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Peixin Yang, PhD

Academic Title:

Professor

Primary Appointment:

Obstetrics, Gynecology and Reproductive Sciences

Secondary Appointment(s):

BioChemistry&Molecular Biology

Administrative Title:

Associate Chair for Research; Director of the Center for the Study of Birth Defects; Deputy Director of Graduate & Postdoctoral Studies

Location:

655 West Baltimore Street

Education and Training

  • 1986-1990 - B.S., Animal Science, Zhejiang Agricultural University, Zhejiang, P. R. China
  • 1990-1993 - M.S., Animal Reproductive Sciences, Nanjing Agricultural University, Nanjing, P. R. China
  • 1994-1999 - Ph.D., Biophysics, Tokyo University of Agriculture & Technology, Japan and Zhejiang University, P. R. China
  • 1999-2002 - University of Nebraska Medical Center, Postdoctoral Research Associate
  • 2008-2009 - BIRCWH scholar (NIH K12), University of Maryland Baltimore

 

Research/Clinical Keywords

Diabetic embryopathy, pregestational diabetes, neural tube defects, congenital heart defects, embryonic vasculopathy, stem cell therapy, autism

Highlighted Publications

Yang P, Zhao Z and Reece EA.  Activation of oxidative stress signaling implicated in apoptosis using a mouse model of diabetic embryopathy. American Journal of Obstetrics and Gynecology. 2008;198(1):130.e1-7.

Li X, Weng H, Xu C, Reece EA, Yang P. Oxidative Stress–Induced JNK1/2 Activation Triggers Proapoptotic Signaling and Apoptosis That Leads to Diabetic Embryopathy. Diabetes. 2012 Aug;61(8):2084-2092.

Li X, Xu C, Yang P. JNK1/2 and endoplasmic reticulum stress as interdependent and reciprocal causation in diabetic embryopathy. Diabetes. 2013;62:599-608.

Xu C, Li X, Wang F, Yang P. Trehalose prevents neural tube defects by correcting maternal diabetes-suppressed autophagy and neurogenesis. American Journal of Physiology Endocrinology and Metabolism. 2013 Sep 1;305(5):E667-678.

Yang P, Li X, Xu C, Reece EA, Eckert R, Zielke R, Wang F. Maternal hyperglycemia activates an ASK1–FoxO3a–Caspase 8 pathway that leads to embryonic neural tube defects. Science Signaling. 2013 Aug 27; 6(290):ra74,1-12.

Additional Publication Citations

Wang F, Wu Y, Gu H, Reece EA, Fang S, Gabbay-Benziv R, Aberdeen G, Yang P. Ask1 gene deletion blocks maternal diabetes-induced endoplasmic reticulum stress in the developing embryo by disrupting the unfolded protein response signalosome. Diabetes. 2015 Mar;64(3):973-988.

Yang P, Reece EA, Wang F, Gabbay-Benziv R. Decoding the oxidative stress hypothesis in diabetic embryopathy through pro-apoptotic kinase signaling. American Journal of Obstetrics and Gynecology. 2015 May;212(5):569-579.

Gu H, Yu J, Dong D, Zhou Q, Wang JY, Yang P. The miR-322-TRAF3 circuit mediates the pro-apoptotic effect of high glucose on neural stem cells. Toxicological Sciences. 2015 Mar;144(1):186-196.

Wu Y, Wang F, Fu M, Wang C, Quon MJ, Yang P. Cellular stress, excessive apoptosis and the effect of metformin in a mouse model of type 2 diabetic embryopathy. Diabetes. 64(7):2526-2536.

Wang F, Wu Y, Quon MJ, Li X, Yang P. ASK1 mediates the teratogenicity of diabetes in the developing heart by inducing ER stress and inhibiting critical factors essential for cardiac development. American Journal of Physiology, Endocrinology and Metabolism. 2015 Sep 1;309(5):E487-99.

Wang F, Fisher S, Zhong J, Wu Y, Yang P. Superoxide dismutase 1 in vivo ameliorates maternal diabetes-induced apoptosis and heart defects through restoration of impaired Wnt signaling. Circulation: Cardiovascular Genetics. 2015 Oct;8(5):665-76. PMID: 26232087.

He C , Mao D , Hua G , Lv X , Chen X , Angeletti P, Dong J , Remmenga S, Rodabaugh K, Zhou J, Lambert P, Yang P, Davis J. The Hippo/YAP pathway interacts with EGFR signaling and HPV to regulate cervical cancer progression. EMBO Molecular Medicine. 2015 Sep 28;7(11):1426-49, PMID: 26417066.

Wang F, Weng H, Quon MJ, Yu J, Wang JW, Hueber AO, Yang P. FADD dominant negative dissipates the proapoptotic signalosome of the unfolded protein response in diabetic embryopathy. American Journal of Physiology Endocrinology and Metabolism. 2015 Nov 15;309(10):E861-73, PMID: 26419589.

Gu H, Yu J, Dong D, Zhou Q, Wang JY, Fang S, Yang P. High glucose-induced CITED2 down-regulation through miR-200b triggers unfolded protein responses and endoplasmic reticulum stress in neural stem cells. Diabetes. 2016 Jan;65(1):149-63, PMID: 26450995. 

Penghua Yang; Shen WB; Reece EA; Chen X; Peixin Yang. High glucose suppresses embryonic stem cell differentiation into neural lineage cells. Biochemical and Biophysical Research Communications. 2016 Apr 1;472(2):306-12.

Dong D, Fu N, Yang P. MiR-17 down-regulation by high glucose stabilizes Thioredoxin-interacting protein and removes thioredoxin inhibition on ASK1 leading to apoptosis. Toxicol Sci. 2016 Mar;150(1):84-96, PMID: 26660634.

Yu J, Wu Y, Yang P. High glucose-induced oxidative stress represses sirtuin deacetylase expression and increases histone acetylation leading to neural tube defects. Journal of Neurochemistry. 2016 May;137(3):371-83, PMID: 26896748.

Zhong J, Xu C, Gabbay-Benziv R, Lin X, Yang P. Superoxide dismutase 2 overexpression alleviates maternal diabetes-induced neural tube defects, restores mitochondrial function and suppresses cellular stress in diabetic embryopathy. Free Radic Biol Med. 2016 Jul;96:234-44, PMID: 27130031

Dong D, Zhang Y, Wang L, Yang P.microRNA expression profiling and functional annotation analysis of their targets during murine embryonic heart development in diabetic pregnancies. Reproductive Toxicology. 2016, 65:365-374.

Research Interests

My research focuses on the molecular mechanism(s) and potential therapeutic approaches of maternal diabetes-induced neural tube defects and cardiovascular defects in the offspring. Currently, I am directing a multi-million NIH-funded research group. My laboratory has made original and significant contributions to the area of maternal diabetes-induced structural birh defects, particularly delineating the molecular mechanism(s) underlying neural tube defects and heart defects and revealing the therapeutic potential of several naturally occurring compounds. Specficially, we have been working the following area:

1. Decoding the oxidative stress hypothesis in diabetic embryopathy through pro-apoptotic kinase signaling.

A decade ago, equipped with a wealth of signaling transduction knowledge, I began to look at the role of pro-apoptotic c-Jun-N-terminal kinase 1/2 (JNK1/2) signaling in diabetic embryopathy. Using the superoxide dismutase 1 (SOD1) Tg mice, we demonstrated that maternal diabetes-induced oxidative stress causes JNK1/2 activation. The JNK1/2 pharmacological inhibitor, SP600125, ameliorated, whereas the JNK1/2 activator, sorbitol, mimics high glucose-induced NTDs. Furthermore, using JNK1 and JNK2 knockout (KO) mice, we provided molecular evidence to support the hypothesis that JNK1/2 activation plays a causal role in the induction of neural tube defects (NTDs) in diabetic pregnancies. JNK1/2 activation leads to activation of transcription factors, c-Jun, ATF2, Elk1 and FoxO3a, caspase 3, 8, and neuroepithelial cell apoptosis. Thus, I was the first one to demonstrate the causality of JNK1/2 in diabetic embryopathy (Biochem Biophys Res Commun 2007; Am J Obstet Gynecol 2008a, b, 2010, 2015; Diabetes 2012).

Impact: My laboratory is among the first to establish a mouse model of diabetic embryopathy. Using genetically modified mice, my group revealed the causal role of JNK1/2 in the induction of neural tube defects in diabetic pregnancies.

2. Unraveling the molecular intermediates upstream and downstream of JNK1/2.

After revealing the role of the JNK1/2 pathway, we focused on the upstream JNK1/2 kinase and the downstream transcription factor and responsive gene. We defined apoptosis signal-regulating kinase 1 (ASK1) as the upstream kinase that is responsible for JNK1/2 activation in diabetic embryopathy. Maternal diabetes-induced oxidative stress triggered ASK1 activation. Deleting the Ask1 gene significantly reduced activation of JNK1/2, FoxO3a, caspase activation and neuroepithelial cell apoptosis leading to NTD reduction. Deleting the FoxO3a gene also blocked the pro-apoptotic effect of maternal diabetes and inhibited NTD incidence. We further elucidated that TRADD, an adaptor protein of TNFa cell death receptor pathway, is a target gene of the ASK1-FoxO3a pathway. This data resulted in a high impact factor paper in Science Signaling, which was introduced by the top journal, Cell, in its section of Leading Edge in its September 26, 2013 issue. Our paper was featured in Science, signaling the August 27, 2013 issue’s cover, a podcast and many media outlets, and formulated the basis for US Patent Number: 12/779,935, entitled “Methods of Treating a Diabetic Embryopathy” (Sci Signal 2013; Diabetes 2015; Am J Obstet Gynecol 2010, 2015).

Impact: The studies lay a foundation for targeting the pro-apoptotic kinases, ASK1 and JNK1/2 as therapeutic targets of diabetic embryopathy.

3. Revealing cellular organelle stress as one of the cause of diabetic embryopathy.

My laboratory was the first group in elucidating the role of ER stress and impaired autophagy in diabetic embryopathy. ER stress was induced in neuroepithelial cells of embryos exposed to diabetes, and treatment with the ER stress inhibitor, 4-PBA, reduced high glucose-induced NTDs. We discovered the reciprocal relationship between JNK1/2 and ER stress in diabetic embryopathy. Autophagy is essential for embryonic neurulation. We found that maternal diabetes suppressed autophagy in neuroepithelial cells, and that restoring autophagy by trehalose, a natural disaccharide, resolved cellular homeostatic imbalance by inhibiting ER stress and mitochondrial dysfunction. Seminal studies using the SOD1 Tg mice demonstrated that maternal diabetes-induced nitrosative stress, lipidperoxidation and protein kinase C are linked to cellular organelle stress. These studies led to a US Provisional Patent Application Number: 61/651,189, entitled: “Use of Trehalose for Prevention of Neural Tube Defects” (Am J Obstet Gynecol 2012, 2013; Am J Physiol Endocrinol Metab 2013; Diabetes 2013).

Impact: These discoveries are entirely new and establish the involvement of cellular stress, endoplasmic reticulum stress and autophagy in neural tube defect formation induced by maternal diabetes.

4. Developing natural compounds as prevention for diabetic embryopathy.

My laboratory has developed a number of natural compounds that target maternal diabetes-induced oxidative stress, cellular organelle stress and the pro-apoptotic kinase signaling. Our studies revealed the protective effects of the green tea polyphenol, epigallocatechin-3-gallate, the autophagy activator, trehalose and a turmeric compound, curcumin, against high glucose-induced cellular stress, apoptosis and NTD formation. These findings provide an array of candidate natural compounds with minimal toxicities for the future development of dietary supplements against birth defects in human diabetic pregnancies (Am J Obstet Gynecol 2010, 2015).

Impact: These findingslay the solid foundation for the development of these natural compounds with minimal toxicities for potential dietary intervention in diabetic embryopathy.

5. Elucidating high glucose as a teratogen.

Using the whole-embryo culture system, we have been able to recapitulate maternal diabetes-induced NTDs in an ex vivo preparation. High glucose induces NTD formation by activating JNK1/2 and FoxO3a leading to neuroepithelial cell apoptosis. This ex vivo system also allowed us to study the impact of high glucose on vasculogenesis and establish the causal relationship between early vasculopathy and late structure anomalies. Maternal diabetes adversely affects neural stem cells in the developing neuroepithelium. Recently, we found that our in vivo findings were recapitulated in a neural stem cell line, C17.2 cell line, which enabled us to study the effect of high glucose on gene regulation. These findings collectively support that high glucose is a teratogen (Am J Obstet Gynecol 2008, 2011, 2015; Toxicological Sciences 2015).

Impact: These studies provide experimental evidence to support the hypothesis that high glucose of diabetes is the cause of diabetic embryopathy and set a foundation for clinical management of euglycemia in diabetic pregnancies.

6. Establishing a type 2 diabetic embryopathy model.

Due to the obesity epidemic, the number of type 2 diabetic women is increasing. We recently established high-fat diet-induced type 2 diabetic embryopathy, which could be inhibited by a type 2 diabetic drug, metformin, whose main function is to reduce blood glucose levels. In this type 2 diabetic embryopathy model, we recapitulated the findings in the type 1 diabetic embryopathy that oxidative stress-induced ER stress and neuroepithelial cell apoptosis are the cause of neural tube defects (Diabetes2015).

Impact: This study developed a suitable model for type 2 diabetic embryopathy model that is not associated with gene mutation and will greatly impact the field in faithfully reflecting type 2 human diabetic pregnancies.

7. Discovering the epigenetic mechanism in diabetic embryopathy.

I was the first investigator to reveal DNA hypermethylation and histone hyperacetylation as the cause of gene dysregulation in diabetic embryopathy (an ADA basic science award). We have linked pro-apoptotic kinase signaling to increased DNA methylation. My group also revealed the critical role of microRNA (miRNA) in maternal diabetes and high glucose-induced neural stem cell apoptosis. To further explore the role of miRNA in diabetes-induced birth defects, I have developed a robust program using miRNA knockout transgenic mice to test the critical involvement of several miRNAs in the etiology of neural tube defects and heart defects (Diabetes 2016 and Toxicological Sciences, 2015).

Impact: These studies bring in the epigenetic concept in the field of diabetic embryopathy.

8. Uncovering the molecular mechanism underling maternal diabetes-induced heart defects.

The field of maternal diabetes-induced heart defects is a significantly understudied area. Our recent studies revealed ASK1-induced ER stress and cardiomyocyte apoptosis as the cause of heart defects. Maternal diabetes induces oxidative stress in the developing heart leading to gene dysregulation. I have established a robust program in this area with several pending R01 applications and organizing a NIH P01 application (Circ Cardiovasc Genet 2015; Am J Physiol Endocrinol Metab 2015).

Impact: These studies significantly improving our understanding in the etiology of heart defects, the most common birth defects in human and lead to the establish of a robust and highly fundable program in heart defects.

Awards and Affiliations

4/2002-3/2003 - The Lalor foundation postdoctoral Fellowship ($3,0000)

1/2008-12/2009 - BIRCWH scholar ($92,593/year, for two years)

2013 - The F. Clarke Fraser New Investigator Award, the Teratology Society.

2013-2018 - Editorial Board, Reproductive Toxicology

7/2013-present - Editorial Board, American Journal of Physiology (Endocrinology and Metabolism)

7/2013-present - Board of Reviewing Editors, Biology of Reproduction

2015-2019 - Regular member of  the Pregnancy and Neonatology Study Section, NIH

Grants and Contracts

03/01/10-02/28/20
Peixin Yang (PI)
"Apoptotic Mechanism of Maternal Diabetes-Induced Neural Tube Defects"
NIH/R01 DK083243 (No Cost Extension)

03/01/14-2/28/18
Peixin Yang (PI)
"Autophagy and its Regulation in Diabetic Embryopathy"
NIH/R01DK101972-01

8/1/16-3/31/20
Peixin Yang (PI)
"Maternal Diabetes-Suppressed Vascular Signaling Induces Vasculopathy and Neural Tube Defects"
NIH/1R01HL131737-01

06/01/14-06/30/18
Peixin Yang (multiple-PI, contact)
"Molecular Signaling Pathways and Cellular Stress in Diabetic Embryopathy"
NIH/1R01DK103024-01

In the News

Other Brief Communications

  1. Narasimhan SD. Eat to Live or Live to Eat? A Little Sugar Goes A Long Way. Cell. 2013 Sep 26;155:5. (Yang P revised the commentary and provided a figure. This commentary introduces our Science Signaling paper 2013 August 27; 6(290):ra74,1-12).

Published Multimedia

  1. Yang P, Reece EA, VanHook AM. Science Signaling Podcast: 2013 Aug 27. Science Signaling. 2013 Aug;6(290):pc22.
  2. UMSOM Research Could Result In New Approach to Prevent Diabetes-Induced Birth Defects. University of Maryland Medical Center News Releases, 2013 Aug 28.
  3. Research Could Result In New Approach To Prevent Diabetes-Induced Birth Defects. University of Maryland School of Medicine News & Events, 2013 Aug 28.
  4. New approach to prevent diabetes-induced birth defects. ScienceDaily, 2013 Aug 28.
  5. Potential new approach to prevent diabetes-induced birth defects. Latest Diabetes Medicine Research & News, 2013 Aug 28.
  6. New Therapy Could Decrease the Risk of Diabetes Related Birth Defects. BabyMed, 2013 Sep 5.
  7. Univ. of Maryland research could result in new approach to prevent diabetes-induced birth defects. Live Network News (LNN), 2013 Aug 28.
  8. Study Data from University of Maryland Update Knowledge of Diabetes (Advances in Revealing the Molecular Targets Downstream of Oxidative Stress-Induced Proapoptotic Kinase Signaling in Diabetic Embryopathy). Health & Medicine Week, 2015 Aug 28.

Previous Experience

 

  • 9/06-6/13 - Assistant Professor (tenure-track), Department of Obstetrics and Gynecology & Reproductive Sciences, University of Maryland School of Medicine
  • 7/10-6/13 - Assistant Professor (tenure-track), secondary appointment, Department of Biochemistry & Molecular Biology, University of Maryland School of Medicine
  • 7/13-2015 - Associate Professor, Department of Obstetrics and Gynecology & Reproductive Sciences, University of Maryland School of Medicine
  • 7/13-2015 - Associate Professor, secondary appointment, Department of Biochemistry & Molecular Biology, University of Maryland School of Medicine
  • 2016-present - Professor with tenure, Department of Obstetrics and Gynecology & Reproductive Sciences, University of Maryland School of Medicine
  • 2016-present - Professor, secondary appointment, Department of Biochemistry & Molecular Biology, University of Maryland School of Medicine