 and 2 in maternal tissues and in the placenta, decreased expression and activity of key amino acid transporters in the placental barrier and fetal growth restriction. Folate sensing by mTOR was demonstrated in cultured trophoblast cells and in human cell lines (HEK293 and MCF7). Thus, we identified a novel molecular link between folate availability and cell function and  propose that mTOR folate sensing in trophoblast cells matches placental nutrient transport and fetal growth to maternal folate status. In proliferating cells, including cancer cells, mTOR may modulate cell growth and proliferation in response to changes in folate availability.  


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A novel mouse model of obesity in pregnancy.
We have recently developed a novel mouse model of maternal obesity, which has important similarities with obesity in pregnant women, including up-regulation of placental transport functions and fetal overgrowth. We believe that this model will provide us with new tools to identify the mechanisms linking maternal obesity to poor fetal short and long-term outcomes.

DHA supplementation to improve placental function.

We are investigating potential strategies for therapeutic modulation of placental function in pregnancy that could allow for new treatment modalities.  We are working toward safe, well-tolerated and effective strategies such as improved omega 3 fatty acid status to modulate placental delivery of nutrients to the fetus and improve growth and optimize body composition.  These efforts are inspired by the need to break the vicious cycle between poor intra-uterine growth and life-long health risk. 

Adiponectin as a novel endocrine link between maternal adipose tissue and placental function.

Almost 2/3 of American women today enter pregnancy either overweight or obese and although many of these women have normal pregnancies there is an increased risk to have pregnancy complications such as fetal overgrowth. These children have a higher risk to develop obesity and diabetes. Adiponectin is a hormone that it is produced in adipose tissue and circulating levels of adiponectin are high in lean and low in obese individuals. We have discovered that adiponectin regulates placental function and in contrast to other tissues, adiponectin causes insulin resistance in the placenta.  In lean women with high adiponectin this results in a “physiological brake”  to prevent excess nutrient transfer to the baby. In obese pregnant women with low adiponectin too much nutrient is transferred to the baby, stimulating growth and fat deposition. We have recently reported that adiponectin supplementation prevents the excess placental delivery of nutrients to the fetus in obese mice and the fetus grows normally and has normal levels of sugar in the blood.

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R01DK089989-02        PI: Powell, Co-I: Jansson               
          04/01/2011- 9/30/2015
Maternal pro-inflammatory status in obesity regulates placental function
This project tests the central hypothesis that free fatty acids and cytokines such as IL-6 and TNF-alpha up-regulates placental amino acid transport in overweight and obese women mediated by placental TLR4 and STAT3 signaling. This mechanism could explain the fetal overgrowth, which is common in mothers with high BMI.

R01HD065007        Multi-PI: Powell and Jansson                   
          12/25/2010–11/30/2015 (NCE)
Adiponectin, placental nutrient transport and fetal growth
This project concerns the role of adiponectin in regulating placental function. The central hypothesis is that adiponectin decreases placental nutrient transport and fetal growth by inhibition of placental insulin signaling.

R24OD016724         PI: Jansson, Co-I: Powell                   
          6/1/2014– 5/31/2018
A novel mouse model of obesity in pregnancy
The objective of this project is to thoroughly characterize a new mouse model of obesity in pregnancy associated with fetal overgrowth and its links to the development of metabolic syndrome in the offspring.

R01HD078376        PI: Jansson, Co-I: Powell                   
          7/1/2014– 6/30/2019     
mTOR as a trophoblast folate sensor
The central hypothesis is that mTOR regulates trophoblast folate uptake and functions as a novel folate sensor mediated by the proton-coupled folate transporter (PCFT). 

R01HD068370        PI: Jansson, Co-I: Powell                   
          7/25/2011 – 6/30/2016
Molecular Mechanisms Regulating Placental Nutrient Transporters
We explore the role of mTOR signaling in the regulation of placental amino acid transporters. Specifically we test the hypothesis that both mTOR Complex 1 (mTORC1) and 2 (mTORC2) regulate placental amino acid transporter activity by affecting the plasma membrane trafficking of transporters. We further propose that the molecular mechanisms involved are distinct in that mTORC1 activation phosphorylates the E3 ubiquitin ligase Nedd4-2, which decreases transporter ubiquitination resulting in increased amino acid transporter expression at the cell surface whereas mTORC 2 activation stimulates the actin skeleton mediated by PKCa.

PO1HD021350-A1 (PI Nathanielsz), Sub project 1          PI: Jansson              
          2/1/2014– 1/31/2019
Mechanisms of placental nutrient sensing in the baboon
We will test the hypothesis that inhibition of placental insulin/IGF-I, leptin and mTOR signaling constitute a key molecular link between maternal nutrient restriction, reduced fetal growth by down-regulation of placental nutrient transporters, which limits fetal supply of amino acids and methyl donors.
     
R03HD078313        Multi-PI: Jansson and Gupta                    
          3/1/2014– 2/28/2016     
IGFBP-1 hyperphosphorylation in IUGR: Role of mTOR and CK2
The central hypothesis in this mechanistic proposal is that inhibition of mTOR signaling and activation of protein kinase CK2 in the fetal liver constitutes a key molecular link between nutrient deprivation and increased IGFBP-1 secretion and phosphorylation in vitro and in IUGR in vivo.

R13HD084096         PI: Jansson                      
          03/16/2015 – 02/28/2020
Placenta Association of the Americas Conference Grant
This award supports an annual one-day conference as a satellite meeting the day before the Annual Scientific Meeting of the Society of Reproductive Investigation (SRI).

R01HD068370-06S1        PI: Jansson                      
          07/01/2015 – 06/30/2016
Molecular Mechanisms Regulating Placental Nutrient Transporters
The objective of the proposed supplement activities is to explore the metabolome of cultured primary human trophoblast cells, and its regulation by mTORC1 and mTORC2 signaling.
  1. Lager S, Ramirez VI, Gaccioli F, Jang B, Jansson T, Powell TL.  Protein expression of fatty acid transporter 2 is polarized to the trophoblast basal plasma membrane and increased in placentas from overweight/obese women.  Placenta. 2016; 40:60-6. 
  2. Rosario FJ, Dimasuay KG, Kanai Y, Powell TL, Jansson T. Regulation of amino acid transporter trafficking by mTORC1 in primary human trophoblast cells is mediated by the ubiquitin ligase Nedd4-2. Clinical Science. (London, England: 1979).  2016. 130 (7): 499-512. 
  3. Rosario FJ, Powell TL, Jansson T. Activation of placental insulin and mTOR signaling in a mouse model of maternal obesity is associated with fetal overgrowth.  American Journal of Physiology. Regulatory, integrative and comparative physiology.  2016. 310(1): R87-93.
  4. Chen YY, Rosario FJ, Shehab MA, Powell TL, Gupta MB, Jansson T. Increased ubiquitination and reduced plasma membrane trafficking of placental amino acid transporter SNAT-2 in human IUGR. Clinical Science.​ (London, England: 1979). 2015. 129(12):1131-41.
  5. Aye ILMH, Rosario F, Powell TL, Jansson T 2015. Adiponectin Supplementation in Pregnant Mice Prevents the Adverse Effects of Maternal Obesity on Placental Function and Fetal Growth. Proc Natl Acad Sci, 112:12858-63.
  6. Chen YY, Rosario F, Powell TL, Han VKM, Gupta MB, Jansson T 2015. Increased ubiquitination and reduced plasma membrane trafficking of placental amino acid transporter SNAT-2 in human. Clin Science 129(12):1131-41.
  7. Rosario F, Kanai, Y, Powell TL, Jansson T. 2015. Increased placental nutrient transport in a novel mouse model of maternal obesity with fetal overgrowth. Obesity, 23(8):1663-70.
  8. Lager S, Jansson T, Powell TL 2014 Differential regulation of placental amino acid transport by saturated and unsaturated fatty acids.  Am J Physiol Cell, 307:C738-44.
  9. Aye ILMH, Gao, X, Weintraub S, Jansson T, Powell TL 2014. Adiponectin inhibits insulin function in primary trophoblasts mediated by PPARα mediated ceramide synthesis. Mol Endo 4:512-24.
  10. Lager S, Gaccioli F, Ramirez V, Jones HN, Jansson T, Powell TL 2013. Oleic acid stimulates System A amino acid transport in primary human trophoblast cells mediated by Toll-Like Receptor 4. J Lip Res 54:725-33.