Shiva Shahrara, PhD

Rheumatology

Shahrara

                    
Office:

835 S. Wolcott Street
Room E807 MSB, M/C 733
Chicago, IL 60612 
Office number: 312-413-7529
Lab number: 312-996-1876

shahrara@uic.edu


     
    
 


Shiva Shahrara, PhD


Associate Professor


Education:

Institution and Location  Degree Completion Date Field of Study 
Stockholm University, Stockholm, Sweden     B.S.   11/1994  Molec. Bio. / Genetics  
Karolinska Institute, Stockholm, Sweden    
Ph.D.
12/1999
Molec. Bio. / Cardiology
Northwestern University Medical School, Chicago, IL 
Postdoctoral Fellowship  6/2000-2/2003  Immunology / Rheumatology 


12/1994-3/1995   

  Predoctoral training at the Molecular and Cell Biology Department of Karolinska Institute, Stockholm, Sweden   
4/1995-12/1999
 
  Graduate Student and Teaching Assistant, Department of Medicine, Cardiology Division, Karolinska Institute, Stockholm, Sweden  
6/2000-2/2003
 
  Postdoctoral fellow, Department of Medicine, Rheumatology Division, Northwestern University Medical School, Chicago, IL  
2/2003-2010 

  Research Assistant Professor of Medicine, Department of Medicine, Rheumatology Division, Northwestern University Medical School, Chicago, IL  
2010-2011 
       
  Research Associate Professor of Medicine, Department of Medicine, Rheumatology Division, Northwestern University Medical School, Chicago, IL  
2011-present             Associate Professor of Medicine, Department of Medicine, Rheumatology Division, University of Illinois at Chicago, Chicago, IL  
2015-present
 
  Tenured Associate Professor of Medicine, Department of Medicine, Rheumatology Division, University of Illinois at Chicago, Chicago, IL  


Honors/Memberships:

1994    Graduation with honors (B.S.) 
1995-1996   Recipient of predoctoral Training Grant from Swedish Heart and Lung Foundation  
1996-1998   Predoctoral Training Grant from Swedish Medical Res. Council and Swedish Society of Med. 
1997-1998    Predoctoral Training Grant from the Foundation of Sigurd and Elsa Golje  
1999   Graduation with honors (Ph.D.) 
2002-2005    Recipient of Arthritis Foundation Postdoctoral Award 
2003-2008    Recipient of Research Scientist Development Award K01(AR049353) 
2008-2009    Recipient of the Sontag Foundation Fellow of the Arthritis National Research Foundation  
2009-2012    Recipient of NIH/NIAMS R03 Award 
2010-2015    Recipient of Department of Defense Investigator award  
2005    Reviewer for Arthritis and Rheumatism  
2007    Member of American College of Rheumatology 
2009    Ad hoc reviewer for American College of Rheumatology Within Our Reach Grant Committee
2009    Reviewer for Journal of Immunology  
2009    Member of American Association of Immunologists  
2011    Chair of American College of Rheumatology Abstract Selection Committee  
2011    Panel Expert in NIH Roundtable  
2012    Associate Editor for American Journal of Clinical and Experimental Immunology  
2012-Present    Chair for ACR Abstract selection committee Annual Meeting  
2013    Reviewer for Nature Communications 
2013    Editor for Journal of Orthopedics & Rheumatology
2014    Adjunct member of the Graduate Faculty  
2014-2017    Recipient of NIH/NIAMS R03 Award 
2015-2019    Recipient of VA Merit award 
2015    Awarded tenure 
2015    Ad hoc reviewer for NIH IRG emphasis panel ZRG1IMM-S (90)S  

Contribution to Science:

 

Discovering the role of TH-17 cells in RA:

My research group has made major contributions to the understanding of RA pathogenesis, as we were the first group that determined that TH-17 cells are markedly elevated in RA synovial fluid compared to RA and normal blood (Arthritis Res Ther 2008).

The NIH R03 and the ACR Within Our Reach funded projects, uncovered that TH-17 cells play a pivotal role in the trafficking of myeloid cells from the circulation into the inflamed RA joints (J Immunol 2009 and 2010). Further we documented that the inflammatory response provoked by IL-17 as a result of myeloid cell migration was further perpetuated through formation of new blood vessels driven by TH-17 cells in the RA joint (J Immunol 2009).

Our breakthrough efforts was recognized by an invited review in the journal, Nature Reviews, entitled “The Possible Role of IL-12 Family Cytokines in RA”. I served as the primary and the principle investigator in all these studies.


a. *Shahrara S, Huang Q, Mandelin AM 2nd, Pope RM: TH-17 cells in rheumatoid arthritis. Arthritis Res. Ther. 10; 4: R93-R100, 2008.


b. *Shahrara S, Pickens SR, Dorfleutner A, Pope RM: IL-17 induces monocyte migration in rheumatoid arthritis. J. Immunol. 182; 6:3884-91, 2009.


c. Pickens SR, Volin MV, Mandelin II AM, Kolls JK, Pope RM, *Shahrara S: IL-17 Contributes to Angiogenesis in Rheumatoid Arthritis. J. Immunol. 184; 6:3233-3241, 2010.


d. *Shahrara S, Pickens SR, Mandelin AM, Huang Q, Karpus W, Kolls JK, Pope RM: IL-17-mediated monocyte migration is partially through CCL2/MCP-1 induction. J. Immunol. 184; 8:4479-4487, 2010.


Identifying novel mediators of RA angiogenesis:

My laboratory is one of the few labs that are focused on identifying the mechanisms that regulate angiogenesis in RA, which are critical yet understudied components of RA pathogenesis. We have an exceptional opportunity to pursue such studies, since we have access to RA specimen and we have the expertise to utilize RA peripheral blood for isolating and maintaining endothelial progenitor cells (Annals Rheum Dis 2014).

Therefore our studies can be directly translated from bench to bed side through increasing the understanding of RA pathology and finding potential novel treatments for RA. As a recognized investigator in the field of endothelial trafficking, I was recently invited to the EULAR 2013 meeting to lecture on the role of chemokines in monocyte endothelial interactions.

My laboratory has identified unique proangiogenic factors including CCL21 (Arthritis Rheum 2011 and 2012), CCL28 (Annals Rheum Dis 2014; this paper was highlighted in 11 scientific websites) and flagellin (J Immunol 2013) whose role in RA angiogenesis was undescribed prior to our published studies. I serve as the principle investigator of these studies which are currently in part supported by the NIH R03.


a. Pickens SR, Chamberlain ND, Volin MV, Pope RM, Mandelin II AM, *Shahrara S: Characterization of CCL19 and CCL21 in rheumatoid arthritis: Arthritis Rheum 63: 914–922, 2011.


b. Pickens SR, Chamberlain ND, Volin MV, Pope RM, Talarico NE, Mandelin AM II, *Shahrara S. Role of the CCL21 and CCR7 pathway in rheumatoid arthritis angiogenesis. Arthritis Rheum. 64: 2471-2481, 2012.


c. Chen Z , Kim S, Essani AB, Volin MV, Vila OM, Swedler W, Arami A, Volkov S, Sweiss S and *Shahrara S. Characterizing the expression and function of CCL28 and its corresponding receptor CCR10 in RA pathogenesis. Annals Rheum Dis, 2013-204530.


d. Kim SJ, Chen Z, Chamberlain ND, Volin MV, Swedler W, Volkov S, Sweiss N, *Shahrara S. Angiogenesis in rheumatoid arthritis is directly fostered by TLR5 ligation and indirectly through IL-17 induction. Arthritis Rheum 65: 2024-2036, 2013.


Uncovering the role of TLR7 and its endogenous ligand in RA:

We show that TLR7 is greatly elevated in RA compared to normal peripheral blood and synovial tissue myeloid cells and its expression closely correlates with disease activity score (DAS)28 and TNF, therefore significance of TLR7 and its endogenous ligand was examined in RA pathogenesis. We discovered that a unique TLR7 endogenous ligand resides in RA synovial fluid microvesicles which can exclusively bind to the endosomal TLR7 and activate RA myeloid cell function.

We document that exosomes released from the live RA synovial fluid macrophages are potentially important source of storage for this specific TLR7 endogenous ligand. Moreover, macrophage cell death mediated through apoptosis or necrosis can further potentiate the discharge of the exosomal TLR7 ligand into the RA synovial fluid. We also uncovered that the TLR7 endogenous ligand can remodel the naïve RA myeloid cells into proinflammatory M1 macrophages and mature osteoclasts. We recently published a paper in Annals Rheum Dis, demonstrating that a novel micro RNA expressed in RA synovial fluid can specifically bind and activate TLR7 function. Additional studies in this project were recently funded by VA merit award and the second paper is published in Arthritis Rheum to reveal the identity of the TLR7 binding micro RNA in RA synovial fluid. I serve as the principle investigator of this project.


a. Chamberlain ND, Kim SJ. Vila OM, Volin MV, Volkov S, Pope RM, Arami S, Mandelin AM II, *Shahrara S. Ligation of TLR7 by rheumatoid arthritis synovial fluid single strand RNA induces transcription of TNF in monocytes. Annals Rheum Dis. 72: 418-426, 2013.


b. Kim S, Chen Z, Essani AB, Elshabrawy HA, Volin MV, Volkov S, Swedler W, Arami S, Sweiss N and *Shahrara S. Identification of a novel TLR7 endogenous ligand in RA synovial fluid that can provoke arthritic joint inflammation. Arthritis Rheumatol 2016 In press.


Determining the impact of IL-7 and IL-7R in RA myeloid cells:

Number of synovial tissue macrophages is the most reliable marker for assessing RA disease severity and response to therapy. Hence a new direction in my lab is identifying the factors that transform naïve myeloid cells into RA M1 macrophages and fully mature RA osteoclasts. To date, research in the IL-7/IL-7R field has focused on its importance in T cell development and function. Our novel findings shift the paradigm by discovering an undefined role for IL-7 in attracting circulating monocytes into the RA joint and subsequently transforming the newly infiltrated cells into proinflammatory M1 macrophages and mature osteoclasts.

Our research laboratory is pursuing a novel avenue of research that will demonstrate whether IL-7’s ability to differentiate naïve myeloid cells into joint M1 macrophages is an important contributor for RA osteoclastogenesis. We recently published two papers on the expression pattern of IL-7 and IL-7R in RA compared to osteoarthritis and normal specimens (Arthritis Rheum 2012) and its importance in attracting myeloid cells from the circulation into the RA joint (J immunol 2013). I serve as the principle investigator in these studies.


a. Pickens SR, Chamberlain ND, Volin MV, Pope RM, Talarico NE, Mandelin AM II and *Shahrara S. Characterization of IL-7 and IL-7R in the pathogenesis of Rheumatoid Arthritis. Arthritis Rheum. 63:2884-2893, 2011.


b. Chen Z, Kim SJ, Chamberlain ND, Pickens SR, Volin MV, Volkov S, Arami S, Christman JW, Prabhakar BS, Swedler W, Mehta A, Sweiss N, *Shahrara S. The novel role of IL-7 ligation to IL-7R in myeloid cells of rheumatoid arthritis and collagen induced arthritis. J Immunol 190: 5256-5266, 2013.


Investigating the significant importance of TLR5 in RA pathogenesis:

Despite the close interaction observed between formation of new blood vessels and differentiation of osteoclasts, the common modulator of angiogenesis and bone erosion is undefined. Therefore, we ask whether TLR5, which is highly expressed on RA synovial tissue macrophages and endothelial cells (J Immunol 2012), is the common modulator that interconnects the function of myeloid cells with vascular endothelium. We uncover for the first time that RA endothelial migration and tube formation is directly mediated through TLR5 ligation. Moreover, TLR5 induction of IL-6 and IL-1 from myeloid cells, promotes TH-17 cell polarization that can indirectly contribute to TLR5 driven angiogenesis (Arthritis Rheum 2013). We also found that the ligation of TLR5 by its agonist, flagellin, strongly promotes RA osteoclast differentiation through induction of receptor activator of nuclear factor kappa-B (RANK) and its corresponding ligand, RANKL.

In addition to the direct effect of TLR5 on osteoclastogenesis, we show that TNF produced from TLR5 activated myeloid cells, is in part responsible for myeloid cell differentiation into mature osteoclasts (J Immunol 2014). Therefore, studies are proposed to examine whether disruption of TLR5 ligation will resolve the arthritic bone neovascularization by inhibiting the direct as well as the indirect effects mediated by TNF and IL-17 on the bone-vasculature interaction. Confirming the novelty of our work, the TLR5 preliminary data submitted as an abstract to the ACR meeting was accepted as “The Discovery of 2012 and 2013” and was presented in a plenary session in 2012 and as an oral presentation in ACR 2013 annual meeting. These findings were later presented in the Military Health System Research Symposium (MHSRS) 2014 meeting. Our break through efforts was also recognized by the research community and as a result our 2014 J Immunol paper was highlighted in Nature Review Rheumatology (9/2014) and National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS) websites https://www.facebook.com/NIH.NIAMS?sk=app_139229522811253 (9/2014) in addition to 14 other scientific websites. I serve as the principle investigator of this project.


a. Chamberlain ND, Vila OM, Volin MV, Volkov S, Pope RM, Swedler W, Mandelin AM 2nd, *Shahrara S. TLR5, a Novel and Unidentified Inflammatory Mediator in Rheumatoid Arthritis that Correlates with Disease Activity Score and Joint TNFα Levels. J Immunol. 189: 475-83, 2012.

b. Kim SJ, Chen Z, Chamberlain ND, Volin MV, Swedler W, Volkov S, Sweiss N, *Shahrara S. Angiogenesis in rheumatoid arthritis is directly fostered by TLR5 ligation and indirectly through IL-17 induction. Arthritis Rheum 65: 2024-2036, 2013.


c. Kim SJ, Chen Z, Chamberlain ND, Essani AE, Volin MV, Volkov S, Amin AM, Gravallese EM, Arami S, Swedler W, Lane NE, Mehta A, Sweiss N, *Shahrara S. Ligation of TLR5 promotes myeloid cell infiltration and differentiation to mature osteoclasts in RA patients. J Immunol., 15;193:3902-3913, 2014.


d. A TLR5-TNF positive feedback loop in rheumatoid arthritis. Bernard NJ. Nature Rev Rheumatology 10, 637 (2014) doi:10.1038/nrrheum.2014.166 Published online 23 September 2014.


Complete List of Published Work in My Bibliography (40 peer reviewed papers):
http://www.ncbi.nlm.nih.gov/myncbi/browse/collection/47174298/?sort=date&direction=descending