Profile

Inflammation is the main mechanism of diseases caused by microbial, autoimmune, metabolic, and physical insults. In fact, we estimate that inflammation mediates over 80% of all major human diseases, including heart attacks, strokes, microbial diseases, metabolic and degenerative diseases, and early cancer. Proinflammatory cues are sensed by pattern recognition receptors such as Toll-like Receptors (TLRs) that are mainstays of innate immunity. These receptors generate signals that are transduced to the nucleus by an intricate network of intracellular adaptors. 

The family of adaptors of longstanding interest to us are importins or karyopherins that transport transcription factors (MW >45 kD) to the nucleus. We provided initial evidence that targeting these adaptors with cell-penetrating peptides termed Nuclear Transport Modifiers (NTM) displaces nuclear import cargo from its binding pocket on importin alpha 5. Thus,  nuclear delivery of proinflammatory transcription factors such as NFkappa B, AP-1, NFAT, and STAT-1 can be attenuated. Hence, proinflammatory reprogramming of the genome is prevented in multiple cells reducing production of inflammatory, procoagulant, proapoptotic, and autoimmune mediators. We accomplished this outcome by designing an innovative platform for intracellular delivery of peptides and proteins that bypass endosomal pathway with its degradative potential.

We have proven the utility of NTM peptides  in preclinical models of septic/toxic shock and in acute lung inflammation caused by bacterial lipopolysaccharide and superantigen as well as in chronic autoimmune diabetes model that mimics Type 1 diabetes. Identification of  importin beta 1 as the second target for NTM peptides led to the subsequent discovery that these NTM peptides also impede nuclear transport of the metabolic regulators, termed Sterol Regulatory Elements Binding Proteins (SREBPs), resulting in a striking decline of cholesterol, triglycerides, and glucose in blood, reduction of fatty liver and atherosclerosis, and prevention of body weight gain in High-Fat Diet –fed animals that mimic the key features of the metabolic syndrome afflicting millions of Americans. Cumulatively, these basic and translational studies provided a firm basis for the transcriptional paradigm of inflammation. 

We also continue our studies of intracellular protein therapy designed as a facile alternative of gene therapy. We have proven the utility of intracellular protein therapy by bioengineering and delivering physiologic suppressor of cytokine signaling 3 (SOCS3) to prevent or treat acute liver inflammation and apoptosis induced by microbial agents in preclinical models. Subsequently, we designed and studied recombinant cell-penetrating suppressor of cytokine signaling 1 (SOCS1) that targets interferon gamma signaling pathway. We discovered a new physiologic function for the adaptor protein CRADD/RAIDD in endothelial cells as anti-inflammatory regulator of vascular inflammation induced by thrombin and endotoxin, and designed its cell-penetrating form (CP-CRADD) to suppress endothelial activation and injury.  

Cumulatively, these studies led to 14 patents owned by Vanderbilt University.

Publications

The following timeline graph is generated from all co-authored publications.

Featured publications are shown below:

  1. New paradigms in sepsis: from prevention to protection of failing microcirculation. Hawiger J, Veach RA, Zienkiewicz J (2015) J Thromb Haemost 13(10): 1743-56
    › Primary publication · 26190521 (PubMed) · PMC5014149 (PubMed Central)
  2. The "genomic storm" induced by bacterial endotoxin is calmed by a nuclear transport modifier that attenuates localized and systemic inflammation. DiGiandomenico A, Veach RA, Zienkiewicz J, Moore DJ, Wylezinski LS, Hutchens MA, Hawiger J (2014) PLoS One 9(10): e110183
    › Primary publication · 25329889 (PubMed) · PMC4203769 (PubMed Central)
  3. The adaptor CRADD/RAIDD controls activation of endothelial cells by proinflammatory stimuli. Qiao H, Liu Y, Veach RA, Wylezinski L, Hawiger J (2014) J Biol Chem 289(32): 21973-83
    › Primary publication · 24958727 (PubMed) · PMC4139214 (PubMed Central)
  4. Targeting nuclear import shuttles, importins/karyopherins alpha by a peptide mimicking the NFκB1/p50 nuclear localization sequence. Zienkiewicz J, Armitage A, Hawiger J (2013) J Am Heart Assoc 2(5): e000386
    › Primary publication · 24042087 (PubMed) · PMC3835248 (PubMed Central)
  5. The innate immunity adaptor SARM translocates to the nucleus to stabilize lamins and prevent DNA fragmentation in response to pro-apoptotic signaling. Sethman CR, Hawiger J (2013) PLoS One 8(7): e70994
    › Primary publication · 23923041 (PubMed) · PMC3726548 (PubMed Central)
  6. Nuclear transport modulation reduces hypercholesterolemia, atherosclerosis, and fatty liver. Liu Y, Major AS, Zienkiewicz J, Gabriel CL, Veach RA, Moore DJ, Collins RD, Hawiger J (2013) J Am Heart Assoc 2(2): e000093
    › Primary publication · 23563994 (PubMed) · PMC3647260 (PubMed Central)
  7. Cutting edge: the "death" adaptor CRADD/RAIDD targets BCL10 and suppresses agonist-induced cytokine expression in T lymphocytes. Lin Q, Liu Y, Moore DJ, Elizer SK, Veach RA, Hawiger J, Ruley HE (2012) J Immunol 188(6): 2493-7
    › Primary publication · 22323537 (PubMed) · PMC3294148 (PubMed Central)
  8. How to approach genome wars in sepsis? Hawiger J, Musser JM (2011) Crit Care 15(6): 1007
    › Primary publication · 22136332 (PubMed) · PMC3388672 (PubMed Central)
  9. In vivo islet protection by a nuclear import inhibitor in a mouse model of type 1 diabetes. Moore DJ, Zienkiewicz J, Kendall PL, Liu D, Liu X, Veach RA, Collins RD, Hawiger J (2010) PLoS One 5(10): e13235
    › Primary publication · 20949090 (PubMed) · PMC2950856 (PubMed Central)
  10. Extended anti-inflammatory action of a degradation-resistant mutant of cell-penetrating suppressor of cytokine signaling 3. Fletcher TC, DiGiandomenico A, Hawiger J (2010) J Biol Chem 285(24): 18727-36
    › Primary publication · 20400504 (PubMed) · PMC2881796 (PubMed Central)
  11. Intracellular delivery of a cell-penetrating SOCS1 that targets IFN-gamma signaling. DiGiandomenico A, Wylezinski LS, Hawiger J (2009) Sci Signal 2(80): ra37
    › Primary publication · 19622834 (PubMed) · PMC2798805 (PubMed Central)
  12. Suppression of acute lung inflammation by intracellular peptide delivery of a nuclear import inhibitor. Liu D, Zienkiewicz J, DiGiandomenico A, Hawiger J (2009) Mol Ther 17(5): 796-802
    › Primary publication · 19259070 (PubMed) · PMC2835128 (PubMed Central)
  13. Fractalkine and CX3CR1 mediate leukocyte capture by endothelium in response to Shiga toxin. Zanchi C, Zoja C, Morigi M, Valsecchi F, Liu XY, Rottoli D, Locatelli M, Buelli S, Pezzotta A, Mapelli P, Geelen J, Remuzzi G, Hawiger J (2008) J Immunol 181(2): 1460-9
    › Primary publication · 18606701 (PubMed)
  14. Granulocyte-macrophage colony-stimulating factor regulates effector differentiation of invariant natural killer T cells during thymic ontogeny. Bezbradica JS, Gordy LE, Stanic AK, Dragovic S, Hill T, Hawiger J, Unutmaz D, Van Kaer L, Joyce S (2006) Immunity 25(3): 487-97
    › Primary publication · 16949316 (PubMed)
  15. Intracellular protein therapy with SOCS3 inhibits inflammation and apoptosis. Jo D, Liu D, Yao S, Collins RD, Hawiger J (2005) Nat Med 11(8): 892-8
    › Primary publication · 16007096 (PubMed)
  16. Interactive sites in the MyD88 Toll/interleukin (IL) 1 receptor domain responsible for coupling to the IL1beta signaling pathway. Li C, Zienkiewicz J, Hawiger J (2005) J Biol Chem 280(28): 26152-9
    › Primary publication · 15849357 (PubMed)
  17. Nuclear import of proinflammatory transcription factors is required for massive liver apoptosis induced by bacterial lipopolysaccharide. Liu D, Li C, Chen Y, Burnett C, Liu XY, Downs S, Collins RD, Hawiger J (2004) J Biol Chem 279(46): 48434-42
    › Primary publication · 15345713 (PubMed)
  18. Suppression of Staphylococcal Enterotoxin B-induced Toxicity by a Nuclear Import Inhibitor. Liu D, Liu XY, Robinson D, Burnett C, Jackson C, Seele L, Veach RA, Downs S, Collins RD, Ballard DW, Hawiger J (2004) J Biol Chem 279(18): 19239-46
    › Primary publication · 14732709 (PubMed)
  19. Receptor/transporter-independent targeting of functional peptides across the plasma membrane. Veach RA, Liu D, Yao S, Chen Y, Liu XY, Downs S, Hawiger J (2004) J Biol Chem 279(12): 11425-31
    › Primary publication · 14699109 (PubMed)
  20. Innate immunity and inflammation: a transcriptional paradigm. Hawiger J (2001) Immunol Res 23(2-3): 99-109
    › Primary publication · 11444396 (PubMed)
  21. Peptide-directed suppression of a pro-inflammatory cytokine response. Liu XY, Robinson D, Veach RA, Liu D, Timmons S, Collins RD, Hawiger J (2000) J Biol Chem 275(22): 16774-8
    › Primary publication · 10751381 (PubMed)
  22. IkappaB kinase complex is an intracellular target for endotoxic lipopolysaccharide in human monocytic cells. Hawiger J, Veach RA, Liu XY, Timmons S, Ballard DW (1999) Blood 94(5): 1711-6
    › Primary publication · 10477696 (PubMed)
  23. Noninvasive intracellular delivery of functional peptides and proteins. Hawiger J (1999) Curr Opin Chem Biol 3(1): 89-94
    › Primary publication · 10021415 (PubMed)
  24. Regulation of NF-kappa B, AP-1, NFAT, and STAT1 nuclear import in T lymphocytes by noninvasive delivery of peptide carrying the nuclear localization sequence of NF-kappa B p50. Torgerson TR, Colosia AD, Donahue JP, Lin YZ, Hawiger J (1998) J Immunol 161(11): 6084-92
    › Primary publication · 9834092 (PubMed)
  25. Cellular import of functional peptides to block intracellular signaling. Hawiger J (1997) Curr Opin Immunol 9(2): 189-94
    › Primary publication · 9099795 (PubMed)
  26. Identification of a functionally important sequence in the cytoplasmic tail of integrin beta 3 by using cell-permeable peptide analogs. Liu XY, Timmons S, Lin YZ, Hawiger J (1996) Proc Natl Acad Sci U S A 93(21): 11819-24
    › Primary publication · 8876221 (PubMed) · PMC38142 (PubMed Central)
  27. Role of the nuclear localization sequence in fibroblast growth factor-1-stimulated mitogenic pathways. Lin YZ, Yao SY, Hawiger J (1996) J Biol Chem 271(10): 5305-8
    › Primary publication · 8621379 (PubMed)
  28. Lipopolysaccharide induces phosphorylation of MAD3 and activation of c-Rel and related NF-kappa B proteins in human monocytic THP-1 cells. Cordle SR, Donald R, Read MA, Hawiger J (1993) J Biol Chem 268(16): 11803-10
    › Primary publication · 8505309 (PubMed)
  29. Proteolytic processing of NF-kappa B/I kappa B in human monocytes. ATP-dependent induction by pro-inflammatory mediators. Donald R, Ballard DW, Hawiger J (1995) J Biol Chem 270(1): 9-12
    › Primary publication · 7814425 (PubMed)
  30. Inhibition of nuclear translocation of transcription factor NF-kappa B by a synthetic peptide containing a cell membrane-permeable motif and nuclear localization sequence. Lin YZ, Yao SY, Veach RA, Torgerson TR, Hawiger J (1995) J Biol Chem 270(24): 14255-8
    › Primary publication · 7782278 (PubMed)
  31. Cell-free pool of CD14 mediates activation of transcription factor NF-kappa B by lipopolysaccharide in human endothelial cells. Read MA, Cordle SR, Veach RA, Carlisle CD, Hawiger J (1993) Proc Natl Acad Sci U S A 90(21): 9887-91
    › Primary publication · 7694295 (PubMed) · PMC47677 (PubMed Central)
  32. Prostacyclin inhibits mobilisation of fibrinogen-binding sites on human ADP- and thrombin-treated platelets. Hawiger J, Parkinson S, Timmons S (1980) Nature 283(5743): 195-7
    › Primary publication · 6985716 (PubMed)
  33. Adenosine diphosphate induces binding of von Willebrand factor to human platelets. Fujimoto T, Hawiger J (1982) Nature 297(5862): 154-6
    › Primary publication · 6281653 (PubMed)
  34. Interaction of artificial phospholipid membranes with isolated polymorphonuclear leucocytic granules. Hawiger J, Collins RD, Horn RG, Koenig MG (1969) Nature 222(5190): 276-8
    › Primary publication · 5778395 (PubMed)
  35. Measurement of fibrinogen and fibrin degradation products in serum by staphylococcal clumping test. Hawiger J, Niewiarowski S, Gurewich V, Thomas DP (1970) J Lab Clin Med 75(1): 93-108
    › Primary publication · 4243578 (PubMed)
  36. Human fibrinogen possesses binding site for staphyococci on Aalpha and Bbeta polypeptide chains. Hawiger J, Hammond DK, Timmons S (1975) Nature 258(5536): 643-5
    › Primary publication · 1207746 (PubMed)
  37. Endotoxin-sensitive membrane component of human platelets. Hawiger J, Hawiger A, Timmons S (1975) Nature 256(5513): 125-7
    › Primary publication · 1097934 (PubMed)