Peixin Yang, PhD

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.

Shen WB, Ni J, Yao R, Goetzinger KR, Harman C, Reece EA, Wang B, Yang P. Maternal obesity increases DNA methylation and decreases RNA methylation in the human placenta. Reprod Toxicol. 2022 Jan;107:90-96. doi: 10.1016/j.reprotox.2021.12.002. Epub 2021 Dec 7. PMID: 34890771

109. Guanlei Wang, Bingbing Wang, Peixin Yang. Epigenetics in congenital heart disease. Journal of American Heart Association, 2022 Apr 5;11(7):e025163. doi: 10.1161/JAHA.121.025163. Epub 2022 Mar 29. PMID: 35348004
110. Bin Wu, Yun Chen, Robert Clark, Emmanuel Akala, Peixin Yang, Bin He, Haijun Gao. AMPK signaling regulates mitophagy and mitochondrial ATP production in human trophoblast cell line BeWo. Frontiers in Bioscience-Landmark, 2022 Apr 1;27(4):118. doi: 10.31083/j.fbl2704118. PMID: 35468677
111. Wei-Bin Shen, Shifa Turan, Bingbing Wang, Liviu Cojocaru, Christopher Harman, James Logue, E. Albert Reece, Matthew B Frieman, Peixin Yang. A SARS-CoV-2 Delta variant case manifests massive placental infection and vertical transmission. Gynecologic and Obstetric Investigation, 2022 May 6. doi: 10.1159/000524905. Online ahead of print. PMID: 35526532
112. Songying Cao, Yanqing Wu, E. Albert Reece, Cheng Xu, Wei-Bin Shen, Sunjay Kaushal, Peixin Yang. Disruptive exosomal regulation and communication across the three germ layers in embryonic anomalies of diabetic pregnancy. Communications Biology, 2022 Jul 1;5(1):648. doi: 10.1038/s42003-022-03614-3. PMID: 35778435
113. Ruofan Yao, Penghua Yang, Katherine R Goetzinger, Kristin L Atkins, Wei-Bin Shen, Bingbing Wang, Peixin Yang. Maternal obesity-associated disruption of polarized lactate transporter MCT4 expression in human placenta. Reproductive Toxicology, 2022 Sep;112:1-6. doi: 10.1016/j.reprotox.2022.06.009. Epub 2022 Jun 22. PMID: 35750090.
114. Wei-Bin Shen, Bingbing Wang, Cheng Xu, Penghua Yang, Peixin Yang. Oxidative stress kinase signaling and impaired insulin receptor signaling precede overt Alzheimer’s disease pathology. Journal of Alzheimer’s Disease, 2022 Sep 26. doi: 10.3233/JAD-215687. Online ahead of print. PMID: 36189587
115. Wei-Bin Shen, James J. Yang, Peixin Yang. RNA hypomethylation and altered DNA methylation machinery in the cortex of ApoE4 carriers and Alzheimer’s disease subjects. Current Alzheimer Research, 2022 Aug 31. doi: 10.2174/1567205019666220831125142. Online ahead of print. PMID: 36045519
116. Jun-yi Zhu, Guanglei Wang, Xiaohu Huang, Hangnoh Lee, Jin-Gu Lee, Penghua Yang, Joyce van de Leemput, Weiliang Huang, Maureen A. Kane, Peixin Yang, Zhe Han. SARS-CoV-2 Nsp6 causes cardiac defects through MGA/MAX complex-1 mediated increased glycolysis. Communications Biology, 2022 Sep 30;5(1):1039. doi: 10.1038/s42003-022-03986-6. PMID: 36180527.
117. Bingbing Wang, Liviu Cojocaru, Wei-Bin Shen, Peixin Yang, Sifa Turan. SARS-CoV-2 infection induces activation of ferroptosis in human placenta. Frontiers in Cell and Developmental Biology, 2022 Nov 8;10:1022747. doi: 10.3389/fcell.2022.1022747. eCollection 2022. PMID: 36425527.
118. Gunasekaran M, Mishra R, Saha P, Morales D, Cheng WC, Jayaraman AR, Hoffman JR, Davidson L, Chen L, Shah AM, Bittle G, Fu X, Tulshyan A, Abdullah M, Kingsbury T, Civin C, Yang P, Davis ME, Bolli R, Hare JM, Sharma S, Kaushal S. Comparative efficacy and mechanism of action of cardiac progenitor cells after cardiac injury. iScience. 2022 Jun 22;25(8):104656. doi: 10.1016/j.isci.2022.104656. eCollection 2022 Aug 19. PMID: 35847554.
119. Wei-Bin Shen, Bingbing Wang, Ruofan Yao, Katherine R Goetzinger, Sheng Wu, Haijun Gao and Peixin Yang. Obesity impacts placental function through activation of p-IRE1a-XBP1s signaling. Frontiers in Cell and Developmental Biology. In press.
120. Xuebin Fu, Rachana Mishra, Ling Chen, Mir Yasir Arfat, Sudhish Sharma, Tami Kingsbury, Muthukumar Gunasekaran, Progyaparamita Saha, Charles Hong, Peixin Yang, Deqiang Li, Sunjay Kaushal. Exosomes Mediated Fibrogenesis in Dilated Cardiomyopathy Through a MicroRNA Pathway. iScience, online 13 January 2023, 105963. https://doi.org/10.1016/j.isci.2023.105963

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.

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

12/21/22-11/30/2027   YANG, PEIXIN (PD/PI)

                                   Intersection of the mTOR/p70S6K1 signaling and the HIPPO-Yap

                                   tissue organizer in neurulation and diabetic embryopathy           

                                   R01 HD108705-01A1

                                   Total Costs: $3,250,000

9/7/22-7/30/2026         YANG, PEIXIN (PD/PI)

                                    Heightened hypoxia and DNA methylation in heart defects of                                                   diabetic embryopathy

                                    R01HL160727

                                    Total Costs: $3,200,000

8/28/20-6/30/24         Peixin Yang (contact PI: 25%) and Sunjay Kaushal (MPI)

“HYPERGLYCEMIA OF MATERNAL DIABETES INDUCES CARDIAC ISL1 POSITIVE PROGENITOR DYSFUNCTION LEADING TO HEART DEFECTS”

                                   NIH/R01 HL153141

                                   Annual Direct Costs: $398,106

                                   Total Costs: $2,460,296

9/01/20 – 8/31/25      YANG, PEIXIN (PI), Albert Reece (MPI) and Wei-Bin Shen (MPI)

                                   NIH/R01HD099843

                                   Epitranscriptomic Alteration and Planar Cell Polarity Signaling In Diabetic Embryopathy           

                                   Total Costs: $3,412,189

5/7/14-2/28/2025       Peixin Yang (PI: 25%)

                                   “Autophagy and its Regulation in Diabetic Embryopathy”

                                   NIH/R01 HD102206

                                   Annual Direct Costs: $331,424

                                   Total Costs: $2,560,250

7/1/20-6/30/2024       Peixin Yang (PI: 25%)

                                   R01 HL151108

                                   “CELLULAR STRESS-INDUCED GENE DYSREGULATION IN HEART DEFECTS FORMATION OF DIABETIC PREGNANCY”

                                   Annual Direct Costs: $ 390,493

                                   Total Costs: $2,413,248

06/01/14-06/30/24     Peixin Yang (25%) (contact PI) and Albert Reece (MPI)

                                   “Molecular Signaling Pathways and Cellular Stress in Diabetic Embryopathy”

                                   NIH/1R01R01 HD100195

                                   Annual Direct Costs: $384,396

                                   Total Costs: about $2,969,458

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.

• 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