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Richard A. F. Clark, M.D.

Professor

Research Focus

Richard Clark

            Over twenty years ago, the Clark laboratory found that skin cell activation is the rate limiting step in new tissue formation of cutaneous wounds ( Am J Path 149:1257-1270, 1996). The activated cells switch their cell surface receptors from those that recognize normal connective tissue, i.e. type 1 collagen, to those that recognize proteins in the provisional wound matrix, i.e. fibrin and fibronectin (FN).  The cell surface integrin switch allows activated parenchymal invasion of the wound space.  As a salient example, αvβ3, a fibrin integrin receptor, is expressed only on capillary sprouts invading the wound clot and is required for endothelial cell invasion of the clot ( Science, 264:569-571,1994, Am J Path 148:1407-1421, 1996). In contrast, connective tissue fibroblasts do not move on pure fibrin gels and express little αvβ3.  Instead, fibroblasts require FN to transmigrate from the collagen-rich connective tissue around a wound into the fibrin/FN-rich wound space ( J Cell Sci, 110:861-870, 1997).  To transmigrate from collagen to FN, fibroblasts switch their surface integrin receptors from collagen integrins (e.g. α2β1) to FN integrins (i.e. α5β1).  This switch is driven by increased FN in the extracellular matrix, an important example of ligand positive-feedback on receptor expression ( J Invest Dermatol, 113:913-919, 1999).  In contrast, autocoids and growth factors induce negative-feedback on receptor expression.  We have also elucidated FN domains that are critical for fibroblast transmigration ( J Invest Dermatol, 121:695-705, 2003). The same FN domains were found to be necessary and sufficient to induce optimal wound healing in a porcine excisional wound model ( Tiss Eng. 12:601-613, 2006, Biomaterials 28:671-679, 2007).

            The years of laboratory bench and animal research on skin injury and repair provided a groundwork for development of a therapy to treat burn injury progression, a clinical unmet need.  A putative therapy arose from our discovery that four sites in FN ( Figure 1) bound and enhanced the ability of platelet-derived growth factor (PDGF)-BB to support fibroblast survival and growth under stress situations ( J Invest Dermatol, 131:84-98, 2011).  From the most robust site in the first type III repeat of FN ( Figure 1), we delineated these activities to a 14-residue peptide (P12) that can also limit burn injury progression in both small and large animal burn models ( J Invest Dermatol, 134:1119-1127, 2014). 

  Peptide from First FN

Figure 1.  Peptide from first FN type III repeat (FNIII 1) binds PDGF-BB.   Schematic of human FN. FN type I repeats are shown as thin rectangles, FN type II repeats as ovals, and FN type III repeats as thick rectangles. PDGF-BB-binding sites (P1, P2, P3, P4) and the RGD cell-binding site are indicated with arrows. P1 contains the P12 sequence.  (b) Sequence of FNIII 1 (FN609-718). Sequences of P1 (FN634-658) and P2 (FN680-704) are underlined. (c) Equilibrium binding of PDGF-BB with anastellin (FN630-704). (d) Kinetic binding of PDGF-BB with FN630-704. Increasing concentrations (6.25–200 nM) of FN630-704 were injected across the biosensor chip coupled with PDGF-BB (first arrow), followed 120 seconds later by a continuing flow of buffer (second arrow). Chip without PDGF-BB was used as a reference. The dissociation constant (Kd) was calculated by averaging the k off  divided by k on.  Sensorgrams are representative of 3 different experiments. c.p.m., counts per minute; RU, relative units. (from J Invest Dermatol, 134:1119-1127, 2014)

            Mechanistically P12 enhances PDGF-BB-induced cell survival and growth by redirecting PDGF-BB/PDGFreceptor (PDGFR) complexes from clathrin-mediated endocytosis to a macropinocytosis-like pathway, thereby augmenting Akt phosphorylation ( J Invest Dermatol, 134:921-929, 2014) ( Figure 2).  Interestingly, while a prolongation of Akt phosphorylation (p-Akt) is observed 2 hours after addition of P12 to a physiologic serum concentration (1nM) of PDGF-BB ( Figure 2, lower panel), a striking magnitude increase in p-Akt is observed 1 hour after P12 is added to wound concentrations (0.1nM or 0.3nM) of PDGF-BB (20) ( Figure 2, upper panel).

P12 increased p-Akt

Figure 2. P12 increased p-Akt at various doses of PDGF-BB in acute wound fluid (upper panel) or PDGF-BB in serum (lower panel) . Adult Human Dermal Fibroblasts (AHDFs) were treated with PDGF-BB+/-P12 in Hanks Balanced Salt Solution (HBSS) at the doses indicated in the figure. Western blots were performed with an antibody against phosphorylated-Akt (p-Akt) and Glyceraldehyde 3-Phosphate Dehydrogenase (GAPDH) was used as loading control. (from J Invest Dermatol, 134:921-929, 2014)

Preclinical efficacy studies have demonstrated that cyclized P12 (cP12) administered by infusion, 4 hours post-burn ( Figure 3), improves wound healing from 30% wound closure in control animals to 70% wound closure in treated animals as judged by 14-day post-burn histomorphometry ( Wd Rep Reg, 24:501-513, 2016).  Furthermore, percent re-epithelization 10d post-burn is also augmented by cP12 and scar depth at 28d post-burn is reduced by cP12 ( Figure 4). 

Discovery Paradigm Timeline

Figure 3. Discovery Paradigm Timeline.  Biopsies for re-epithelialization are stained with hematoxylin and eosin (H&E) and analyzed for % re-epithelialization (re-epithelized wound surface/total wound surface x 100) by a dermatopathologist blinded to the protocol.  Biopsies for scar depth are bisected, fixed and stained with H&E.  Scar depth measured on H&E stained sections by three vertical lines from the epidermal-dermal junction on both bisected specimens.  The six lengths are summed and divided by six to acquire the median scar depth for that specimen.

Cyclized P12

Figure 4. Cyclized P12 (cP12) infusions), speed healing, and attenuate scarring in porcine burns when administerd 4h post-burn.  Percent re-epithelialization and scar depth were quantified as described in Figure 2. (from Wd Rep Reg, 24:501-513, 2016).

NeoMatrix Therapeutics, Inc. (NMT, a company founded Dr. Clark) submitted an IND August 2017, which was activated September 2017.  NMT has recently submitted a proposal to begin clinical trials, entitled, “ A Phase 1 Randomized, Placebo-Controlled, Single Ascending Dose Study to Examine the Safety, Tolerability, and Pharmacokinetics of cP12 in Healthy Adults.” cP12 therapy for “prevention of burn injury progression of acute, deep dermal burns in hospitalized patients" has already been given Orphan Drug Designation.  Now, since cP12 treatment for burns has an active IND and is targeted to fill an unmet need of a critical medical condition, NMT will submit a FAST TRACK request to the FDA.  A Phase 2a clinical trial has been outlined and with guidance from the FDA an acceptable protocol will be written. 

Education

  • S.B. Massachusetts Institute of Technology, Boston, MA, 1966
  • M.S. Department of Microbiology, University of Rochester School of Medicine and Dentistry, Rochester, NY, 1971
  • M.D. University of Rochester School of Medicine and Dentistry, Rochester, NY, 1971

Professional Experience

Internship and Residencies:

1971-1972 Medical Intern, Strong Memorial Hospital, Rochester, NY
1972-1973 Medical Resident, Strong Memorial Hospital, Rochester, NY
1976-1977 Dermatology Resident, Massachusetts General Hospital, Boston, MA

Research Fellowships:

1973-1976 Clinical Associate, Laboratory of Clinical Investigation, National Institute of Allergy and Infectious Disease, National Institutes of Health
1977-1978 Dermatology Fellow, Massachusetts General Hospital, Boston, MA

Academic Appointments:

1979-1981 Instructor in Dermatology, Harvard Medical School
1981-1986 Assistant Professor in Medicine and Dermatology, University of Colorado Health Sciences Center
1986-1990 Associate Professor in Dermatology and Medicine, University of Colorado Health Sciences Center
1990- Professor, Department of Dermatology, Stony Brook University
1990-2003 Chair, Department of Dermatology, Stony Brook University
2000-2003 Adjunct Professor, Department of Bioengineering, Stony Brook University
2001- Adjunct Professor of Medicine, Stony Brook University
2003- Professor of Biomedical Engineering, Stony Brook University
2003- Director, Center for Tissue Engineering

Hospital Appointments:

1979-1981 Clinical Associate in Dermatology, Massachusetts General Hospital, Boston, MA
1980-1981 Research Associate in Pathology, Beth Israel Hospital, Boston, MA
1980-1981 Assistant in Dermatology, Beth Israel Hospital, Boston, MA
1981-1988 Member, Division of Clinical Immunology, Department of Medicine, National Jewish Center, Denver, CO
1986-1988 Director, Dermatology Program, Departments of Medicine and Pediatrics, National Jewish Center, Denver, CO
1988-1990 Head, Division of Dermatology, Departments of Medicine and Pediatrics, National Jewish Center, Denver, CO
1990-2003 Chief of Service, Dermatology, University Hospital, Stony Brook University
2003- Member, Dermatology Service, University Hospital, Stony Brook University

Honors and Awards

1962-1966 Store Scholarship, Massachusetts Institute of Technology
1966-1968 Alumni Scholarship, University of Rochester School of Medicine and Dentistry
1968-1971 Clinical Investigator Training Fellowship
1970 Election to Alpha Omega Alpha
1971 Distinction in Research, University of Rochester School of Medicine  & Dentistry
1975 American Academy of Allergy Travel Grant
1979 Society for Investigative Dermatology Award
1979 Boston Medical Foundation Award
1989 Election to the American Society for Clinical Investigation
1993 Election to the American Dermatology Association
1995 Teaching Award, Department of Dermatology, Stony Brook University
1996 NIH Merit Award
1997 Election to the New York Dermatology Society
1999 Election to the American Association of Physicians
1999 Elected Fellow, American Association for the Advancement of Science
2001 Program Excellence Award , Department of Dermatology, Stony Brook University
2002 Scholar, Harvard-Macy Institute, Leadership in Education
2006 President's Award, Distinguished PhD Student, Kaustabh Ghosh (Thesis Advisor)
2009 President's Award, Distinguished PhD Student, Zhi Pan (co-Thesis Advisor)
2011 Senior Author - Best Poster, American Burn Association Annual Meeting, 1 st author, Doug Hirth, 2 nd year Med Student
2012 Teaching Award, Department of Biomedical Engineering, Stony Brook University
2013 Senior Author Finalist, Excellence in Translational Research, Wound Healing Society Annual Meeting, 1 st author, Jia Zhu, 5 th year Graduate Student
2015 Elected Honorary Member of the Society for Investigative Dermatology
2015 Service Award, Department of Dermatology
2016 Elected to Stony Brook University Chapter of National Academy of Inventors
2017 First Place Award: Industrial Research & Development, Wound Healing Annual Meeting, San Diego, CA, April 5-8, 2017

Professional Activities and Affiliations

Licensure and Certifications:

1972 National Board of Medical Examiners
1974 American Board of Internal Medicine
1977 American Board of Allergy and Clinical Immunology
1980 American Board of Dermatology
1981 State of Colorado
1990 State of New York

Professional Society Memberships:

1977 Dermatology Foundation (DF)
1979 American Association for the Advancement of Science (AAAS)
1979 American Federation for Clinical Research (AFCR)
1980 Society for Investigative Dermatology (SID)
1981 American Academy of Dermatology (AAD)
1983 American Academy of Allergy and Immunology (AAAI)
1983 American Society of Cell Biology (ASCB)
1989 American Society for Clinical Investigation (ASCI)
1990 Wound Healing Society (WHS)
1990 Long Island Dermatology Society
1990 Association of Professors of Dermatology (APD)
1991 Suffolk County Dermatology Society
1993 American Dermatology Association (ADA)
1994 New York Academy of Medicine, Dermatology Section
1997 New York Dermatology Society
1999 American Association of Physicians (AAP)
2000 American Association of Medical Colleges (AAMC)
2004 Tissue Engineering Society International (TESI)

Professional Society, NIH, Editorial Board Offices and Committee Assignments:

1989- Scientific Board, Eczema Association for Science and Education
1990-1997 Associate Editor, J Cell Biochem
1990-1994 Board of Directors, WHS
1990-1996 Chair of Ethics Committee, WHS
1990-1994 Chair, AAD and AAAI Liaison Task Force
1991-1994 Scientific Board of Advisors, Curative Technologies, Inc.
1992-1994 Program Committee, AAAI
1992-1996 Member, NIA Liaison Committee, AAD
1993-1996 Chair of Government Relations Committee, WHS
1993-2000 Vice-Chair, Leader's Society, Dermatology Foundation
1993-1996 Medical and Scientific Committee, Dermatology Foundation
1993-1994 Chair, Dermatology Disease Section, AAAI
1994-1995 Secretary, New York Academy of Medicine, Dermatology Section
1994- Scientific Board, Dystrophic Epidermolysis Bullosa Research Association
1995-1996 President, New York Academy of Medicine, Dermatology Section
1995-1996 President-elect, WHS
1995-1999 Executive Committee, WHS
1995-1999 NIAMS Special Grants Review Committee
1996-1997 President, WHS
1996-1999 Scientific Board of Advisors, Vitex, Inc.
1997-1999 Vice-President, WHS
1997-1999 Chair, Nominations Committee, WHS
1997-2000 Chair, Government Relations Committee, WHS
1997- Institutional Representative , ASCI
1997-2002 Member, Government and Public Relations Committee, SID
1998-2000 Chair, Government and Public Relations Committee, SID
1998-1999 Member, Publications Committee, SID
1999-2003 Board of Directors, APD
2000- Representative , Academic Societies (CAS), AAMC
2001-2005 Chair, NIA Liaison Task Force, AAD
2001-2005 Member, Research Committee, AAD
2001-2006 Patient Advocate Liaison, SID
2002-2006 Chair, Patient Advocate Task Force, AAD
2002-2006 Member, Government Affairs Committee, AAD
2002-2006 Member, Research Committee, AAD
2002-2004 Treasurer , Long Island Dermatology Society
2002-2008 President-elect, Long Island Dermatology Society
2002-2007 Associate Editor, Journal of Investigative Dermatology
2002 Selection Committee for the AOA Glaser Teaching Award, AAMC
2002-2007 Member, Scientific Advisory Committee, Ad Hoc Group for Medical Research Funding, AAMC
2003-2007 Member, Board of Directors, Society for Investigative Dermatology
2003 Cutaneous Biology Core Center, Ad Hoc Study Section
2004-2009 Member, Long Range Planning Committee, Society for Investigative Dermatology
2004-2006 Secretary, Long Island Dermatology Society
2004 Member, NIAMS Skin Branch Long Range Planning Committee
2004 External Advisory Board Member, Cleveland Clinic, Depart. Biomedical Engineering
2005-2009 Member, Research Committee, AAD
2006 Scientific Advisory Board Member, Clinical Tissue Engineering Center, Cleveland, OH
2006-2008 Vice-President, Long Island Dermatology Society
2006-2008 Scientific Advisory Board Member, Omrix, Biopharmaceuticals, Ltd
2007 NIAMS Special Emphasis Panel (MOSS) Study Section
2007-2017 Wound Healing and Regeneration Section Editor, Journal of Investigative Dermatology
2008-2010 President, Long Island Dermatology Society
2008 NIAMS Special Emphasis Panel (MOSS) Study Section
2008 DOD Review Panel, Deployment Related Medical Research Program (DRMRP)
2008-2009 President-elect, Society for Investigative Dermatology
2008-2013 Director: Skin, Burn and Nonscar Healing Program, Rutgers-Cleveland Clinic Consortium (RCCC), Armed Forces Institute of Regenerative Medicine (AFIRM)
2009-2010 President, Society for Investigative Dermatology
2009-2010 President, New York Dermatology Society
2009-2017 Scientific Board of Advisors, RESBIO, Rutgers University
2009 NIAMS Special Emphasis Panel (MOSS) for Challenge Grant Reviews
2010 NIAMS Ancillary Studies Panel for P50 proposals
2010-2011 Immediate Past-President, Society for Investigative Dermatology
2010-2011 Member, Board of Directors, Society for Investigative Dermatology
2010-2011 Chair, Search Committee for Secretary-Treasurer, Society for Investigative Dermatology
2010-2013 Member, Nominations Committee, Society for Investigative Dermatology
2011 External Advisor, Skin Disease Research Center, University of Alabama, Birmingham
2012 NIAMS Ancillary Studies Panel for P50 proposals
2013 Chair, Nominations Committee, Society for Investigative Dermatology
2013-2018 co-Focus Leader, Skin Regeneration, Armed Forces Institute of Regenerative Medicine II
2014 Chair, Biomedical Engineering Faculty Search Committee
2014- Chair, Executive Committee, Biomedical Engineering
2015-2017 President, School of Medicine Faculty Senate

Publications

Publications via Google Scholar

Patents

  • US Patent 5,958,874 Recombinant fibronectin-based extracellular matrix for wound healing, September 28, 1999.
  • US Patent 6,194,378 Fibronectin peptides-based extracellular matrix for wound healing, February 27, 2001.
  • US Patent 6,268,215 Recombinant keratinocytes, July 31, 2001.
  • US Patent 6,723,302 Model for cell migration and use thereof, April 20, 2004.
  • US Patent 6,946,140 Methods and compositions for enhancing fibroblast migration, Sept 20, 2005.
  • US Patent 8,691,944 Fibronectin polypeptides and uses thereof. April 8, 2014.
  • US Patent 8,759,300 Fibronectin polypeptides and uses thereof. June 24, 2014

Courses Taught

  • BME 404 - Essentials of Tissue Engineering
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