Li Biosketch

BIOGRAPHICAL SKETCH

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

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

Scientific Appointments

Honors

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/