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Li Biosketch

BIOGRAPHICAL SKETCH

NAME: Li, Ji
eRA COMMONS USERNAME (credential, e.g., agency login): DRJILI
POSITION TITLE: Professor of Physiology
EDUCATION/TRAINING  

INSTITUTION AND LOCATION	DEGREE (if applicable)	Completion Date MM/YYYY	FIELD OF STUDY
Lanzhou University, Lanzhou	B.S.	06/1989	Biochemistry
Lanzhou University, Lanzhou	M.S.	06/1992	Biophysics
Lanzhou University, Lanzhou	Ph.D.	06/1998	Cell Biology
Sichuan University, Chengdu	Postdoc	06/2000	Molecular Medicine
NIH/National Institute on Aging, Baltimore	Postdoc	03/2002	Signal Transduction
Yale School of Medicine, New Haven	Postdoc	06/2003	Physiology

Personal Statement

I have the expertise, leadership, training, expertise, and motivation necessary to successfully carry out the proposed research project. I have a broad background in biochemistry and physiology, with specific training and expertise in key research areas for physiology and pharmacology. I finished my postdoctoral fellowship at the National Institute on Aging (NIA/NIH) and at Yale School of Medicine. To complement my skills in basic science, I have acquired new skills in translational research and disease-oriented investigations by working extensively with established clinical investigators and by frequently attending Grand Rounds. As PI or Co- Investigator on several previous NIH-funded grants, I laid the groundwork for the proposed research by spearheading novel projects related to understanding a fundamental question regarding the cardiac metabolic alterations in the cardiovascular diseases and neurodegenerative diseases such as Alzheimer’s disease. In addition, I successfully administered the projects, collaborated with other researchers, and produced several peer-reviewed publications from each project. As a result of these previous experiences, I am aware of the importance of frequent communication among project members and of constructing a realistic research plan, timeline, and budget.

Ongoing and recently completed projects that I would like to highlight include:

R01AG049835
Li (PI)
07/15/15-06/30/21
AMPK Signaling in Response to Ischemic Insults in Aging

R01GM124108
Li (PI)
05/01/18-03/31/23
Activated Protein C and Cardiac Inflammatory Response

Citations:

1. Ma, H., Wang, J., Thomas, D.P., Tong, C., Leng, L., Wang, W.K., Merk, M., Zierow, S., Bernhagen, J., Ren, J., Bucala, R. & Li, J. (2010). Impaired macrophage migration inhibitory factor (MIF)-AMPK activation and ischemic recovery in the senescent heart. Circulation122:282-292. PMID: 20606117; PMCID: PMC2907453 (This paper has been selected by Circulation Editors’ Pick: Most Read Articles in Molecular Cardiology, Circulation, 124:e927, 2011)
2. Quan, N., Sun, W., Wang, L., Chen, X., Bogan, J.S., Zhou, X., Cates, C., Liu, Q., Zheng, Y. & Li, (2017). Sestrin2 prevents age-related intolerance to ischemia and reperfusion injury by modulating substrate metabolism. FASEB J31:4153-4167. PMID: 28592638 (Editorial Commentary: Levi, B. (2017). Science Translational Medicine 9(395):eaan194, DOI: 10.1126/scitranslmed.aan6194) PMID: 28637927
3. Wang, L., Quan, N., Sun, W., Chen, X., Cates, C., Rousselle, T., Zhou, X., Zhao, X., & Li, J. (2018) Cardiomyocyte specific deletion of Sirt1 gene sensitizes myocardium to ischemia and reperfusion injury.Cardiovascular Research 114:805-821. PMID: 29409011 (Editorial Commentary: Chen Q, Lesnefsky EJ, A new strategy to decrease cardiac injury in aged heart following ischaemia-reperfusion: enhancement of the interaction between AMPK and SIRT1. Cardiovascular Research 114:771-772, 2018). PMID: 29596586
4. Fatmi, M.K., Ren, D., Fedorova, J., Zoungrana, L.I., Wang, H., Davitt, K., Li, Z., Iglesias, M., Lesnefsky, E.J., Krause-Hauch, M. & Li, J. (2023) Cardiomyocyte Pdk4 response is associated with metabolic maladaptation in aging. Aging Cell22: e13800. PMID: 36797808

Positions, Scientific Appointments, and Honors Positions

2023-present	Co-Director, Mississippi Center for Heart Research, UMMC, Jackson, MS
2023-present	Professor, Department of Physiology and Biophysics, University of Mississippi Medical Center (UMMC), Jackson, MS
2019-2023	Professor, Department of Surgery, University of South Florida (USF), Tampa, FL
2015-2019	Associate Director, Mississippi Center for Heart Research, UMMC
2015-2019	Associate Professor, Department of Physiology and Biophysics, University of Mississippi Medical Center (UMMC), Jackson, MS
2009-2015	Assistant Professor, Department of Pharmacology and Toxicology, School of Medicine and Biomedical Sciences, University at Buffalo-SUNY, Buffalo, NY
2008-2009	Director, Center for Cardiovascular Research & Alternative Medicine, Univ. Wyoming
2007-2009	Assistant Professor, Division of Pharmaceutical Sciences, University of Wyoming School of Pharmacy, Laramie, WY
2003-2007	Associate Research Scientist, Division of Cardiovascular Medicine, Yale University School of Medicine, New Haven, CT
1992-1995	Instructor, Molecular Biology Laboratory, Cancer Research Center, Xiamen University, Xiamen, China

Scientific Appointments

2022-	Editorial Board Member, Diabetes (Wiley)
2021-	NIH Therapeutic Development and Preclinical Studies (TDPS) Study Section, ad hoc reviewer
2020-present	Member, Society for Redox Biology and Medicine (SfRBM)
2020-present	Associate Editor, Frontiers in Cardiovascular Medicine (Frontiers)
2020-2021	American Diabetes Association (ADA) Targeted COVID-19 Grant Review Panel, ad hoc reviewer
2016-	NIH Cardiac Contractility, Hypertrophy, and Failure (CCHF) Study Section, ad hoc reviewer
2016-	Department of Veterans Affairs (VA) Cardiovascular Studies-A (CARA) Study Section, ad hoc reviewer
2016-	NIH Surgery, Anesthesiology, and Trauma (SAT) Study Section, ad hoc reviewer
2016-2017	AHA Committee of Strategically Focus Research Network-Heart Failure, ad hoc reviewer

2015-2016	NIH Aging Systems and Geriatrics (ASG) Study Section, ad hoc reviewer
2015-	NIH Special Emphasis Panels ZDK1 GRB-7 (M1) 1, R13 Conference Grant Applications, ad hoc reviewer
2014-	DoD Peer Reviewed Medical Research Program, Discovery-Metabolic Disease (DIS-MD), ad hoc reviewer
2014-	NIH Special Emphasis Panels Zrg1 BDCN-L02 SEP, ad hoc reviewer
2014-	NIH Special Emphasis Panels Zrg1 BDCN-N02 M SEP, Cognition, Diabetic Neuropathy and Metabolomics, ad hoc reviewer
2013-	NIH Myocardial Ischemia and Metabolism (MIM) Study Section, ad hoc reviewer
2013-2016	Associate Editor, Life Sciences (Elsevier)
2013-2014	Associate Editor, PLoS Neglected Tropical Diseases (PLoS)
2010-2015	Member, American Society for Pharmacology & Experimental Therapeutics (ASPET)
2009-present	American Diabetes Association (ADA) Research Grant Review Committee, members
2008-present	Member, The Academy of Cardiovascular Research Excellence (ACRE)
2006-2011	Member, American Heart Association (AHA) Grant Review Committee: Cardiology Regulation
2005-present	Member, American Diabetes Association (ADA)
2003-present	Member, American Heart Association and American Stroke Association (AHA/ASA)
2000-2003	Member, American Society for Biochemistry and Molecular Biology (ASBMB)

Honors

2016	Gold level of the Excellence in Research Awards, University of Mississippi Medical Center
2014-2015	American Heart Association (AHA) Innovative Research Award
2009	New Investigator Award, University of Wyoming, Laramie, WY
2009	Seed Award, College of Health Sciences, University of Wyoming, Laramie, WY
2008	Participant, 16th Annual Summer Training Course in Experimental Aging Research/NIH, June 14-19, Seattle, WA
2008-2013	American Heart Associate (AHA) National Scientist Development Award
2006	Travel Award for the American Heart Association (AHA) Scientific Session, Chicago, IL
2002	NIH FARE (Fellow Award for Research Excellence) Award, Bethesda, MD

 

Contributions to Science

1. Oxidative stress signaling pathways. My early publications directly addressed the fact that natural antioxidants extracted from herb medicine can inhibit proliferation and induce apoptosis of tumor cells via modulating intracellular redox status. At the cellular level, oxidants elicit a wide spectrum of responses ranging from proliferation to growth arrest, to senescence, to death. The particular outcome observed varies significantly with cell type and conditions, but largely reflects the strength of the stimulus and the balance between the activities of a variety of signaling pathways that are activated. The mitogen-activated protein (MAP) kinases play a central role in orchestrating many short- and long-term changes in the cell in response to extracellular stimuli. The fact that a broad variety of extracellular signals conscript MAP kinase cascades to convey their specific messages suggests that MAP kinase cascades serve a myriad of purposes and the cascades need to be tightly controlled. The activities of all MAP kinases are regulated through reversible phosphorylation of two different amino acid residues in the Thr-Xaa-Tyr signature motifs in their kinase subdomain. In mammalian cells, inactivation of MAP kinases is primarily conducted by a family of dual-specificity MAP kinase phosphatases (MKPs) with MKP-1 being the archetype. By providing evidence and simple clinical approaches, this body of work has provided MKP-1 as a negative regulator of the macrophage inflammatory response and as a potential target for the development of anti-inflammatory drugs in relevant medical settings well into the future. I served as the primary investigator or co- investigator in all these

1. Li, J., Gorospe, M., Hutter, D., Barnes, J., Keyse, S.M. & Liu, Y. (2001) Transcriptional induction of MKP-1 in response to stress is associated with histone H3 phosphorylation/acetylation. Mol Cell Biol21: 8213-8224. PMID: 11689710; PMCID: PMC99986
2. Li, J., Gorospe, M., Barnes, J. & Liu, Y. (2003) Tumor promoter arsenite stimulates histone H3 phosphoacetylation of proto-oncogenes c-fos and c-jun chromatin in human diploid fibroblasts. J Biol Chem278:13183-13191. PMID: 12547826
3. Wang, J., Ma, H., Tong, C., Zhang, H., Lawlis, G.B., Li, Y., Zang, M., Ren, J., Nijland, M., Ford, S.P., Nathanielsz, P.W. & Li, J. (2010) Overnutrition and maternal obesity in sheep pregnancy alter the JNK-IRS-1 signaling cascades and cardiac function in the fetal heart. FASEB J24:2066-2076. PMID: 20110268; PMCID: PMC2874473
4. Han, Y., Sun, W., Ren, D., Zhang, J., He, Z., Fedorova, J., Sun, X., Han, F., & Li, J. (2020) SIRT1 agonism modulates cardiac NLRP3 inflammasome through pyruvate dehydrogenase during ischemia and reperfusion. Redox Biol34: 101538, PMID: 32325423; PMCID: PMC7176991

     2. AMPK signaling in ischemic heart. In addition to the contributions described above, with a team of collaborators, I directly documented the effects of macrophage migration inhibitor factor (MIF) on cardiac AMP-activated protein kinase (AMPK) activity. This work allowed us to demonstrate definitively that small molecular compounds of MIF agonist can trigger cardiac AMPK signaling and limit cardiac ischemic damage by augmentation of the affinity between MIF and its receptor, CD74. These original results inform our thinking of how cardiac AMPK signaling pathways respond to MIF and other endogenous cytokines, and they have significant mechanistic and physiological implications. We revealed that a stress inducible protein, Sesn2, serves as a scaffold protein mediating ischemic AMPK activation through recruiting upstream LKB1 in the heart.

1. Li, J., Miller, E.J., Ninomiya-Tsuji, J., Russell, R.R. & Young, L.H. (2005) AMP-activated protein kinase activates p38 mitogen-activated protein kinase by increasing p38 MAPK recruitment to TAB1 in the ischemic heart. Circ Res97:872-879. PMID: 16179588
2. Miller, E.J.*, Li, J.*, Leng, L., McDonald, C., Atsumi, T., Bucala, R. & Young, L.H. (*equal contribution). (2008). Macrophage migration inhibitory factor stimulates AMP-activated protein kinase. Nature451:578-582. PMID:18235500
3. Wang, J., Tong, C., Yan, X., Yeung, E., Gandavadi, S., Hare, A.A., Du, X., Chen, Y., Xiong, H., Ma, , Leng, L., Young, L.H., Jorgensen, W.L., Li, J.* & Bucala, R.* (*Corresponding authors) (2013) Limiting cardiac ischemic injury by pharmacologic augmentation of MIF-AMPK signal transduction. Circulation128:225-236. PMID: 23762877; PMCID: PMC3781594
4. Morrison, A., Chen, L., Wang, J., Zhang, M., Yang, H., Ma, Y., Budanov, A., Lee, J.H., Karin, M. & Li, J. (2015) Sestrin2 promotes LKB1-mediated AMPK activation in the ischemic heart. FASEB J29:408-417. PMID: 25366347; PMCID: PMC4314228

   3. The application of AMPK agonist for cardiovascular diseases. I have been successful in building comprehensive models for the cardioprotection of AMPK against myocardial infarction caused by ischemia and reperfusion. My research has been able to explain the kinetic mechanisms by which endogenous cytokines modulate cardiac AMPK signaling pathways and to characterize the role of protease activated receptor-1 in the endogenous activated protein C (APC) mediated cardioprotection against ischemic injury. We also identified that antidiabetic drugs such as rosiglitazone, empagliflozin and metformin benefit heart’s contractile functions under pathological conditions through activation of cardiac AMPK signaling that maintains cardiac metabolic homeostasis and mitochondrial integrity.

1. Morrison, A., Yan, X., Tong, C. & Li, J. (2011) Acute rosiglitazone treatment is cardioprotective against ischemia/reperfusion injury by modulating AMPK, Akt, and JNK signaling in non-diabetic mice. Am J Physiol-Heart Cir Physiol301:H895-H902. PMID: 21666107
2. Li, J., Qi, D., Cheng, H., Hu, X., Miller, E.J., Wu, X., Russell, K.S., Mikush, N., Zhang, J., Xiao, L., Sherwin, R.S. & Young, L.H. (2013) Urocortin 2 autocrine/paracrine and pharmacologic effects to activate AMP-activated protein kinase in the heart.Proc Natl Acad Sci USA110:16133-16138.PMID: 24043794; PMCID: PMC3791748
3. Sun, X., Han, F., Lu, Q., Li, X., Ren, D., Zhang, J., Han, Y., Xiang, Y.K. & Li, J. (2020) Empagliflozin ameliorates obesity-related cardiac dysfunction by regulating Sestrin2-mediated AMPK-mTOR signaling and redox homeostasis in high-fat diet-induced obese mice. Diabetes69:1292-1305. PMID: 32234722
4. Li, Z., Wang, H., Zoungrana, L.I., James, A., Slotabec, L., Didik, S., Fatmi, M.K., Krause-Hauch, M., Lesnefsky, E.J. & Li, J. (2023) Administration of metformin rescues age-related vulnerability to ischemic insults through mitochondrial energy metabolism. Biochem Biophys Res Commun659: 46-53. Doi: 10.1016/j.bbrc.2023.04.004 PMID: 37031594. PMCID: PMC10190118

    4. Activated protein C signal transduction in the heart. Engineering of APC by site-directed mutagenesis provided a signaling selective APC mutant APC-2Cys that lack anticoagulant activity but retains normal cell signaling activities. This APC-2Cys mutant exerts multiple potent cytoprotective activities, which require the G-protein–coupled receptor, protease-activated receptor 1 (PAR1). We revealed a fundamental mechanism of APC’s cardioprotection against ischemic damage through AMP-activated protein kinase (AMPK) signaling, more recently, we further unveiled an intriguing phenomenon that administration of the recombinant APC can rescue the tolerance of the aged heart to ischemic insults during ischemia and reperfusion. We have generated a point mutation (EPCR^R84A/R84A) knock-in mouse model harboring a variant of EPCR (R84A) which lacks the ability to bind APC. EPCR^R84A/R84Amice provided clear evidence that EPCR is a critical mediator for APC/PAR1-AMPK signaling pathways in response to ischemic insults. The discovery will expand the importance of EPCR in regulating many pathophysiological processes and provide clues for the development of new therapeutic options to treat cardiovascular diseases.

1. Wang, J., Yang, L., Rezaie, A.R. & Li, J. (2011) Activated protein C protects against myocardial ischemia/reperfusion injury through AMP-activated protein kinase signaling. J Thromb Haemost9:1308-1317. PMID: 21535395
2. Ren, D., Quan, N., Fedorova, J., Zhang, J., He, Z. & Li, J. (2020) Sestrin2 modulates cardiac inflammatory response during ischemia and reperfusion. Redox Biol34: 101556. PMID: 32447260;PMCID: PMC7248240
3. Zhang, J., He, Z., Fedorova, J., Logan, C., Bates, L., Davitt, K., Le, V., Murphy, J., Li, M., Wang, M., Lakatta, E.G., Ren, D. & Li, J. (2021) Alterations in mitochondrial dynamics with age-related Sirtuin1/Sirtuin3 deficiency impair cardiomyocyte contractility. Aging Cell20: e13419. PMID: 34316536
4. Jovanovic, A., Xu, B., Zhu, C., Ren, D., Wang, H., Krause-Hauch, M., Abel, E.D., Li, J. & Xiang,Y.K. (2023) Characterizing adrenergic regulation of glucose transporter 4-mediated glucose uptake and metabolism in the heart. JACC: Basic to Translational Science.https://doi.org/10.1016/j.jacbts.2022.11.008

     5. Impaired AMPK signaling in age-related cardiovascular and Alzheimer’s disease. We have identified an anti-aging protein, Sirtuin 1 (SIRT1), which acts as a regulator of the cardiac AMPK signaling cascade. This new discovery calls attention to the possibility that cardiac SIRT1 could be a good pharmacological target for modulating the aging-related increases in susceptibility to ischemia and reperfusion mediated cardiac injury. This possibility has not been explored, and it motivates me to develop a new project to investigate the basis of the observed differences between young and aged hearts and to delineate the mechanisms that control the cardiac resistance to ischemic insults. We uncovered the impaired AMPK activation in aging could be due to AMPK upstream LKB1 hyperacetylation in the aged heart that lack of cardiac SIRT1 activity. The impaired AMPK activation in aging results in maladaptive metabolic response during pathological stress conditions including Alzheimer’s disease in aging.

1. Xu, B., Li, M., Wang, Y., Zhao, M., Morotti, S., Shi, Q., Wang, Q., Barbagallo, F., Teoh, J.P., Reddy, G.R., Bayne, E., Liu, Y., Shen, A., Puglisi, J.L., Ge, Y., Li, J., Grandi, E., Nieves-Clintron, M. & Xiang, Y.K. (2020) GRK5 controls SAP97-dependent cardiotoxic b1 andrenergic receptor-CaMKKIIsignaling in heart failure. Cir Res127:796-810. PMID: 32507058
2. Ren, D., He, Z., Fedorova, J., Zhang, J., Wood, E., Zhang, X., Kang, D.E. & Li, J. (2021) Sestrin2 maintains OXPHOS integrity to modulate cardiac substrate metabolism during ischemia and reperfusion. Redox Biol38: 101824. PMID: 33316744; PMCID: PMC7734306
3. Murphy, J., Le, T.N.V., Fedorova, J., Yang, Y., Krause-Hauch, M., Davitt, K., Zoungrana, L.I., Fatmi, M.K., Lesnefsky, E.J., Li, J. & Ren, D. (2022) The cardiac dysfunction caused by metabolic alterations in Alzheimer’s disease. Front Cardiovasc Med9: 850538. PMID: 35274014; PMCID:PMC8902161
4. Zoungrana, L.I., Krause-Hauch, M., Wang, H., Fatmi, M.K., Bates, L., Li, Z., Kulkarni, P., Ren, D. & Li, J. (2022) The interaction of mTOR and Nrf2 in neurogenesis and its implication in neurodegenerative diseases. Cells11: 2048. doi: 10.3390/cells11132048. PMID: 35805130. PMCID:PMC9265429.

 Complete List of Published Work in MyBibliography:

 https://www.ncbi.nlm.nih.gov/myncbi/1PUq_ZtsywmAt/bibliography/public/