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Matthias Clauss, Ph.D.

Associate Research Professor of Cellular & Integrative Physiology
Indiana Center for Vascular Biology & Medicine (ICVBM)
VA Medical Center - C3108
1481 West 10th Street
Indianapolis, Indiana 46202

E-mail: mclauss@iupui.edu
Phone: 317-988-4076

Education/Training

1982, Diploma (MS equivalent), Albert-Einstein-University of Ulm, Germany
1988, Ph.D., Ruprecht-Karls-University, Heidelberg, Germany
1988-91, Postdoctoral Fellowship, Columbia University, New York City, NY

Research Biography Summary

Personal Statement

Vascular function and repair is involved in many diseases, in particular in those of the cardiopulmonary system. My research program is concerned with the mechanisms of vascular endothelial cell activation and aims to identify the links between inflammation and blood vessel function and repair. A specific focus is on the regulation of survival (VEGF) and anti-survival (EMAP II) factors and their receptor-mediated signaling. Currently, I have two main projects in my laboratory; one analyzes the role of EMAP II in diseases, while the other one explores how HIV-1 infection can cause increased risk for cardiovascular diseases. My research on EMAP II culminated in the development of a humanized EMAP II neutralizing antibody as therapeutic tool for treating cigarette smoke induced emphysema. This neutralizing antibody is currently advancing towards IND approval for clinical trials. Regarding the HIV-1 studies we have identified an intracellular protein, HIV-Nef, as a likely candidate for cardiovascular and pulmonary disease development, even in the presence of anti-retroviral drugs. 

CONTRIBUTIONS TO SCIENCE

 1.    The vascular endothelial growth factor (VEGF) links angiogenesis with vascular permeability and inflammation

During my past work I was the first to link the hypoxia induced angiogenic protein VEGF (also known as vascular permeability factor VPF) with endothelial activation and inflammation. My publication in the Journal of Experimental Medicine in 1990 has been cited over 700 times because it established that endothelial cell and monocytes cooperate in processes of tissue repair and angiogenesis (blood vessel growth). Our subsequent studies identified specific ligands to the two receptors which are specific for monocytes and endothelial cells (for example in Journal of Biological Chemistry 1996 cited over 600 times). This pioneering work enabled us to compare the role of monocytes and endothelial cells in compensatory arteriogenesis, which was published in Circulation Research in 2003 and cited over 190 times. We further were able to identify specific signal transduction pathways dissecting physiological angiogenesis from vascular permeability and from proinflammatory angiogenesis. To be able to differentiate vascular permeability from angiogenesis is important because anti-inflammatory and edema reducing therapy should not affect angiogenesis and tissue repair. Because of this significance our in FASEB Journal 2003 published identification of the p38 MAP kinase as a molecular switch between VEGF-induced angiogenesis and vascular hyperpermeability was cited more than 100 times.

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    • Clauss M, Gerlach M, Gerlach H, Brett J, Wang F, Familetti PC, Pan Y-CE, Olander JV, Connolly DT, Stern D (1990) Vascular permeability factor: A tumor-derived polypeptide that induces endothelial cell and monocyte procoagulant activity, and promotes monocyte migration. J. Exp. Med. 172: 1535-1545.    PMC2188755
    • Clauss M, Weich H, Breier G, Knies U, Röckl W, Waltenberger J, Risau W (1996) The vascular endothelial growth factor receptor flt-1 mediates biological activities: Implications for a functional role of placenta growth factor in monocyte activation and chemotaxis. J. Biol. Chem. 271: 17629-17634. PMID: 8663424
    • Pipp F, Heil M, Issbrücker K, Ziegelhoeffer T, Martin S, van den Heuvel J, Weich H, Fernandez B, Schaper W, Clauss M (2003) The VEGFR-1 selective VEGF-homologue PlGF is arteriogenic: evidence for a monocyte mediated mechanism, Circ. Res. 92:378-385. PMID: 12600898
    • Issbrücker K, Marti HH Hippenstiel S, Springmann G, Voswinckel R, Gaumann  A, Breier G, Drexler H, Suttorp N, Clauss M (2003) p38 MAPK - a molecular switch between angiogenesis and vascular permeability. FASEB J. 17: 262-264. PMID: 12490545  

 2.    The TNFa receptors I and II as Yin and Yang regulators of cell proliferation, cell death and repair in vascular endothelial and endothelial progenitor cells

Tumor Necrosis Factor a (TNF) is most commonly studied in its soluble form after it is cleaved by a proinflammatory metalloproteinase (ADAM17 or TACE) from its natural transmembrane form. We were the first to determine that while soluble TNFa exclusively activates TNFRI (FEBS Letter 1996), its transmembrane form selectively activates TNFRII in endothelial cells (Cell 1995, which was cited 800 times). In subsequent studies we and other could demonstrate the significance of these findings, which is that transmembrane TNF has opposing activities than soluble TNF because TNFRII lacks the death domain of TNFRI and also the TNFRII has less proinflammatory and more prosurvival and repair functions than the TNFRI. Surprisingly transmembrane TNF emerged as a VEGF activity supporting factor as we could demonstrate that it was permissive for VEGF acting as vascular permeability in rodent and tissue culture models. This finding was published in Blood 2001 and cited over 70 times. Furthermore, transgenic endothelial overexpression of transmembrane TNF led to increased angiogenesis, possibly involving endothelial progenitor cells as we have shown 2006 in the Journal of Vascular Research in 2006. This publication was awarded as the best publication 2004-2006 by the European Society of Microcirculation.

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    • Clauss M, Grell M, Fangman C, Fiers W, Scheurich P, Risau W (1996) Synergistic induction of endothelial tissue factor by tumor necrosis factor and vascular endothelial growth factor: functional analysis of the tumor necrosis factor receptors. FEBS Letters 390: 334-338. PMID: 8706889
    • Grell M, Douni E, Wajant H, Löhden M, Clauss M, Maxeiner B, Georgopoulos S, Lesslauer W, Kollias G, Pfizenmaier K. Scheurich P (1995) The transmembrane form of tumor necrosis factor (TNF) is the prime activating ligand of the 80 kDa TNF receptor. Cell: 83(5):793-802. PMID: 8521496
    • Clauss M, Sunderkotter C, Sveinbjornsson, B, Hippenstiel S. Willuweit A, Marino M, Haas E, Seljelid R, Scheurich P, Suttorp N, Grell M, Risau W (2001) A permissive role of tumor necrosis factor in vascular endothelial growth factor induced vascular permeability.  Blood 97(5):1321-9.  PMID: 11222376
    • Rajashekhar G, Willuweit A, Patterson CE, Sun P, Hilbig A, Breier G, Helisch A, Clauss M (2006) Continuous endothelial cell activation increases angiogenesis: evidence for the direct role of endothelium linking angiogenesis and inflammation. J. Vasc. Res. 43: 193-204. PMID: 16410682  

 3.    Inflammation as a modulator of endothelial repair and angiogenesis

Acute and chronic inflammation is among the key reasons for vascular pathologies. Regenerative cells such as endothelial progenitor cells (EPC; also known as ECFC) are believed to be a major source of healthy endothelial cells that could replenish the inflamed and injured endothelium. However, our own work demonstrated that EPCs themselves are vulnerable to accelerated aging as evidenced by a p38-mediated upregulation of the senescence protein p16INK4a when stimulated by the pro-inflammatory cytokine TNF-α (Zhang, FASEB in 2009 – cited over 50 times). In contrast, more recently we found an opposing role of the p38 MAP in mature endothelial cells and proinflammatory angiogenesis as it occurs in prostate tumors (J Cell Physiol. in 2011). These findings are exciting as inhibition of the p38 MAP kinase would be a mean to protect endothelial progenitor from inflammation-induced premature senescence and make them more efficient for tissue repair in these conditions while unwanted angiogenesis in tumors could be inhibited.

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    • Rajashekhar G, Kamocka M, Renwick A, Suckow M, Wolter WR, Badve S, Sanjeevaiah AR Pumiglia K, Rosen E, and Clauss M (2011) Pro-inflammatory angiogenesis is mediated by p38 MAP kinase. J Cell Physiol. 226(3):800-08. PMID: 20803566
    • Zhang Y, Herbert BS, Rajashekhar G, Ingram DA, Yoder MC, Clauss M, Rehman J.  "Premature Senescence in Endothelial Progenitor Cells is Induced by Tumor Necrosis Factor-alpha.FASEB Journal 23:1358-1365, 2009. PMID: 19124561 

 4.    The anti-angiogenic and proinflammatory EMAP II is a key factor in pulmonary emphysema

We could show that EMAP II gene expression correlated with apoptosis and accumulation of macrophages in the developing mouse embryo. This publication in PNAS (un-facilitated track 2), which was cited over 110 times, is significant because it supposed that release of the monocyte-chemoattractant EMAP II causes accumulation of monocytes at the sites of tissue remodeling to clear dying cells without inflammation, a function of EMAP II which we contributed to physiological (embryo etc), but not to pathological conditions such as reperfusion injury or hypoxia (such as Am J Pathol. 2003). The links between apoptosis and hypoxia with EMAP II expression and inflammation, prompted my research focus to shift towards the lung. In 2011 we could demonstrate that inducible transgenic EMAP II expression was sufficient to cause emphysema in mice and that an EMAP II-neutralizing monoclonal antibody could stop progression of pulmonary emphysema in long term cigarette smoke-exposed mice. Interestingly, EMAP II activity is linked to concomitant upregulation of its apoptosis mediating receptor, CXCR3 (predominately CXCR3B, in AJRCMB 2012). These findings are important as there is currently no treatment which can cure or at least stop the progression of emphysema in people.

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    • Matschurat S, Knies UE, Person V, Fink L, Stoelcker B, Ebenebe C, Behrensdorf HA, Schaper J, Clauss M (2003) Regulation of EMAP II by Hypoxia. Am J Pathol. 2003 Jan;162(1):93-103. PMID: 12507893 
    • Clauss M, Voswinckel R, Rajashekhar G, Sigua NL, Fehrenbach H, Rush NI, Garrison J, Schweitzer KS, Yildirim AO, Kamocki K, Fisher AJ, Gu Y, Safadi B, Nikam S, Hubbard WC, Tuder RM, Presson RG Jr, Sethi S, and Petrache I. (2011). Lung endothelial monocyte activating protein II is a novel therapeutic target in murine emphysema. J. Clin. Invest., 121(6):2470-2479. PMC3104742
    • Green LA, Petrusca D, Rajashekhar G, Gianaris T, Schweitzer KS, Wang L, Justice MJ, Petrache I, Clauss M, (2012). Cigarette Smoke-Induced CXCR3 Receptor Upregulation Mediates Endothelial Apoptosis. Am J Respir Cell Mol Biol. 47: 807-814. PMC3547093
    • Knies UE, Behrensdorf HA, Mitchell C, Deutsch U, Risau W, Drexler H, Clauss M (1998) Regulation of endothelial monocyte-activating polypeptide II-release by apoptosis. Proc. Natl. Acad. Sci. U. S. A. 95: 12322-12327. PMC22830.

 5.    The role of HIV-envelope and HIV-Nef in vascular disease developmentWe address the recent discovery that patients with HIV infections are at increased for developing cardiovascular and pulmonary diseases. We could demonstrate that anti-inflammatory drugs such as pentoxifylline could downregulate proinflammatory adhesion proteins and chemokines (AIDS Res HR). In terms of our pulmonary research focus with EMAP II, we found that concerted upregulation of EMAP II and its receptor, CXCR3 would mediate gp120-induced apoptosis in lung microvascular endothelial cells (AJP Lung 2013). Based on our finding that HIV-infected T cell are very toxic to coronary vascular endothelial cells and that this effect is not observed with Nef-deficient HIV virus, we demonstrated that Nef was transferred from T cells to endothelial cells as a mediator of endothelial dysfunction and cell death. These findings published in PLosOne are relevant for the HIV infected population as vascular complications including pulmonary emphysema and hypertension as well as cardiovascular disease are common in HIV positive patients. Importantly, we could demonstrate Nef protein in circulating uninfected blood cells and even in HIV patients on anti-retroviral therapy with no detectable viral loads (AIDS Res. Hum. Retroviruses 2015).

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    • Green LA, Yi R, Petrusca D, Wang T, Elghouche A, Gupta SK, Petrache I, Clauss M. (2013). HIV envelope protein gp120-induced apoptosis in lung microvascular endothelial cells by concerted upregulation of EMAP II and its receptor, CXCR3. Am J Physiol. Lung Cell Mol Physiol. 306(4):L372-82. PMC392022
    • Green LA, Kim C, Gupta SK, Rajashekhar G, Rehman J, Clauss M. (2012) Pentoxifylline Reduces Tumor Necrosis Factor-α and HIV-Induced Vascular Endothelial Activation. AIDS Res Hum Retroviruses. 10:1207-15 PMC3448099
    • Wang T, Green LA, Gupta SK, Kim C, Wang L, Almodovar S, Flores SC, Prudovsky IA, Jolicoeur P, Liu Z, Clauss M. (2014) Transfer of intracellular HIV Nef to endothelium causes endothelial dysfunction. PLoS One. 2014 Mar 7;9(3):e91063. PMC394668
    • Wang T, Green LA, Gupta SK, Byrd D, Tohti A, Yu Q, TwiggIII HL, Clauss M. (2014) Intracellular Nef protein detected in PBMCs from HIV patients. AIDS Res Hum Retroviruses. 31(2):217-20. PMC4313413

Complete List of Published Work in My Bibliography:

http://www.ncbi.nlm.nih.gov/pubmed/?term=Clauss+M%5BAuthor%5D+and+endothelial

RESEARCH SUPPORT

NIH/NHLBI 1R01HL1 29843-01: HIV-Nef protein and endothelial dysfunction (07/01/2015 - 06/30/2019) Major Goals: To validate signal transduction inhibitors of Nef transfer to and activity in the vascular endothelium using various tissue culture and transgenic mouse models of tissue specific Nef expression. Role: Principal Investigator

NIH/NIA 5R21HL120390-02, HIV-Nef protein is disseminated in blood cells and causes endothelial dysfunction (2014-2016).
Major Goals: To analyze the role of Nef in endothelial dysfunction in vitro.  Role: PI

NIH/NHLBI, 1 UO1 HL121831-01: Genomic Analysis of Immunity and Lung Inflammation in HIV Infection (2013 – 2018).
Major Goals: Understanding the late complications of treated HIV infection. The main hypothesis is that persistent virus infection (HIV, CMV, EBV, others) leads to chronic immune activation, immunosenescence, chronic inflammation, and subsequently the late complications found in the HAART era.  Role: Co-investigator (PI: Dr. Homer L. Twigg III)

NIH/NHLBI 1R43HL127873-01: Development of a Fully Humanized Antibody for Treating Lung Emphysema (2015 – 2016)    
Major Goals: To fully humanize and improve binding of a neutralizing antibody to EMAP II, and to validate its capacity to block pulmonary emphysema formation.  Role: Principal Investigator

 

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Linden Green, PhD, postdoctoral fellow.

Research: I am interested in the link between inflammation and endothelial stem cell exhaustion by cellular senescence. I am currently identifying a novel transmembrane protein, which comprises both a marker of endothelial stemness and a mechanism how to protect these stem cells from inflammation-induced exhaustion. In addition, I aim to understand how HIV infection can contribute to diseases linked to vascular endothelial cells such as lung emphysema and cardiovascular diseases. My main hypothesis is that in the viremic state the HIV envelope protein gp120 mediates vascular dysfunction and inflammation, while HIV-Nef protein maintains vascular pathologies through continued Nef-protein production during combined anti-retroviral therapy.

Carrier: BS in Microbiology in 2004 from IU Bloomington and PhD in Microbiology and Immunology in 2010 from IU School of Medicine. Sponsored by the NIH T32 training grant “Adult stem cells in vascular biology” (HL079995) since 2010.

tina.jpg

Tina Wang, BS, MS, PhD student.

Research: I study how HIV-Nef protein can cause endothelial dysfunction, potentially leading to cardiovascular disease. In focus of my research are the ability of Nef-protein to travel from cell to cell leading to dissemination, and the signaling pathways of Nef protein-induced endothelial activation and cell death.

Carrier: Bachelor degree in Molecular Biology and Biotechnology from the University of Sheffield, UK in 2008 and Master in Microbiology and Immunology from IU School of Medicine in 2010. Sponsored by the NIH grant “HIV, Inflammation, and Endothelial Dysfunction” HL095149 since 2011 and recently awarded with an American Heart Association pre-doctoral fellowship grant (13PRE14780025). 

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Ru Yi, MD, postdoctoral fellow.

Research: I strive to elucidate the link between cigarette smoke-induced EMAPII production and iNOS mediated protein nitration. My main hypothesis is that blocking feed forward loops associated with these links can stop lung emphysema progression and restore hidden repair functions of the lung.

 Carrier: Bachelor degree in Pre-med from Peking University, China in 2003, M.D degree from Peking Union Medical College, China in 2008 and the USMLE in 2012. Sponsored by the NIH grants “EMAPII, a molecular link of inflammation and apoptosis in pulmonary emphysema” (HL090950) and “HIV, Inflammation, and Endothelial Dysfunction” (HL095149) since 2012.

 

 

2014

Wang T, Jiang Z, Hou W, Li Z, Cheng S, Green L, Wang Y, Wen X, Cai L, Clauss M, Wang Z. HIV Tat protein affects circadian rhythmicity by interfering with the circadian system. HIV Med. 2014 Apr 20. doi: 10.1111/hiv.12154. [Epub ahead of print] PMID: 24750691

 
Wang T, Green LA, Gupta SK, Kim C, Wang L, Almodovar S, Flores SC, Prudovsky IA, Jolicoeur P, Liu Z, Clauss M. Transfer of intracellular HIV Nef to endothelium causes endothelial dysfunction. PLoS One. 2014 Mar 7;9(3):e91063. doi: 10.1371/journal.pone.0091063. eCollection 2014. PMID:  24608713

 2013

Gupta SK, Mi D, Dubé MP, Saha CK, Johnson RM, Stein JH, Clauss MA, Mather KJ, Desta Z, Liu Z (2013).
Pentoxifylline, inflammation, and endothelial function in HIV-infected persons: a randomized, placebo-controlled trial. PLoS One. 2013 Apr 9;8(4):e60852 doi: 10.1371/journal.pone.0060852. Print 2013.ClinicalTrials.gov NCT00796822. PMID: 23593327

Green LA, Yi R, Petrusca D, Wang T, Elghouche A, Gupta SK, Petrache I, Clauss M. (2013). HIV envelope protein gp120-induced apoptosis in lung microvascular endothelial cells by concerted upregulation of EMAP II and its receptor, CXCR3. Am J Physiol Lung Cell Mol Physiol. 2013 Dec 6. [Epub ahead of print]. PMID: 24318111

2012

Rajashekhar,G, Gupta, A, Marin, A, Friedrich, J, Willuweit, A, Berg, DT, Cramer, MS, Sandusky, SE, Sutton, TA, Basile, DP, Grinnell, BW and Clauss, M. (2012). Soluble thrombomodulin reduces inflammation and prevents microalbuminuria induced by chronic endothelial activation in transgenic mice. Am. J. Renal Physiol. 302(6): F703-12. PubMed

Green LA, Kim C, Gupta SK, Rajashekhar G, Rehman J, Clauss M. Pentoxifylline Reduces Tumor Necrosis Factor-α and HIV-Induced Vascular Endothelial Activation (2012 in press).  AIDS Res Hum Retroviruses: 28(10):1207-15. PubMed

Green LA, Petrusca D, Rajashekhar G, Gianaris T, Schweitzer KS, Wang L, Justice MJ, Petrache I, Clauss M (2012 in press). Cigarette Smoke-Induced CXCR3 Receptor Upregulation Mediates Endothelial Apoptosis. Am J Respir Cell Mol Biol.2012 Dec;47(6):807-14.doi:10.1165/rcmb.2012-0132OC.Epub 2012 Aug30.PMID:22936405

 

2011

Rajashekhar G, Kamocka M, Marin A, Suckow MA, Wolter WR, Badve S, Sanjeevaiah AR, Pumiglia K, Rosen E, and Clauss M.  Pro-inflammatory angiogenesis is mediated by p38 MAP kinase.
J Cell Physiol 226(3):800-808, Mar 2011. PubMed

Clauss M, Voswinckel R, Rajashekhar G, Sigua NL, Fehrenbach H, Rush NI, Schweitzer KS, Yildirim AÖ, Kamocki K, Fisher AJ, Gu Y, Safadi B, Nikam S, Hubbard WC, Tuder RM, Twigg HL 3rd, Presson RG, Sethi S, Petrache I.  Lung endothelial monocyte-activating protein II is a mediator of cigarette smoke-induced emphysema in mice. J. Clin. Invest. 121(6):2470-2479, June 2011. PubMed

Kim C, Gupta SK, Green, L, Taylor BM, Deuter, M, Desta, Z and Clauss M (2011) Abacavir, didanosine, and tenofovir do not induce inflammatory, apoptotic, or oxidative stress genes in coronary endothelial cells: Antivir. Ther. 2011;16(8):1335-9. PubMed 


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