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V. Michael Holers, MD

Professor, Division Head


 Dr. Holers research group performs both basic and translational research. A longstanding interest has been to decipher the roles of complement receptors and membrane regulatory proteins in the immune response, with a special emphasis on autoimmune diseases. Complement is a complex system of serum proteins which, upon activation, covalently bind targets (bacteria, viruses, immune complexes) and marks them as foreign. The interaction of complement with B cell receptors also results in substantial enhancement of humoral and cellular immunity. In addition to this role, excessive activation of complement is centrally involved in autoimmunity and the tissue damage that occurs in many inflammatory diseases involving organs such as the kidney. The Holers’ laboratory has developed human and mouse models in which to study these complement related biologic processes and to develop novel complement inhibitors. Candidate therapeutics derived from these studies have been advanced to clinical trials in humans.

With regard to translational research, Dr. Holers is a co-founder of SERA (Studies of the Etiology of Rheumatoid Arthritis), which is focused on understanding the early pathogenesis and natural history of RA. In that regard, it is now known that autoimmune diseases such as RA begin years before clinical signs and symptoms are apparent, when at-risk individuals manifest highly predictive autoantibodies in their serum. By studying individuals in this period of time, SERA investigators have made novel findings suggesting that RA is initiated through a process linked to mucosal inflammation. This observation also suggests that additional therapeutic and/or prevention strategies could be considered for individuals in this at-risk but asymptomatic period. It is also relevant to determine how individuals transition from this autoantibody-positive, at-risk period to clinically active disease, and several studies are underway that are related to understanding these questions. Finally, the SERA investigator Dr. Kevin Deane has initiated the first RA prevention trial, designated StopRA, in asymptomatic individuals. The goal of this study is to prevent or delay the onset of arthritis in highly at-risk individuals.


1993              Arrived at UCD
 

1983-1985    Research Fellowship in Rheumatology - Washington University School of Medicine


1983-1985    Research Associate - Howard Hughes Medical Institute, St. Louis, MO


1981-1983    Clinical Fellowship in Rheumatology- University of Colorado School of Medicine, 

                       Denver, CO


1979-1981    Residency - Internal Medicine Barnes Hospital, St. Louis MO


1978-1979    Internship - Internal Medicine Barnes Hospital, St. Louis MO
 

Medical School: Washington University School of Medicine, St. Louis, Missouri 

2008-Present   Scoville Professor of Rheumatology – University of Colorado Denver

2000-Present   Head, Division of Rheumatology - University of Colorado Denver
  
1998-Present   Professor of Immunology - University of Colorado Denver
 
1997-Present   Present Professor of Medicine - University of Colorado Denver
 
1993-2008   Smyth Professor of Rheumatology - University of Colorado Denver
 
1994-1998       Professor of Immunology - University of Colorado Denver
 
1993-1997       Associate Professor of Medicine (with tenure) - University of Colorado Denver
 
1992-1993       Associate Professor of Medicine (with tenure) - Washington University 
                         School of Medicine
 
1987-1993       Member - Division of Biology and Biomedical Sciences, Washington University 
                         School of Medicine
 
1987-1993       Assistant Professor of Pathology - Washington University School of Medicine
 
1986-1993       Assistant Investigator - Howard Hughes Medical Institute
 
1986-1992       Assistant Professor of Medicine - Washington University School of Medicine

1985-1986       Instructor in Medicine - Washington University School of Medicine


PROFESSIONAL SOCIETY MEMBERSHIPS:

American Federation of Clinical Research

American College of Rheumatology

American Association of Immunologists

American College of Physicians

American Society for Clinical Investigation

Western Society for Clinical Investigation

International Complement Society

American Association of Physicians

Henry Kunkel Society

Clinical Immunology Society

 

EDITORIAL AND REVIEW:
1992-99             Associate Editor, Journal of Immunology
1995-2000         Associate Editor, Arthritis & Rheumatism

2013-                 Consulting Editor, Journal of Clinical Investigation

Ad hoc reviews  Immunity, Journal of Experimental Medicine,Journal of Clinical 
                          Investigation, Nature, Nature Immunology, Proceedings of the National 
                          Academy of Science, Molecular Immunology, Blood, Journal of Immunology,
                          Arthritis and Rheumatism

 

NATIONAL PEER GRANT REVIEW SERVICE:
1989-93             National Arthritis Foundation Biomedical Research Grant Review Committee

1993                  Ad hoc member "Research in causal mechanisms of SLE" RFA Study Section, 

                           NIAMS

1993                  Ad hoc member ALY Study Section, NIAID

1993-                 NIH P0-1 and R0-1 ad hoc reviews, special study sections

1993-                 Ad hoc reviewer for VA Career Development Awards

1991-                 Ad hoc reviewer for National Science Foundation

1996-2000        Member, Allergy and Immunology (ALY) Study Section, Center for Scientific 

                         Review, NIH

2000-02            Pfizer Postdoctoral Fellowship Academic Advisory Board

2000-                Ad hoc reviewer for Immune Tolerance Network
2000-06            Chair, Scientific Advisory Board, North American Rheumatoid Arthritis

                         Consortium (NARAC)

2001-04           Abbott Postdoctoral Fellowship Review Panel

2001-05           Advisory Board, Multiple Autoimmune Diseases Genetic  Consortium (MADGC)

2003                 Ad hoc member "Microcirculation and Target Organ Damage in Rheumatic and
                         Skin Diseases" RFA Study Section, NIAMS

2003-04           Chair, American College of Rheumatology Research and Education Foundation
                         Research Review Panel

2005                Chair, NIH CSR Special Study Section for Systemic Lupus Erythematosus 
                        Applications

2007-10           Chair, NIH CSR Special Study Sections

2012                Member, NIAMS P60 Centers Review Study Section

 

NATIONAL PROFESSIONAL ACTIVITIES:
1992-                 American College of Rheumatology Abstract Selection Subcommittees
1997                  Subcommittee Chairman, American College of Rheumatology National Meeting
                           Abstract Selection Committee

1995-98            Member, Committee on Research, American College of Rheumatology

1997-98            Annual Meeting Planning Committee, American College of Rheumatology
1998                  ACR Basic Research Conference Co-Organizer
1995, 1998       Co-Chair, Complement Symposium, AAI Meeting

1998-2000        National Arthritis Foundation Publications Committee

1998-2000        International Complement Workshop Organizing Committee

1999                  Co-Chair, ACR Basic Research Conference

1999-2002        Chair, Committee on Research, American College of Rheumatology

1999-2002        Member, Board of Directors, American College of Rheumatology Research
                            and Education Foundation

2000-02, 2004  Arthritis Foundation Fellows Research Conference Planning Committee
2000-01             Blue Ribbon Panel on Research, National Arthritis Foundation

2000-04             Founding Member and Secretary, International Complement Society

2002                  Member, NIH Study Section Boundaries Team for Integrated Review 
                           Group (IRG) #10 (Immunology)

2001-03            Member, Abstract Oversight Committee, American College of Rheumatology

2002-04            Member, Board of Directors, American College of Rheumatology

2003-06            Program Committee Block Chair, American Association of Immunologists

2003-04            Chair, Task Force on Research Funding, American College of Rheumatology

2003-08            Steering Committee, NIH/NIAMS SLE Biomarkers Consortium

2004-07            Site Director, Lupus Clinical Trials Consortium 

2004-07            Chair, Scientific Advisory Council, American College ofRheumatology
                           Research and Education Foundation

2004-10            Member, Board of Directors, American College of Rheumatology 
                          Research and Education Foundation

2007                 Member, ad hoc, FDA Guidance Panel “Abatacept”

2005-06           Chair, Rheumatoid Arthritis Initiative Task Force,American College 
                          of Rheumatology Research and Education Foundation

2007-09           Member, Nominating Committee, Henry Kunkel Society

2007-09           Member, ITN Strategic Planning Group for Autoimmunity

2011                 Co-Chair, NIAMS Arthritis Biology Research Roundtable
2011-12           Co-Chair, American College of Rheumatology Blue Ribbon Task Force
                          on Academic Rheumatology

2011-16           Member, Scientific Advisory Board, Lupus Research Institute

2011-2104       Member, American College of Rheumatology Board of Directors
2012-16           Member, International Complement Society Board of Directors

2012-13           Member, NIAMS Centers Evaluation Working Group

2013                 Member, NIAMS Target Evaluation Consortium Working Group

2013-16           Member, National Arthritis Foundation RA Task Force

2013-                Member, Arthritis Foundation Great West Region Medical and Scientific
                          Committee

2014-15           Chair, American College of Rheumatology Division Directors Task Force

2014-15           Member, American College of Rheumatology Finance Committee

2014-16           President-Elect, International Complement Society

2015-               Member, NIAMS Advisory Council

2015-               Chair, American College of Rheumatology Division Directors Special Committee

2015-16           Chair, Accelerating Medicines Partnership RA/SLE NLC Executive Committee

2017-               President, International Complement Society

 

COMMUNITY ACTIVITIES:
1994-2008      Member, Board of Directors, Rocky Mountain Chapter, Arthritis Foundation

1996-2005      Executive Committee of the Board of Directors, Rocky Mountain Chapter, 
                         Arthritis Foundation
1997-2000      Chair, Medical and Education Committee, Rocky Mountain Chapter, Arthritis
                         Foundation
1998-2000      Secretary, Rocky Mountain Chapter, Arthritis Foundation

1999-2001      Member, Colorado Arthritis Advisory Committee

2000-02          House of Delegates, National Arthritis Foundation

2000-02          Chair-Elect, Rocky Mountain Chapter, Arthritis Foundation

2002-03          Chair, Rocky Mountain Chapter, Arthritis Foundation

2003-05          Chair, Board Development Committee, Rocky Mountain Chapter, Arthritis

                         Foundation

1974          Phi Beta Kappa 

1985          American Rheumatism Association Senior Fellowship Award

1988-91    Hulda Irene Duggan Investigator, Arthritis Foundation

1993         Member, American Society for Clinical Investigation (ASCI)

1996         Ecker Lectureship, Case Western Reserve University, Cleveland,OH

1997         Robert Wood Johnson Award, Arthritis Foundation

1997         Schwartz-Weinstein Research Award, Arthritis Foundation Rocky Mountain Chapter

1998         Harmon Foundation Award, Arthritis Foundation, Rocky Mountain Chapter

1999         Kroc Lectureship, University of Iowa, Iowa City, IA

1999         Volunteer Leadership Award, National Arthritis Foundation

2000         Member, American Association of Physicians (AAP)

2002         Member, Henry Kunkel Society

2003         Pfizer Visiting Professor, Medical University of South Carolina

2004         Inventor of the Year, University of Colorado Denver, School of Medicine

2007         Ogryzlo Day Merck Frosst Canada and Schering Canada Visiting Professor, 
                  University of Toronto

2008         Ephraim P. and Jean S. Engleman Visiting Professor, University of California San

                  Francisco
2008         Pfizer Visiting Professor, Emory University School of Medicine

2008         American College of Rheumatology Distinguished Basic Investigator Award

2009         University of Colorado Technology Transfer Lifetime Pinnacle Awardee
2009         Kroc Lectureship, University of Texas Southwestern, Dallas, TX

2009         Eric Bywaters Lectureship, Hammersmith Hospital, London, UK

2009         Physician Pro Tempore, Hospital for Special Surgery, New York, NY

2009         Christian Lectureship, Hospital for Special Surgery, New York, NY

2009         Freyberg Lectureship, Hospital for Special Surgery, New York, NY

2010         Senior Fellow of the American Asthma Foundation

2011         Castle Connolly Top Doctor

2011         Zvaifler Lectureship, University of California San Diego, San Diego,CA

2014         Cochran Lectureship, University of Alabama Birmingham

2015         Rheumatology Research Foundation Memorial Lectureship, San Francisco, CA

2016         Lane Lectureship, University of Washington

2016         Everett D. Reese Immunology and Rheumatology Lecturer, Ohio State University

2016         The Walter Bauer Lectureship, Harvard Medical School

The basic and translational research focus of my research is on two areas.

 

The first is the roles of complement receptors and membrane regulatory proteins in the immune response, with a special emphasis on and the role of complement in inflammatory and autoimmune diseases.


With regard to this area, complement is a complex system of serum proteins which, upon activation, covalently bind targets (bacteria, viruses, immune complexes, cell membranes) and marks them as foreign. These covalently attached complement fragments bind high affinity receptors on lymphocytes and FDCs. The interaction of complement with B cell receptors results in substantial enhancement of humoral immunity. In addition to this role, excessive activation of complement is centrally involved in the tissue damage that occurs in many inflammatory diseases involving organs such as the kidney. My laboratory has developed human and mouse models in which to study these complement related biologic processes.

 

The second are is the pathogenic role of autoantibodies and other biomarkers in the evolution of autoimmunity in RA from the pre-symptomatic autoantibody-positive period through the onset of clinically active disease.


With regard to the second area, we now know that autoimmune diseases such as RA, SLE and Type 1 Diabetes Mellitus begin years before clinical signs and symptoms are apparent. That is because these individuals manifest highly predictive autoantibodies in their serum. This observation suggests that we must extend our study of the genetic epidemiology of autoimmune diseases such as RA into this important period, and that additional therapeutic and/or prevention strategies should be considered for individuals in this at-risk but asymptomatic period. It is also relevant to determine how individuals transition from this autoantibody-positive, at-risk period to clinically active disease. My research group has established several ongoing studies in RA that are related to these questions.


Specific areas of emphasis include:

  
1.  Roles of complement receptor type 2 (CR2, CD21) in B lymphocyte development and activation. Using both human and mouse CR2 as a model, we are analyzing the ways by which CR2 regulates B lymphocyte responses to antigens bound by complement. The specific mechanisms by which CR2 and other complement receptors act to modify B lymphocyte responses are incompletely understood, though we have shown that CR2 deficient mice have a markedly impaired humoral immune response. We are now studying the signaling responses of these receptor deficient B lymphocytes. We have also recently created human CR2 transgenic mice as a way to study structure-function relationships and the effects of over-expression of receptors on B cell development and tolerance. Finally, we are determining the three dimensional structure of the CR2 ligand binding sites for its three ligands (C3d, Epstein-Barr virus and CD23) using NMR, x-ray crystallographic and other structural techniques.


2.  Analysis of the role of complement during the development of SLE, RA and other autoimmune and inflammatory diseases. A recent interest is on the role of specific complement activation pathways (classical, alternative and lectin) in the initiation of injury. In murine studies we are using complement receptor knockouts and complement inhibitors we developed to determine how the alteration of these systems affects self tolerance and tissue injury. A major finding has been to determine that the alternative pathway and its amplification loop are absolutely essential to generate pathologic complement activation fragments in antibody-dependent and –independent disease models and to develop new generations of inhibitors to take advantage of that observation.  In patients, we have led a therapeutic trial of a complement inhibitor in patients with SLE and active glomerular disease and continue to be focused on learning how complement inhibition can positively affect patients with various human diseases.


3.   In addition to the above areas of emphasis, a study of pre-disease autoimmunity in patients at risk for the development of RA has also been initiated in collaboration with Dr. Jill Norris of the Department of Preventive Medicine and other members of the Division of Rheumatology such as Drs. Kevin Deane and Kristen Demoruelle. By using unique human populations at risk for developing RA, we are determining what RA-associated autoantibodies and other biomarkers are present that could predict the development of clinical disease. In addition, we have developed an animal model of the pathogenic role of a newly described autoantibody system directed to citrullinated antigens, commonly called anti-CCP antibodies. These studies have clearly shown that these autoantibodies are pathogenic and are opening up additional therapeutic targets and opportunities.

 

 

PATENTS (granted):
1. “3-Dimensional Structure of Complement Receptor Type 2 and Uses Thereof”, U.S. Patent 6,820,011, November 16, 2004
2. “Targeting complement factor H for treatment of diseases”, U.S. Patent 7,759,304, July 20, 2010
3.  “Anti-factor B antibodies” U.S. Patent 7,999,082, August 16, 2011
4. “Humaneered anti-factor B antibody” U.S. Patent 7,964,705, June 21, 2011
5.  “Complement receptor 2 targeted complement modulators”, U.S. Patent 8,007,804, August 30, 2011
6. “Biomarkers for rheumatoid arthritis”, European Patent 2158326, June 20, 2012
7. “Inhibition of factor B, the alternative complement pathway, and methods related thereto” U.S Patent 8652475, February 18, 2014
8. “Non-invasive detection of complement-mediated inflammation using CR2-targeted nanoparticles” U.S. Patent 8,840,868, September 23, 2014
9. “Inhibition of the alternative complement pathway for treatment of traumatic brain injury, spinal cord injury and related conditions” U.S. Patent 8,911,733, December 14, 2014

Publications (NCBI publication list)